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Sample records for necrosis factor-alpha receptor

  1. Tumour necrosis factor-alpha (TNF), lymphotoxin and TNF receptor levels in serum from patients with Wegener's granulomatosis

    DEFF Research Database (Denmark)

    Jónasdóttir, O; Petersen, J; Bendtzen, K

    2001-01-01

    Wegener's granulomatosis (WG) is a systemic inflammatory disease with vasculitis as the key feature. Abnormal expression of tumour necrosis factor alpha (TNFalpha) is considered of prime pathogenic importance in several inflammatory diseases. The effects of TNFa are mediated by TNF receptors (TNF...

  2. Circulating tumour necrosis factor alpha & soluble TNF receptors in patients with Guillain-Barre syndrome.

    Science.gov (United States)

    Radhakrishnan, V V; Sumi, M G; Reuben, S; Mathai, A; Nair, M D

    2003-05-01

    Tumour necrosis factor-alpha (TNF-alpha) is regarded as one of the immune factors that can induce demyelination of peripheral nerves in patients with Guillian-Barre syndrome (GBS). This present study was undertaken to find out the role of TNF-alpha and soluble TNF receptors in the pathogenesis of GBS; and to study the effect of intravenous immunoglobulin (ivIg) therapy on the serum TNF-alpha and soluble TNF receptors in patients with GBS. Thirty six patients with GBS in progressive stages of motor weakness were included in this study. The serum TNF-alpha and soluble TNF receptors (TNF-RI, TNF-RII) were measured in the serum samples of these patients before and after ivIg therapy by a sandwich ELISA. Of the 36 patients with GBS, 26 (72.2%) showed elevated serum TNF-alpha levels prior to ivIg therapy. Following a complete course of ivIg therapy there was a progressive decrease in the serum TNF-alpha concentrations in these 26 patients. On the other hand, the soluble TNF receptors, particularly TNF-RII showed an increase in the serum of GBS patients following ivIg therapy. The results indicate that ivIg reduces the serum TNF-alpha concentrations in the GBS patients having elevated levels prior to ivIg therapy. Elevated serum levels of soluble TNF receptors following ivIg therapy may play a protective role by inhibiting the demyelinating effect of TNF-alpha in the peripheral nerves of patients with GBS.

  3. Histamine suppresses gene expression and synthesis of tumor necrosis factor alpha via histamine H2 receptors

    OpenAIRE

    1991-01-01

    Histamine and tumor necrosis factor alpha (TNF-alpha) can each contribute to the pathogenesis of allergic reactions and chronic inflammatory diseases. We now report the effect of histamine on gene expression and total cellular synthesis of TNF-alpha. Lipopolysaccharide (LPS)-induced synthesis of TNF-alpha in peripheral blood mononuclear cells (PBMC) from 18 healthy donors was suppressed by histamine concentrations from 10(-6) to 10(-4) M, levels comparable with those measured in tissues after...

  4. Tumour necrosis factor-alpha (TNF), lymphotoxin and TNF receptor levels in serum from patients with Wegener's granulomatosis

    DEFF Research Database (Denmark)

    Jónasdóttir, O; Petersen, J; Bendtzen, K

    2001-01-01

    Wegener's granulomatosis (WG) is a systemic inflammatory disease with vasculitis as the key feature. Abnormal expression of tumour necrosis factor alpha (TNFalpha) is considered of prime pathogenic importance in several inflammatory diseases. The effects of TNFa are mediated by TNF receptors (TNF......-R), and these receptors are often found in soluble forms (sTNF-R), which can modulate TNFalpha actions. To evaluate the clinical importance of the TNF family of cytokines, the serum levels of TNFalpha, TNFbeta, now termed lymphotoxin (LTalpha), and sTNF-R1 and sTNF-R2 were measured by ELISA in 8 patients with WG during...... of the relative amounts of TNFalpha and sTNF-R indicated that TNFalpha was mostly bound to its soluble receptors. In WG, the serum levels of sTNF-R1 and sTNF-R2 were dramatically increased (p...

  5. Tumour necrosis factor-alpha (TNF), lymphotoxin and TNF receptor levels in serum from patients with Wegener's granulomatosis

    DEFF Research Database (Denmark)

    Jónasdóttir, O; Petersen, J; Bendtzen, K

    2001-01-01

    Wegener's granulomatosis (WG) is a systemic inflammatory disease with vasculitis as the key feature. Abnormal expression of tumour necrosis factor alpha (TNFalpha) is considered of prime pathogenic importance in several inflammatory diseases. The effects of TNFa are mediated by TNF receptors (TNF......-R), and these receptors are often found in soluble forms (sTNF-R), which can modulate TNFalpha actions. To evaluate the clinical importance of the TNF family of cytokines, the serum levels of TNFalpha, TNFbeta, now termed lymphotoxin (LTalpha), and sTNF-R1 and sTNF-R2 were measured by ELISA in 8 patients with WG during...... active disease and during immunosuppressive treatment, and in 11 healthy controls in parallel. Serum concentrations of TNFalpha were undetectable in all except two controls (18%) and three patients with WG (37%). After 7 days of therapy, six of the WG patients had measurable TNFalpha levels. Examination...

  6. Tumor necrosis factor-alpha and its receptors in epithelial ovarian cancer.

    Directory of Open Access Journals (Sweden)

    Jacek Nikliński

    2010-05-01

    Full Text Available The aim of the present study was to characterize the expression pattern of tumor necrosis factor (TNF-alpha and its receptors (TNF-Rs in the epithelial ovarian cancer (EOC and compare these results with the outcome of 126 patients. Presence of TNF-alpha, TNFR-1 and TNFR-2 were studied by Western blotting and immunohistochemistry. The proportion of samples positive for TNF-alpha and TNF-R2 was higher in epithelial ovarian cancer patients than in benign ovarian diseases (p<0.001 and p=0.016, respectively. Immunostaining intensity of TNF-R2 were correlated with tumor stage (p<0.001 and with reduced mean survival time (MST (p=0.002. The results of the present study suggested that tissue expression of TNF-R2 in epithelial ovarian cancer was correlated with the highest risk of cancer progression. Thus, the clinical value of activated TNF system in epithelial ovarian cancer needs to be further investigated.

  7. Nutrition, anthropometry, gastrointestinal dysfunction, and circulating levels of tumour necrosis factor alpha receptor I and interleukin-1 receptor antagonist in children during stem cell transplantation

    DEFF Research Database (Denmark)

    Andreassen, B. U.; Pærregaard, Anders; Michaelsen, Kim F.

    2008-01-01

    To evaluate anthropometry, nutrition and gastrointestinal dysfunction, and to characterize the relation between these parameters and the inflammatory activity evaluated by plasma levels of soluble tumour necrosis factor alpha receptor I (sTNFRI) and interleukin-1 receptor antagonist (IL-1Ra) levels...... during stem cell transplantation (SCT) in children. Clinical assessments and blood sampling were performed on days -3, 0, +7, +15 and +31 in eight children undergoing SCT. Energy intake, anthropometry, gastrointestinal dysfunction (WHO toxicity score) and sTNFRI and IL-1Ra were evaluated. The energy...

  8. The expression of tumor necrosis factor-alpha, its receptors and steroidogenic acute regulatory protein during corpus luteum regression

    Directory of Open Access Journals (Sweden)

    Arfuso Frank

    2008-11-01

    Full Text Available Abstract Background Corpus luteum (CL regression is known to occur as two parts; functional regression when steroidogenesis declines and structural regression when apoptosis is induced. Previous studies suggest this process occurs by the production of luteolytic factors, such as tumour necrosis factor-alpha (TNF-alpha. Methods We examined TNF-alpha, TNF-alpha receptors (TNFR1 and 2 and steroidogenic acute regulatory (StAR protein expression during CL regression in albino Wistar rats. CL from Days 16 and 22 of pregnancy and Day 3 post-partum were examined, in addition CL from Day 16 of pregnancy were cultured in vitro to induce apoptosis. mRNA was quantitated by kinetic RT-PCR and protein expression examined by immunohistochemistry and Western blot analyses. Results TNF-alpha mRNA increased on Day 3 post-partum. TNFR were immunolocalized to luteal cells, and an increase in TNFR2 mRNA observed on Day 3 post-partum whilst no change was detected in TNFR1 mRNA relative to Day 16. StAR protein decreased on Day 3 post-partum and following trophic withdrawal but no change was observed following exogenous TNF-alpha treatment. StAR mRNA decreased on Day 3 post-partum; however, it increased following trophic withdrawal and TNF-alpha treatment in vitro. Conclusion These results demonstrate the existence of TNFR1 and TNFR2 in rat CL and suggest the involvement of TNF-alpha in rat CL regression following parturition. Furthermore, decreased StAR expression over the same time points was consistent with the functional regression of the CL.

  9. Ethanol increases tumor necrosis factor-alpha receptor-1 (TNF-R1) levels in hepatic, intestinal, and cardiac cells.

    Science.gov (United States)

    Rodriguez, Diego A; Moncada, Claudio; Núñez, Marco T; Lavandero, Sergio; Ponnappa, Biddanda C; Israel, Yedy

    2004-05-01

    Chronic ethanol consumption leads to cell injury in virtually every tissue. Tumor necrosis factor-alpha (TNF-alpha) constitutes a major factor in the development of alcohol-induced liver injury. In alcohol-dependent subjects, elevated levels of plasma TNF-alpha are strongly predictive of mortality. Binding of TNF-alpha to TNF-alpha receptor-1 (TNF-R1) activates death domain pathways, leading to necrosis and apoptosis in most tissues, and it also increases the expression of intercellular adhesion molecules (i.e., ICAM-1), which promote inflammation. We determined whether ethanol exposure leads to increases in cellular TNF-R1. We incubated HepG2 human hepatoma cells and H4-II-E-C3 rat hepatoma cells with 25, 50, and 100 mM ethanol for various intervals of time up to 48 h. Human colonic adenocarcinoma cells (Caco-2 cells) and neonatal rat primary cardiomyocytes were also incubated with different concentrations of ethanol. Levels of TNF-R1 were measured either by a sandwich enzyme-linked immunosorbent assay (ELISA) method or by determining the extracellular transmembrane domain of TNF-R1 by an intact-cell ELISA method. Ethanol exposure for 48 h increased TNF-R1 levels in human hepatoma cells in a dose-dependent manner. Levels increased significantly by 164% at 50 mM and by 240% at 100 mM ethanol. Effects were time dependent and did not reach a plateau at 48 h. Similar increases in TNF-R1 were also observed in rat hepatoma cells (90% at 50 mM and 230% at 100 mM ethanol). Under similar conditions, Caco-2 cells showed a significant 80% increase in TNF-R1 levels at 200 mM ethanol, a concentration found in intestine. Neonatal rat primary cardiomyocytes showed TNF-R1 increases of 36% at 50 mM and 44% at 100 mM ethanol. These results indicate that exposure of different cell types to pharmacologic concentrations of ethanol increases TNF-R1 levels and may augment TNF-alpha-mediated cell injury in different tissues.

  10. Forward and Reverse Signaling Mediated by Transmembrane Tumor Necrosis Factor-Alpha and TNF Receptor 2: Potential Roles in an Immunosuppressive Tumor Microenvironment

    OpenAIRE

    Qu, Yang; Zhao, Gang; Li, Hui

    2017-01-01

    Tumor necrosis factor-alpha (TNF-α) is a pleiotropic inflammatory cytokine produced mainly by activated macrophages, lymphocytes and other cell types. Two distinct forms of TNF-α have been identified: soluble TNF-α (sTNF-α) and transmembrane TNF-α (mTNF-α). mTNF-α, which is the precursor of sTNF-α, can be cleaved by the TNF-α converting enzyme (TACE) and is released as sTNF-α. sTNF-α binds primarily to TNF receptor 1 (TNFR1) and plays an important role in the inflammatory immune response, whe...

  11. alpha-MSH and its receptors in regulation of tumor necrosis factor-alpha production by human monocyte/macrophages.

    Science.gov (United States)

    Taherzadeh, S; Sharma, S; Chhajlani, V; Gantz, I; Rajora, N; Demitri, M T; Kelly, L; Zhao, H; Ichiyama, T; Catania, A; Lipton, J M

    1999-05-01

    The hypothesis that macrophages contain an autocrine circuit based on melanocortin [ACTH and alpha-melanocyte-stimulating hormone (alpha-MSH)] peptides has major implications for neuroimmunomodulation research and inflammation therapy. To test this hypothesis, cells of the THP-1 human monocyte/macrophage line were stimulated with lipopolysaccharide (LPS) in the presence and absence of alpha-MSH. The inflammatory cytokine tumor necrosis factor (TNF)-alpha was inhibited in relation to alpha-MSH concentration. Similar inhibitory effects on TNF-alpha were observed with ACTH peptides that contain the alpha-MSH amino acid sequence and act on melanocortin receptors. Nuclease protection assays indicated that expression of the human melanocortin-1 receptor subtype (hMC-1R) occurs in THP-1 cells; Southern blots of RT-PCR product revealed that additional subtypes, hMC-3R and hMC-5R, also occur. Incubation of resting macrophages with antibody to hMC-1R increased TNF-alpha concentration; the antibody also markedly reduced the inhibitory influence of alpha-MSH on TNF-alpha in macrophages treated with LPS. These results in cells known to produce alpha-MSH at rest and to increase secretion of the peptide when challenged are consistent with an endogenous regulatory circuit based on melanocortin peptides and their receptors. Targeting of this neuroimmunomodulatory circuit in inflammatory diseases in which myelomonocytic cells are prominent should be beneficial.

  12. The effect of a metalloproteinase inhibitor (GI5402) on tumor necrosis factor-alpha (TNF-alpha) and TNF-alpha receptors during human endotoxemia

    NARCIS (Netherlands)

    Dekkers, P. E.; Lauw, F. N.; ten Hove, T.; te Velde, A. A.; Lumley, P.; Becherer, D.; van Deventer, S. J.; van der Poll, T.

    1999-01-01

    Tumor necrosis factor-alpha (TNF-alpha) is released from the cell surface by cleavage of pro-TNF-alpha by metalloproteinases (MPs). In cell cultures, inhibition of MPs has been found not only to reduce the release of TNF-alpha, but also to enhance the surface expression of TNF-alpha and TNF-alpha

  13. Effect of deficiency of tumor necrosis factor alpha or both of its receptors on Streptococcus pneumoniae central nervous system infection and peritonitis.

    Science.gov (United States)

    Wellmer, A; Gerber, J; Ragheb, J; Zysk, G; Kunst, T; Smirnov, A; Brück, W; Nau, R

    2001-11-01

    Tumor necrosis factor alpha (TNF-alpha) and TNF-beta are key mediators in bacterial inflammation. We therefore examined the role of TNF-alpha and its two receptors in murine pneumococcal central nervous system infection. TNF-alpha knockout mice and age- and sex-matched controls and TNF receptor (p55 and p75)-deficient mice and heterozygous littermates were infected intracerebrally with a Streptococcus pneumoniae type 3 strain. Mice were monitored until death or were killed 36 h after infection. Bacterial titers in blood, spleen, and brain homogenates were determined. Leukocyte infiltration and neuronal damage were assessed by histological scores. TNF-alpha-deficient mice died earlier than the controls after intracerebral infection although overall survival was similar. TNF-alpha deficiency did not inhibit leukocyte recruitment into the subarachnoid space and did not lead to an increased density of bacteria in brain homogenates. However, it caused a substantial rise of the concentration of S. pneumoniae cells in blood and spleen. Spleen bacterial titers were also increased in p55- and p75-deficient mice. TNF receptor-deficient mice showed decreased meningeal inflammation. Neuronal damage was not affected by either TNF-alpha or TNF receptor deficiency. In a murine model of pneumococcal peritonitis, 10(2) CFU of S. pneumoniae produced fatal peritonitis in TNF-alpha-deficient, but not wild-type, mice. Early leukocyte influx into the peritoneum was impaired in TNF-alpha-deficient mice. The lack of TNF-alpha or its receptors renders mice more susceptible to S. pneumoniae infections.

  14. The effects of dexamethasone and chlorpromazine on tumour necrosis factor-alpha, interleukin-1 beta, interleukin-1 receptor antagonist and interleukin-10 in human volunteers.

    Science.gov (United States)

    Bleeker, M W; Netea, M G; Kullberg, B J; Van der Ven-Jongekrijg, J; Van der Meer, J W

    1997-01-01

    Tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) are pro-inflammatory cytokines that play an important role in severe infections, whereas IL-1 receptor antagonist (IL-1ra) and IL-10 are anti-inflammatory cytokines that counteract their effects. Chlorpromazine and dexamethasone protect mice against lethal endotoxaemia by decreasing circulating concentrations of TNF-alpha and IL-1 beta. We investigated whether administration of chlorpromazine or dexamethasone to human volunteers is able to modulate the lipopolysaccharide (LPS)-stimulated cytokine production capacity in whole blood. Blood samples were taken before and several time-points after medication. Circulating cytokine concentrations were low in all samples. LPS-induced TNF-alpha and IL-1 beta production in whole blood was inhibited by dexamethasone treatment, while chlorpromazine had no effect. When peripheral blood mononuclear cells were stimulated in vitro with LPS, the addition of chlorpromazine (1-100 ng/ml) had no modulatory action on TNF-alpha, IL-1 beta, IL-1ra or IL-10 synthesis. The chlorpromazine concentrations measured in circulation of volunteers were eight to 40 times lower than the concentrations shown to be effective in mice. In conclusion, chlorpromazine inhibits TNF-alpha and IL-1 beta production in mice at concentrations that cannot be reached in humans, thus precluding its usage in clinical anti-cytokine strategies. In contrast, dexamethasone is an effective inhibitor of pro-inflammatory cytokine production. PMID:9378493

  15. Decreased Progesterone Receptor B/A Ratio in Endometrial Cells by Tumor Necrosis Factor-Alpha and Peritoneal Fluid from Patients with Endometriosis.

    Science.gov (United States)

    Chae, Uisoo; Min, Jin Young; Kim, Sung Hoon; Ihm, Hyo Jin; Oh, Young Sang; Park, So Yun; Chae, Hee Dong; Kim, Chung Hoon; Kang, Byung Moon

    2016-11-01

    Progesterone resistance is thought to be a major factor that contributes to progression of endometriosis. However, it is not clear what causes progesterone resistance in endometriosis. This study aimed to assess whether cytokines or peritoneal fluid can affect progesterone receptor (PR) expression in endometrial cells and to verify whether PR expression is reduced in endometriosis. The PR-B/A ratio was measured via real-time polymerase chain reaction after in vitro culture, in which endometrial cells were treated with either tumor necrosis factor-alpha (TNF-α), interleukin-1 beta, or peritoneal fluid obtained from women with advanced-stage endometriosis. Immunohistochemistry was performed to compare PR-B expression between eutopic and ectopic endometrial tissues from women with and without advanced-stage endometriosis. The PR-B/A ratio was significantly decreased by treatment with either TNF-α (p=0.011) or peritoneal fluid from women with advanced-stage endometriosis (p=0.027). Immunoreactivity of PR-B expression was significantly lower during the secretory phase than during the proliferative phase in endometrial tissues from control subjects (pendometriosis compared with eutopic endometrium tissues from control subjects. Progesterone resistance in endometriosis may be caused by proinflammatory conditions in the pelvic peritoneal microenvironment.

  16. Tumour necrosis factor alpha (TNF-α) genetic polymorphisms and ...

    Indian Academy of Sciences (India)

    2Department of Occupational Health and Environmental Health, School of Public Health at Guangxi Medical University,. Nanning, Guangxi 530021, People's Republic of China. Abstract. Epidemiological studies have evaluated the association between tumour necrosis factor alpha (TNF-α)-308G/A and (TNF-α)-. 238G/A ...

  17. Tumour necrosis factor-alpha gene polymorphisms in Iranian ...

    African Journals Online (AJOL)

    ... progressive inflammatory destructive process of the bile ducts. This study evaluated the relationship between single-nucleotide polymorphisms in the promoter region of tumour necrosis factor-alpha (TNF-α) gene and bilaiary atresia. Materials and Methods: Genomic deoxyribonucleic acid from 16 patients with established ...

  18. Tumour necrosis factor alpha and interleukin 10 gene ...

    Indian Academy of Sciences (India)

    Tumour necrosis factor alpha and interleukin 10 gene polymorphisms and the risk of ischemic stroke in south Indian population. Shehnaz Sultana Venkata K. Kolla Yasovanthi Jeedigunta Pranay K. Penagaluru Sindhu Joshi P. Usha Rani P. P. Reddy. Research Note Volume 90 Issue 2 August 2011 pp 361-364 ...

  19. Regulation of human lung fibroblast C1q-receptors by transforming growth factor-beta and tumor necrosis factor-alpha.

    Science.gov (United States)

    Lurton, J; Soto, H; Narayanan, A S; Raghu, G

    1999-03-01

    Transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha) are two polypeptide mediators which are believed to play a role in the evolution of idiopathic pulmonary fibrosis (IPF). We have evaluated the effect of these two substances on the expression of receptors for collagen (cC1q-R) and globular (gC1q-R) domains of C1q and on type I collagen in human lung fibroblasts. Two fibroblast subpopulations differing in C1q receptor expression were obtained by culturing human lung explants in medium containing fresh human serum and heated plasma-derived serum and separating them based on C1q binding [Narayanan, Lurton and Raghu: Am J Resp Cell Mol Biol. 1998; 17:84]. The cells, referred to as HH and NL cells, respectively, were exposed to TGF-beta and TNF-alpha in serum-free conditions. The levels of mRNA were assessed by in situ hybridization and Northern analysis, and protein levels compared after SDS-polyacrylamide gel electrophoresis and Western blotting. NL cells exposed to TGF-beta and TNF-alpha contained 1.4 and 1.6 times as much cC1q-R mRNA, respectively, whereas in HH cells cC1q-R mRNA increased 2.0- and 2.4-fold. The gC1q-R mRNA levels increased to a lesser extent in both cells. These increases were not reflected in protein levels of CC1q-R and gC1q-R, which were similar to or less than controls. Both TGF-beta and TNF-alpha also increased procollagen [I] mRNA levels in both cells. Overall, TNF-alpha caused a greater increase and the degree of response by HH fibroblasts to both TGF-beta and TNF-alpha was higher than NL cells. These results indicated that TGF-beta and TNF-alpha upregulate the mRNA levels for cC1q-R and collagen and that they do not affect gC1q-R mRNA levels significantly. They also indicated different subsets of human lung fibroblasts respond differently to inflammatory mediators.

  20. The Neutrophil Response Induced by an Agonist for Free Fatty Acid Receptor 2 (GPR43) Is Primed by Tumor Necrosis Factor Alpha and by Receptor Uncoupling from the Cytoskeleton but Attenuated by Tissue Recruitment

    DEFF Research Database (Denmark)

    Björkman, Lena; Mårtensson, Jonas; Winther, Malene

    2016-01-01

    by tumor necrosis factor alpha (TNF-α) in a process associated with a recruitment of easily mobilizable granules, but neutrophils recruited to an aseptic inflammation in vivo were nonresponding. Superoxide production induced by Cmp1 was increased in latrunculin A-treated neutrophils, but no reactivation......Ligands with improved potency and selectivity for free fatty acid receptor 2 (FFA2R) have become available, and we here characterize the neutrophil responses induced by one such agonist (Cmp1) and one antagonist (CATPB). Cmp1 triggered an increase in the cytosolic concentration of Ca(2......+), and the neutrophils were then desensitized to Cmp1 and to acetate, a naturally occurring FFA2R agonist. The antagonist CATPB selectively inhibited responses induced by Cmp1 or acetate. The activated FFA2R induced superoxide anion secretion at a low level in naive blood neutrophils. This response was largely increased...

  1. Tumor necrosis factor alpha converting enzyme: an encouraging target for various inflammatory disorders.

    Science.gov (United States)

    Bahia, Malkeet S; Silakari, Om

    2010-05-01

    Tumor necrosis factor alpha is one of the most common pro-inflammatory cytokines responsible for various inflammatory disorders. It plays an important role in the origin and progression of rheumatoid arthritis and also in other autoimmune disease conditions. Some anti-tumor necrosis factor alpha antibodies like Enbrel, Humira and Remicade have been successfully used in these disease conditions as antagonists of tumor necrosis factor alpha. Inhibition of generation of active form of tumor necrosis factor alpha is a promising therapy for various inflammatory disorders. Therefore, the inhibition of an enzyme (tumor necrosis factor alpha converting enzyme), which is responsible for processing inactive form of tumor necrosis factor alpha into its active soluble form, is an encouraging target. Many tumor necrosis factor alpha converting enzyme inhibitors have been the candidates of clinical trials but none of them have reached in to the market because of their broad spectrum inhibitory activity for other matrix metalloproteases. Selectivity of tumor necrosis factor alpha converting enzyme inhibition over matrix metalloproteases is of utmost importance. If selectivity is achieved successfully, side-effects can be over-ruled and this approach may become a novel therapy for treatment of rheumatoid arthritis and other inflammatory disorders. This cytokine not only plays a pivotal role in inflammatory conditions but also in some cancerous conditions. Thus, successful targeting of tumor necrosis factor alpha converting enzyme may result in multifunctional therapy.

  2. Targeted Cancer Therapy with Tumor Necrosis Factor-Alpha

    Directory of Open Access Journals (Sweden)

    Weibo Cai Ph.D.

    2008-01-01

    Full Text Available Tumor necrosis factor-alpha (TNF-α, a member of the TNF superfamily, was the first cytokine to be evaluated for cancer biotherapy. However, the clinical use of TNF-α is severely limited by its toxicity. Currently, TNF-α is administered only through locoregional drug delivery systems such as isolated limb perfusion and isolated hepatic perfusion. To reduce the systemic toxicity of TNF-α, various strategies have been explored over the last several decades. This review summarizes current state-of-the-art targeted cancer therapy using TNF-α. Passive targeting, cell-based therapy, gene therapy with inducible or tissue-specific promoters, targeted polymer-DNA complexes, tumor pre-targeting, antibody-TNF-α conjugate, scFv/TNF-α fusion proteins, and peptide/TNF-α fusion proteins have all been investigated to combat cancer. Many of these agents are already in advanced clinical trials. Molecular imaging, which can significantly speed up the drug development process, and nanomedicine, which can integrate both imaging and therapeutic components, has the potential to revolutionize future cancer patient management. Cooperative efforts from scientists within multiple disciplines, as well as close partnerships among many organizations/entities, are needed to quickly translate novel TNF-α-based therapeutics into clinical investigation.

  3. Tumor necrosis factor-alpha modulates effects of aryl hydrocarbon receptor ligands on cell proliferation and expression of cytochrome P450 enzymes in rat liver "stem-like" cells

    Czech Academy of Sciences Publication Activity Database

    Umannová, Lenka; Zatloukalová, Jiřina; Machala, M.; Krčmář, P.; Májková, Z.; Hennig, B.; Kozubík, Alois; Vondráček, Jan

    2007-01-01

    Roč. 99, č. 1 (2007), s. 79-89 ISSN 0388-1350 R&D Projects: GA ČR(CZ) GA524/05/0595 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : tumor necrosis factor-alpha * xenobiotic metabolizing enzymes * dioxin Subject RIV: BO - Biophysics

  4. Analysis of cognition, motor performance and anxiety in young and aged tumor necrosis factor alpha receptor 1 and 2 deficient mice

    NARCIS (Netherlands)

    Naude, Petrus J W; Dobos, Nikoletta; van der Meer, Dennis; Mulder, Cornelis; Pawironadi, Kim G D; den Boer, Johan A; van der Zee, Eddy A; Luiten, Paulus; Eisel, Ulrich L M

    2014-01-01

    TNF-α plays important functional roles in the central nervous system during normal physiological circumstances via intricate signaling mechanisms between its receptors, TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Although the roles of TNFR1 and TNFR2 in the diseased brain have received

  5. Circulating levels of tumor necrosis factor-alpha receptor 2 are increased in heart failure with preserved ejection fraction relative to heart failure with reduced ejection fraction: evidence for a divergence in pathophysiology.

    Directory of Open Access Journals (Sweden)

    Brendan N Putko

    Full Text Available Various pathways have been implicated in the pathogenesis of heart failure (HF with preserved ejection fraction (HFPEF. Inflammation in response to comorbid conditions, such as hypertension and diabetes, may play a proportionally larger role in HFPEF as compared to HF with reduced ejection fraction (HFREF.This study investigated inflammation mediated by the tumor necrosis factor-alpha (TNFα axis in community-based cohorts of HFPEF patients (n = 100, HFREF patients (n = 100 and healthy controls (n = 50. Enzyme-linked immunosorbent assays were used to investigate levels of TNFα, its two receptors (TNFR1 and TNFR2, and a non-TNFα cytokine, interleukin-6 (IL-6, in plasma derived from peripheral blood samples. Plasma levels of TNFα and TNFR1 were significantly elevated in HFPEF relative to controls, while levels of TNFR2 were significantly higher in HFPEF than both controls and HFREF. TNFα, TNFR1 and TNFR2 were each significantly associated with at least two of the following: age, estimated glomerular filtration rate, hypertension, diabetes, smoking, peripheral vascular disease or history of atrial fibrillation. TNFR2 levels were also significantly associated with increasing grade of diastolic dysfunction and severity of symptoms in HFPEF.Inflammation mediated through TNFα and its receptors, TNFR1 and TNFR2, may represent an important component of a comorbidity-induced inflammatory response that partially drives the pathophysiology of HFPEF.

  6. Skin cancer associated with commonly prescribed drugs: tumor necrosis factor alpha inhibitors (TNF-αIs), angiotensin-receptor blockers (ARBs), phosphodiesterase type 5 inhibitors (PDE5Is) and statins -weighing the evidence.

    Science.gov (United States)

    Nardone, Beatrice; Orrell, Kelsey A; Vakharia, Paras P; West, Dennis P

    2018-02-01

    Skin cancers, including both malignant melanoma (MM) and nonmelanoma skin cancer (NMSC), are the most commonly diagnosed cancers in the US. The incidence of both MM and NMSC continues to rise. Areas covered: Current evidence for an association between four of the most commonly prescribed classes of drugs in the U.S. and risk for MM and NMSC is reported. Medline was searched (January 2000 to May 2017) for each drug in the classes and for 'basal cell carcinoma', 'squamous cell carcinoma', 'non-melanoma skin cancer', 'skin cancer' and 'melanoma'. Skin cancer risk information was reported for: tumor necrosis factor alpha inhibitors (TNF-αIs), angiotensin-receptor blockers (ARBs), phosphodiesterase type 5 inhibitors (PDE5Is) and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)-reductase inhibitors (statins). Expert opinion: Since skin cancer risk is associated with all four classes of these commonly prescribed drugs that represent nearly 20% of the Top 100 drugs in the U.S., these important findings warrant enhanced education, especially for prescribers and those patients at high risk for skin cancer.

  7. The interaction between menstrual cycle, Tumour Necrosis Factor alpha receptors and sex hormones in healthy non-obese women – results from an observational study

    Directory of Open Access Journals (Sweden)

    Paweł Rzymski

    2014-09-01

    Full Text Available There is growing evidence that TNF-alpha and its two receptors play an important role in hormonal regulation, metabolism, inflammation and cancer. The biological effects of TNF-alpha are mediated by two receptors, p55 and p75. The aim of this study was to analyze serum concentrations of p55 and p75 and hormonal status in healthy women during the normal menstrual cycle. Eight women aged 20–22 with regular menstrual cycles were scheduled for examination on 3[sup]rd[/sup] , 8[sup]th[/sup] , 14[sup]th[/sup] and 25[sup]th [/sup] day of their menstrual cycle. We only observed a positive correlation of p75 subunit with prolactin level (correlation coefficient 0.417; p=0.0116 and negative correlation with insulin level (correlation coefficient -0.35; p=0.032 and HOMA[sub]IR[/sub] insulin resistance index correlation coefficient 0.39; p=0.0185. Furthermore, a negative correlation of p55/p75 ratio with prolactin (correlation coefficient -0.42; p=0.0101 and a positive correlations of p55/p75 ratio with insulin level (correlation coefficient 0.43; p=0.008 and HOMA[sub]IR[/sub] insulin resistance factor correlation coefficient 0.45; p=0.0065 were found.

  8. [Cellular adhesion signal transduction network of tumor necrosis factor-alpha induced hepatocellular carcinoma cells].

    Science.gov (United States)

    Zheng, Yongchang; Du, Shunda; Xu, Haifeng; Xu, Yiyao; Zhao, Haitao; Chi, Tianyi; Lu, Xin; Sang, Xinting; Mao, Yilei

    2014-11-18

    To systemically explore the cellular adhesion signal transduction network of tumor necrosis factor-alpha (TNF-α)-induced hepatocellular carcinoma cells with bioinformatics tools. Published microarray dataset of TNF-α-induced HepG2, human transcription factor database HTRI and human protein-protein interaction database HPRD were used to construct and analyze the signal transduction network. In the signal transduction network, MYC and SP1 were the key nodes of signaling transduction. Several genes from the network were closely related with cellular adhesion.Epidermal growth factor receptor (EGFR) is a possible key gene of effectively regulating cellular adhesion during the induction of TNF-α. EGFR is a possible key gene for TNF-α-induced metastasis of hepatocellular carcinoma.

  9. Correlation Between Tumor Necrosis Factor Alpha and Proteinuria ...

    African Journals Online (AJOL)

    Serum tumor necrosis factor-α (TNF-α), urine TNF-α and C-reactive protein (CRP) levels were measured in all subjects. Correlations between these inflammatory parameters and degree of proteinuria, duration of diabetes and degree of glycemic control were examined. Results: Levels of the three inflammatory parameters ...

  10. Glaucomatous neurodegeneration: An eye on tumor necrosis factor-alpha

    OpenAIRE

    Renu Agarwal; Puneet Agarwal

    2012-01-01

    Glaucoma, a neurodegenerative disease, is currently being treated by modulation of one of its primary risk factors, the elevated intraocular pressure. Newer therapies that can provide direct neuroprotection to retinal ganglion cells are being extensively investigated. Tumor necrosis factor-α, a cytokine, has been recognized to play an important role in pro and antiapoptotic cellular events. In this paper we review the relevant literature to understand (1) The association of increased expressi...

  11. Biodentine Reduces Tumor Necrosis Factor Alpha-induced TRPA1 Expression in Odontoblastlike Cells.

    Science.gov (United States)

    El Karim, Ikhlas A; McCrudden, Maelíosa T C; McGahon, Mary K; Curtis, Tim M; Jeanneau, Charlotte; Giraud, Thomas; Irwin, Chris R; Linden, Gerard J; Lundy, Fionnuala T; About, Imad

    2016-04-01

    The transient receptor potential (TRP) ion channels have emerged as important cellular sensors in both neuronal and non-neuronal cells, with TRPA1 playing a central role in nociception and neurogenic inflammation. The functionality of TRP channels has been shown to be modulated by inflammatory cytokines. The aim of this study was to investigate the effect of inflammation on odontoblast TRPA1 expression and to determine the effect of Biodentine (Septodent, Paris, France) on inflammatory-induced TRPA1 expression. Immunohistochemistry was used to study TRPA1 expression in pulp tissue from healthy and carious human teeth. Pulp cells were differentiated to odontoblastlike cells in the presence of 2 mmol/L beta-glycerophosphate, and these cells were used in quantitative polymerase chain reaction, Western blotting, calcium imaging, and patch clamp studies. Immunofluorescent staining revealed TRPA1 expression in odontoblast cell bodies and odontoblast processes, which was more intense in carious versus healthy teeth. TRPA1 gene expression was induced in cultured odontoblastlike cells by tumor necrosis factor alpha, and this expression was significantly reduced in the presence of Biodentine. The functionality of the TRPA1 channel was shown by calcium microfluorimetry and patch clamp recording, and our results showed a significant reduction in tumor necrosis factor alpha-induced TRPA1 responses after Biodentine treatment. In conclusion, this study showed TRPA1 to be modulated by caries-induced inflammation and that Biodentine reduced TRPA1 expression and functional responses. Copyright © 2016 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  12. The tumor necrosis factor-alpha-induced protein 8 family in immune homeostasis and inflammatory cancer diseases.

    Science.gov (United States)

    Luan, Y Y; Yao, Y M; Sheng, Z Y

    2013-01-01

    Within the immune system homeostasis is maintained by a myriad of mechanisms that include the regulation of immune cell activation and programmed cell death. The breakdown of immune homeostasis may lead to fatal inflammatory diseases. We set out to identify genes of tumor necrosis factor-alpha-induced protein 8 (TNFAIP8) family that has a functional role in the process of immune homeostasis. Tumor necrosis factor-alpha-induced protein 8 (TNFAIP8), which functions as an oncogenic molecule, is also associated with enhanced cell survival and inhibition of apoptosis. Tumor necrosis factor-alpha-induced protein 8-like 2 (TIPE2) governs immune homeostasis in both the innate and adaptive immune system and prevents hyper-responsiveness by negatively regulating signaling via T cell receptors and Toll-like receptors (TLRs). There also exist two highly homologous but uncharacterized proteins, TIPE1 and TIPE3. This review is an attempt to provide a summary of TNFAIP8 family associated with immune homeostasis and inflammatory cancer diseases.

  13. Tumor necrosis factor-alpha increases myocardial microvascular transport in vivo

    DEFF Research Database (Denmark)

    Hansen, P R; Svendsen, Jesper Hastrup; Høyer, S

    1994-01-01

    Tumor necrosis factor-alpha (TNF-alpha) is a primary mediator in the pathogenesis of tissue injury, and high circulating levels of TNF-alpha are found in a variety of pathological conditions. In open-chest anesthetized dogs, the effects of intracoronary recombinant human TNF-alpha (rTNF-alpha; 100...

  14. Effect of tumor necrosis factor-alpha infusion on the incretin effect in healthy volunteers

    DEFF Research Database (Denmark)

    Nielsen, Signe Tellerup; Lehrskov-Schmidt, Louise; Krogh-Madsen, Rikke

    2013-01-01

    Type 2 diabetes mellitus (T2DM) is associated with peripheral insulin resistance, impaired incretin effect, and increased plasma levels of tumor necrosis factor-alpha (TNF-α). Whereas TNF-α infusion at a dose that induces systemic inflammation in healthy volunteers has been demonstrated to induce...

  15. Passive immunization against tumor necrosis factor-alpha impairs host defense during pneumococcal pneumonia in mice

    NARCIS (Netherlands)

    van der Poll, T.; Keogh, C. V.; Buurman, W. A.; Lowry, S. F.

    1997-01-01

    Streptococcus pneumoniae is the most frequent cause of community-acquired pneumonia. We sought to determine the role of tumor necrosis factor-alpha (TNF) in the pathogenesis of pneumococcal pneumonia. Induction of pneumonia in C57B1/6 mice by intranasal inoculation with 10(6) colony-forming units

  16. New Method of Inhibition of Activity of Tumor Necrosis Factor Alpha In Patients with Psoriasis.

    Science.gov (United States)

    Gerasun, Borys A

    2016-01-01

    A new method of reduction of tumor necrosis factor alpha activity via intradermal immunization with inactivated autoleukocytes (patent UA97493 (2015) [1]) has been presented in the article. New patents from various countries have been analyzed [2-7]. Patients with psoriasis (24) with high level of tumor necrosis factor alpha in their blood (. 30pg/ml) were immunized with autoleukocytes. Leukocytes were isolated by centrifuging plasma, obtained after precipitation of a patient's heparinized peripheral venous blood. Precipitate was suspended in 1.0 - 1.5ml of a patient's blood serum and 0.1ml of blood was injected into the skin of the back. For determination of autoleukocyte immunization efficacy, concentration of tumor necrosis factor alpha in a patient's blood was compared prior to immunization and at different periods after immunization. In 30 days after single immunization, a considerable decrease in cytokine concentration was observed in all patients (100%); it reduced to zero in 16 out of 24 of immunized individuals (66.7%). The degree of reduction and duration of the achieved effect were individual, thus, if necessary the immunization was repeated several times. The procedure was well tolerated, and general condition of patients was improved. The method of reduction of tumor necrosis factor alpha activity is recommended for implementation into clinical practice.

  17. Influence of age on the outcome of antitumour necrosis factor alpha therapy in rheumatoid arthritis.

    NARCIS (Netherlands)

    Radovits, B.J.; Kievit, W.; Fransen, J.; Laar, M.A. van der; Jansen, T.L.Th.A.; Riel, P.L.C.M. van; Laan, R.F.J.M.

    2009-01-01

    OBJECTIVE: To investigate the influence of age on the effectiveness and tolerance of antitumour necrosis factor alpha (TNFalpha) therapy in rheumatoid arthritis (RA). METHODS: 730 patients of the Dutch Rheumatoid Arthritis Monitoring (DREAM) register were categorised into three groups according to

  18. Increased voluntary exercise in mice deficient for tumour necrosis factor-alpha and lymphotoxin-alpha.

    NARCIS (Netherlands)

    Netea, M.G.; Kullberg, B.J.; Vonk, A.G.; Verschueren, I.; Joosten, L.A.B.; Meer, J.W.M. van der

    2007-01-01

    BACKGROUND: The endogenous mediators playing a role in the sensing of fatigue and cessation of exercise are yet to be characterized. We hypothesized that proinflammatory cytokines, in particular tumour necrosis factor-alpha (TNFalpha) and lymphotoxin-alpha (LT) transmit signals leading to fatigue.

  19. The effect of anti-tumor necrosis factor alpha agents on postoperative anastomotic complications in Crohn's disease

    DEFF Research Database (Denmark)

    El-Hussuna, Alaa Abdul-Hussein H; Krag, Aleksander; Olaison, Gunnar

    2013-01-01

    Patients with Crohn's disease treated with anti-tumor necrosis factor alpha agents may have an increased risk of surgical complications.......Patients with Crohn's disease treated with anti-tumor necrosis factor alpha agents may have an increased risk of surgical complications....

  20. Tumor Necrosis Factor-Alpha Targeting Can Protect against Arthritis with Low Sensitization to Infection

    Directory of Open Access Journals (Sweden)

    Nadia Belmellat

    2017-11-01

    Full Text Available Tumor necrosis factor-alpha (TNF-α blockade is an effective treatment for rheumatoid arthritis (RA and other inflammatory diseases, but in patients, it is associated with reduced resistance to the infectious agents Mycobacterium tuberculosis and Listeria monocytogenes, among others. Our goal was to model infection and arthritis in mice and to compare etanercept, a currently used anti-TNF-α inhibitor, to an anti-TNF-α vaccine. We developed a murine surrogate of the TNF-α kinoid and produced an anti-murine TNF-α vaccine (TNFKi composed of keyhole limpet hemocyanin conjugated to TNF-α, which resulted in anti-TNF-α antibody production in mice. We also used etanercept (a soluble receptor of TNF commonly used to treat RA as a control of TNF neutralization. In a mouse model of collagen-induced arthritis, TNFKi protected against inflammation similar to etanercept. In a mouse model of acute L. monocytogenes infection, all TNFKi-treated mice showed cleared bacterial infection and survived, whereas etanercept-treated mice showed large liver granulomas and quickly died. Moreover, TNFKi mice infected with the virulent H37Rv M. tuberculosis showed resistance to infection, in contrast with etanercept-treated mice or controls. Depending on the TNF-α blockade strategy, treating arthritis with a TNF-α inhibitor could result in a different profile of infection suceptibility. Our TNFKi vaccine allowed for a better remaining host defense than did etanercept.

  1. Tumor Necrosis Factor-Alpha and Receptor Activator of Nuclear Factor-κB Ligand Augment Human Macrophage Foam-Cell Destruction of Extracellular Matrix Through Protease-Mediated Processes

    DEFF Research Database (Denmark)

    Skjøt-Arkil, Helene; Barascuk, Natasha; Larsen, Lise Korsager

    2012-01-01

    , a major component of extracellular matrix (ECM) in plaques, and to establish whether the pro-inflammatory molecules, tumor necrosis factor (TNF)-alpha, and receptor activator of nuclear factor-κB ligand (RANK-L) increase this degradation. CD14+ monocytes isolated from peripheral blood were differentiated...

  2. Evidence of a role of tumor necrosis factor alpha in refractory asthma.

    Science.gov (United States)

    Berry, Mike A; Hargadon, Beverley; Shelley, Maria; Parker, Debbie; Shaw, Dominick E; Green, Ruth H; Bradding, Peter; Brightling, Christopher E; Wardlaw, Andrew J; Pavord, Ian D

    2006-02-16

    The development of tumor necrosis factor alpha (TNF-alpha) antagonists has made it feasible to investigate the role of this cytokine in refractory asthma. We measured markers of TNF-alpha activity on peripheral-blood monocytes in 10 patients with refractory asthma, 10 patients with mild-to-moderate asthma, and 10 control subjects. We also investigated the effects of treatment with the soluble TNF-alpha receptor etanercept (25 mg twice weekly) in the patients with refractory asthma in a placebo-controlled, double-blind, crossover pilot study. As compared with patients with mild-to-moderate asthma and controls, patients with refractory asthma had increased expression of membrane-bound TNF-alpha, TNF-alpha receptor 1, and TNF-alpha-converting enzyme by peripheral-blood monocytes. In the clinical trial, as compared with placebo, 10 weeks of treatment with etanercept was associated with a significant increase in the concentration of methacholine required to provoke a 20 percent decrease in the forced expiratory volume in one second (FEV1) (mean difference in doubling concentration changes between etanercept and placebo, 3.5; 95 percent confidence interval, 0.07 to 7.0; P=0.05), an improvement in the asthma-related quality-of-life score (by 0.85 point; 95 percent confidence interval, 0.16 to 1.54 on a 7-point scale; P=0.02), and a 0.32-liter increase in post-bronchodilator FEV1 (95 percent confidence interval, 0.08 to 0.55; P=0.01). Patients with refractory asthma have evidence of up-regulation of the TNF-alpha axis. (ClinicalTrials.gov number, NCT00276029.). Copyright 2006 Massachusetts Medical Society.

  3. Elevated Dengue Virus Nonstructural Protein 1 Serum Levels and Altered Toll-Like Receptor 4 Expression, Nitric Oxide, and Tumor Necrosis Factor Alpha Production in Dengue Hemorrhagic Fever Patients

    Directory of Open Access Journals (Sweden)

    Denise Maciel Carvalho

    2014-01-01

    Full Text Available Background. During dengue virus (DV infection, monocytes produce tumor necrosis factor alpha (TNF-α and nitric oxide (NO which might be critical to immunopathogenesis. Since intensity of DV replication may determine clinical outcomes, it is important to know the effects of viral nonstructural protein 1 (NS1 on innate immune parameters of infected patients. The present study investigates the relationships between dengue virus nonstructural protein 1 (NS1 serum levels and innate immune response (TLR4 expression and TNF-α/NO production of DV infected patients presenting different clinical outcomes. Methodology/Principal Findings. We evaluated NO, NS1 serum levels (ELISA, TNF-α production by peripheral blood mononuclear cells (PBMCs, and TLR4 expression on CD14+ cells from 37 dengue patients and 20 healthy controls. Early in infection, increased expression of TLR4 in monocytes of patients with dengue fever (DF was detected compared to patients with dengue hemorrhagic fever (DHF. Moreover, PBMCs of DHF patients showed higher NS1 and lower NO serum levels during the acute febrile phase and a reduced response to TLR4 stimulation by LPS (with a reduced TNF-α production when compared to DF patients. Conclusions/Significance. During DV infection in humans, some innate immune parameters change, depending on the NS1 serum levels, and phase and severity of the disease which may contribute to development of different clinical outcomes.

  4. Tumor necrosis factor-alpha regulates the Hypocretin system via mRNA degradation and ubiquitination.

    Science.gov (United States)

    Zhan, Shuqin; Cai, Guo-Qiang; Zheng, Anni; Wang, Yuping; Jia, Jianping; Fang, Haotian; Yang, Youfeng; Hu, Meng; Ding, Qiang

    2011-04-01

    Recent studies recognize that Hypocretin system (also known as Orexin) plays a critical role in sleep/wake disorders and feeding behaviors. However, little is known about the regulation of the Hypocretin system. It is also known that tumor necrosis factor alpha (TNF-α) is involved in the regulation of sleep/wake cycle. Here, we test our hypothesis that the Hypocretin system is regulated by TNF-α. Prepro-Hypocretin and Hypocretin receptor 2 (HcrtR2) can be detected at a very low level in rat B35 neuroblastoma cells. In response to TNF-α, Prepro-Hypocretin mRNA and protein levels are down-regulated, and also HcrtR2 protein level is down-regulated in B35 cells. To investigate the mechanism, exogenous rat Prepro-Hypocretin and rat HcrtR2 were overexpressed in B35 cells. In response to TNF-α, protein and mRNA of Prepro-Hypocretin are significantly decreased (by 93% and 94%, respectively), and the half-life of Prepro-Hypocretin mRNA is decreased in a time- and dose-dependent manner. The level of HcrtR2 mRNA level is not affected by TNF-α treatment; however, HcrtR2 protein level is significantly decreased (by 86%) through ubiquitination in B35 cells treated with TNF-α. Downregulation of cellular inhibitor of apoptosis protein-1 and -2 (cIAP-1 and -2) abrogates the HcrtR2 ubiquitination induced by TNF-α. The control green fluorescent protein (GFP) expression is not affected by TNF-α treatment. These studies demonstrate that TNF-α can impair the function of the Hypocretin system by reducing the levels of both Prepro-Hypocretin and HcrtR2. Copyright © 2010 Elsevier B.V. All rights reserved.

  5. Cyclic nucleotides differentially regulate the synthesis of tumour necrosis factor-alpha and interleukin-1 beta by human mononuclear cells

    NARCIS (Netherlands)

    Endres, S; Fülle, H J; Sinha, B; Stoll, D; Dinarello, C A; Gerzer, R; Weber, P.C.

    Recent reports have shown that phosphodiesterase (PDE) inhibitors suppress production of tumour necrosis factor-alpha (TNF-alpha) in mouse macrophages. In the present study we show that theophylline, pentoxifylline and 3-isobutyl-1-methylxanthine markedly suppress the lipopolysaccharide

  6. High Serum Interleukin-10 and Tumor Necrosis Factor Alpha Levels in Chronic Paracoccidioidomycosis

    Science.gov (United States)

    Fornari, M. C.; Bava, A. J.; Guereño, M. T.; Berardi, V. E.; Silaf, M. R.; Negroni, R.; Diez, R. A.

    2001-01-01

    In patients with chronic paracoccidioidomycosis (n = 10), levels of tumor necrosis factor alpha, interleukin-10, and interleukin-2 in serum, measured by enzyme-linked immunosorbent assay (in picograms per milliliter, as mean ± standard error of the mean), were higher than in normal controls (n = 8): 186 ± 40 versus 40 ± 7 (P < 0.05), 203 ± 95 versus 20 ± 8 (P = 0.001), and 96.3 ± 78.57 versus 1.19 ± 1.19 (P = 0.045), respectively. Gamma interferon and interleukin-4 levels were similar in patients and controls. PMID:11527826

  7. Interleukin-10 and tumour necrosis factor-alpha serum levels in chronic Chagas disease patients.

    Science.gov (United States)

    Vasconcelos, R H T; Azevedo, E de A N; Diniz, G T N; Cavalcanti, M da G A de M; de Oliveira, W; de Morais, C N L; Gomes, Y de M

    2015-07-01

    In Chagas disease, chronically infected individuals may be asymptomatic or may present cardiac or digestive complications, and it is well known that the human immune response is related to different clinical manifestations. Different patterns of cytokine levels have been previously described in different clinical forms of this disease, but contradictory results are reported. Our aim was to evaluate the serum levels of interleukin-10 and tumour necrosis factor-alpha in patients with asymptomatic and cardiac Chagas disease. The serum interleukin-10 levels in patients with cardiomyopathy were higher than those in asymptomatic patients, mainly in those without heart enlargement. Although no significant difference was observed in serum tumour necrosis factor-alpha levels among the patients, we found that cardiac patients also present high levels of this cytokine, largely those with heart dilatation. Therefore, these cytokines play an important role in chronic Chagas disease cardiomyopathy. Follow-up investigations of these and other cytokines in patients with chronic Chagas disease need to be conducted to improve the understanding of the immunopathology of this disease. © 2015 John Wiley & Sons Ltd.

  8. The effect of anti-tumor necrosis factor alpha agents on postoperative anastomotic complications in Crohn's disease: a systematic review.

    Science.gov (United States)

    El-Hussuna, Alaa; Krag, Aleksander; Olaison, Gunnar; Bendtsen, Flemming; Gluud, Lise L

    2013-12-01

    Patients with Crohn's disease treated with anti-tumor necrosis factor alpha agents may have an increased risk of surgical complications. We assessed the effect of anti-tumor necrosis factor alpha on postoperative complications in patients with Crohn's disease undergoing abdominal surgery. Studies were identified through electronic and manual searches. Observational studies on patients with Crohn's disease undergoing laparoscopic or open abdominal surgery were included. Anti-tumor necrosis factor alpha agents were administered within 3 months before surgery. The primary outcome was anastomotic complications including overt dehiscence, intra-abdominal abscess, and enteric fistulas. Fourteen studies on 679 patients in the intervention (anti-tumor necrosis factor alpha) group and 2363 controls were included. Random-effects meta-analysis found no difference in anastomotic complications between the 2 groups (7.6% versus 8.2%; risk ratio, 0.91; 95% CI, 0.56-1.48). There was clear heterogeneity between studies. In subgroup analyses, the anti-tumor necrosis factor alpha increased anastomotic complications in trials with a lower risk of bias, but not in the studies with a higher bias risk (risk ratio, 1.63; 95% CI, 1.03-2.60 and risk ratio, 0.17; 95% CI, 0.05-0.60). In the overall analysis and in studies with a lower bias risk, anti-tumor necrosis factor alpha agents increased the risk of nonanastomotic surgical complications, major medical complications, and minor medical complications. Limitations of observations studies. In studies with a low risk of bias, anti-tumor necrosis factor alpha agents increased the risk of anastomotic complications. Inadequate bias control may lead to an underestimated risk of anastomotic complications.

  9. Influence of βS-globin haplotypes and hydroxyurea on tumor necrosis factor-alpha levels in sickle cell anemia.

    Science.gov (United States)

    Laurentino, Marília Rocha; Maia, Pedro Aurio; Barbosa, Maritza Cavalcante; Bandeira, Izabel Cristina Justino; Rocha, Lilianne Brito da Silva; Gonçalves, Romelia Pinheiro

    2014-03-01

    Sickle cell anemia is a chronic inflammatory disease characterized by an increased production of proinflammatory cytokines including tumor necrosis factor-alpha. Hydroxyurea, by decreasing the polymerization of hemoglobin, reduces inflammatory states. The effect of the genetic polymorphisms of sickle cell patients on tumor necrosis factor-alpha levels remains unknown. The aim of this study was to investigate the association of tumor necrosis factor-alpha levels with β-globin haplotypes and the use of hydroxyurea. A cross-sectional study was performed of 67 patients with sickle cell anemia diagnosed at steady-state in a referral hospital in Fortaleza, Ceará, Brazil. A group of 26 healthy individuals was used as control. βS-haplotype analysis was performed by restriction fragment length polymorphism-polymerase chain reaction. The tumor necrosis factor-alpha levels were measured by the enzyme-linked immunosorbent assay test. Laboratory data (complete blood count and fetal hemoglobin) and information regarding the use of hydroxyurea were obtained from medical records. Statistical analysis was performed using R software with the Kruskal-Wallis and Mann-Whitney tests. Statistical significance was established for p-values sickle cell anemia had significantly higher tumor necrosis factor-alpha levels than controls (p-values sickle cell anemia patients who were receiving hydroxyurea treatment than those who were not (p-value = 0.1249). Sickle cell anemia patients with Bantu/n genotype had significantly higher levels than patients with the Bantu/Benin genotype (p-value = 0.0021). In summary, βS-globin haplotypes, but not hydroxyurea therapy, have a role in modulating tumor necrosis factor-alpha levels in sickle cell anemia adults at steady-state. Many previous studies have investigated prognosis and inflammatory states in sickle cell anemia patients, but the discovery that tumor necrosis factor-alpha levels vary according to the genetic polymorphism of the patient is a

  10. Tumor necrosis factor alpha selectively sensitizes human immunodeficiency virus-infected cells to heat and radiation

    International Nuclear Information System (INIS)

    Wong, G.H.; McHugh, T.; Weber, R.; Goeddel, D.V.

    1991-01-01

    We report here that infection of the human T-cell line HUT-78 with human immunodeficiency virus (HIV) increases its sensitivity to heat and radiation toxicity. A possible explanation for this result may be the reduced expression of manganous superoxide dismutase (MnSOD) in HIV-infected cells compared to uninfected cells. Tumor necrosis factor alpha (TNF-alpha) further sensitizes HIV-infected cells but not uninfected cells to heat and radiation. This is consistent with the ability of TNF-alpha to induce the expression of MnSOD in uninfected but not in HIV-infected cells. HIV-infected HUT-78 cell lines engineered to overexpress MnSOD are more resistant to heat and radiation than HIV-infected cells that do not overexpress MnSOD. However, treatment with TNF-alpha still sensitizes these cells to heat and radiation

  11. Serum tumour necrosis factor alpha in osteopenic and osteoporotic postmenopausal females: A cross-sectional study in Pakistan.

    Science.gov (United States)

    Murad, Rafat; Shezad, Zahra; Ahmed, Saara; Ashraf, Mussarat; Qadir, Murad; Rehman, Rehana

    2018-03-01

    To compare biochemical parameters serum tumour necrosis factor alpha, calcium, magnesium, bone-specific alkaline phosphatase and vitamin D in postmenopausal women. This cross-sectional study was carried out from June 2015 to July 2016 at Jinnah Medical and Dental College, Karachi, and comprised postmenopausal women. Bone mineral density done by dual energy X-ray absorptiometryscan categorised subjects by World Health Organisation classification into normal (T score > -1) osteopenic (T score between -1 and -2.5) and osteoporotic (T score osteoporotic. There was significant difference in mean body mass index, serum tumour necrosis factor alpha and calcium in all the three groups (posteoporotic group (posteoporotic groups (p>0.05). A significant difference was observed for mean tumour necrosis factor alpha values between normal and osteoporotic groups (posteoporotic groups (p>0.05). Increased bone turnover in postmenopausal osteopenic women can be predicted by increased serum cytokine.

  12. Influence of ?S-globin haplotypes and hydroxyurea on tumor necrosis factor-alpha levels in sickle cell anemia

    Directory of Open Access Journals (Sweden)

    Marília Rocha Laurentino

    2014-04-01

    Full Text Available Background: Sickle cell anemia is a chronic inflammatory disease characterized by an increased production of proinflammatory cytokines including tumor necrosis factor-alpha. Hydroxyurea, by decreasing the polymerization of hemoglobin, reduces inflammatory states. The effect of the genetic polymorphisms of sickle cell patients on tumor necrosis factor-alpha levels remains unknown. Objective: The aim of this study was to investigate the association of tumor necrosis factor-alpha levels with β-globin haplotypes and the use of hydroxyurea. Methods: A cross-sectional study was performed of 67 patients with sickle cell anemia diagnosed at steady-state in a referral hospital in Fortaleza, Ceará, Brazil. A group of 26 healthy individuals was used as control. βS-haplotype analysis was performed by restriction fragment length polymorphism-polymerase chain reaction. The tumor necrosis factor-alpha levels were measured by the enzyme-linked immunosorbent assay test. Laboratory data (complete blood count and fetal hemoglobin and information regarding the use of hydroxyurea were obtained from medical records. Statistical analysis was performed using R software with the Kruskal-Wallis and Mann-Whitney tests. Statistical significance was established for p-values < 0.05 for all analyses. Results: The mean age of the participants was 35.48 years. Patients with sickle cell anemia had significantly higher tumor necrosis factor-alpha levels than controls (p-values < 0.0001. Tumor necrosis factor-alpha levels were lower in sickle cell anemia patients who were receiving hydroxyurea treatment than those who were not (p-value = 0.1249. Sickle cell anemia patients with Bantu/n genotype had significantly higher levels than patients with the Bantu/Benin genotype (p-value = 0.0021. Conclusion: In summary, βS-globin haplotypes, but not hydroxyurea therapy, have a role in modulating tumor necrosis factor-alpha levels in sickle cell anemia adults at steady-state. Many

  13. Tipping the balance: anti-tumour necrosis factor alpha therapy may damage cerebral nerve reservation.

    Science.gov (United States)

    Lin, Yun; Zou, Qinghua; Li, Haitao

    2009-12-01

    Anti-tumour necrosis factor alpha therapy has transformed the treatment of certain inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease and ankylosing spondylitis, but onset of demyelinating events associated with multiple sclerosis as an adverse event was continuously reported, and such adverse events were only viewed as occasional. Multiple sclerosis is an autoimmune demyelinating disorder affecting central nervous system, with varied clinical manifestations of cognitive, visual and motor network disorder. Recently, there is increasing evidence from functional magnetic resonance that cortical reorganization, a property that allows the central nervous system to adapt itself to various brain insults, which was viewed as to limit the clinical expression of tissue damage in patients with multiple sclerosis. In light of the mentioned above, we hypothesis that cerebral tissue damage may existed in a broader aspects of patients treated with anti-tumour necrosis factor therapy, but its clinical manifestations from brain lesions were compensated by cortical reorganization. In other words, cerebral nerve reservation may be damaged by the therapy. If confirmed, the hypothesis may lead to a safety concern of the therapy, and an insight of the pathophysiology of both multiple sclerosis and certain inflammatory diseases.

  14. Associations of tumor necrosis factor alpha receptor type 1 with kidney function decline, cardiovascular events, and mortality risk in persons with coronary artery disease: Data from the Heart and Soul Study.

    Science.gov (United States)

    Park, Meyeon; Maristany, Daniela; Huang, Debbie; Shlipak, Michael G; Whooley, Mary

    2017-08-01

    Tumor necrosis factor receptor type 1 (TNFR1) is associated with kidney disease and mortality risk in various populations. Whether or not kidney function mediates mortality risk is unknown. We evaluated associations of TNFR1 levels with measures of kidney function, cardiovascular events, and mortality in a population of veterans with stable ischemic heart disease. TNFR1 was measured from baseline serum samples in the Heart and Soul Study; elevated levels were defined by the highest quartile (Q4, >3.4 ng/ml). We evaluated associations of high TNFR1 with baseline estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (ACR) and with longitudinal changes in eGFR (rapid loss), as well as with incident myocardial infarction (MI), heart failure hospitalizations (HF), and mortality over a median follow-up time of 8.9 years. Covariates included demographics and comorbid conditions. Among 985 participants who had TNFR1 measurements, median TNFR1 was 2.33 ng/ml (IQR 1.8-3.1). Relative to Q1, Q4 had higher risk of eGFR <60 ml/min/1.73 m 2 (RR 11.71 [95% CI 5.46, 25.11]); ACR ≥ 30 mg/g (2.44 [1.15, 5.19]); and rapid loss in kidney function (2.10 [1.12, 3.92]). Although TNFR1 Q4 was associated with MI, HF, and mortality after demographic adjustment, there were no associations in fully-adjusted models (1.04 [0.44, 2.49]; 1.02 [0.48, 2.15]; 1.42 [0.88, 2.28], respectively). Levels of TNFR1 are associated longitudinally with kidney function decline but not with MI, HF or mortality risk after adjustment. Kidney disease may mediate the risk of MI, HF, and mortality associated with TNFR1. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Characteristics of recovery from the euthyroid sick syndrome induced by tumor necrosis factor alpha in cancer patients

    NARCIS (Netherlands)

    Feelders, R. A.; Swaak, A. J.; Romijn, J. A.; Eggermont, A. M.; Tielens, E. T.; Vreugdenhil, G.; Endert, E.; van Eijk, H. G.; Berghout, A.

    1999-01-01

    Cytokines have been implicated in the pathogenesis of the euthyroid sick syndrome. Isolated limb perfusion (ILP) with recombinant human tumor necrosis factor alpha (rTNF) and melphalan in patients with melanoma or sarcoma is accompanied by high systemic TNF levels. We examined the prolonged effects

  16. Lipopolysaccharide induces expression of tumour necrosis factor alpha in rat brain : inhibition by methylprednisolone and by rolipram

    NARCIS (Netherlands)

    Buttini, M; Mir, A; Appel, K; Wiederhold, KH; Limonta, S; GebickeHaerter, PJ; Boddeke, HWGM

    1997-01-01

    1 We have investigated the effects of the phosphodiesterase (PDE) type TV inhibitor rolipram and of the glucocorticoid methylprednisolone on the induction of tumour necrosis factor alpha (TNF-alpha) mRNA and protein in brains of rats after peripheral administration of lipopolysaccharide (LPS). 2

  17. Mitochondria mediate tumor necrosis factor-alpha/NF-kappaB signaling in skeletal muscle myotubes

    Science.gov (United States)

    Li, Y. P.; Atkins, C. M.; Sweatt, J. D.; Reid, M. B.; Hamilton, S. L. (Principal Investigator)

    1999-01-01

    Tumor necrosis factor-alpha (TNF-alpha) is implicated in muscle atrophy and weakness associated with a variety of chronic diseases. Recently, we reported that TNF-alpha directly induces muscle protein degradation in differentiated skeletal muscle myotubes, where it rapidly activates nuclear factor kappaB (NF-kappaB). We also have found that protein loss induced by TNF-alpha is NF-kappaB dependent. In the present study, we analyzed the signaling pathway by which TNF-alpha activates NF-kappaB in myotubes differentiated from C2C12 and rat primary myoblasts. We found that activation of NF-kappaB by TNF-alpha was blocked by rotenone or amytal, inhibitors of complex I of the mitochondrial respiratory chain. On the other hand, antimycin A, an inhibitor of complex III, enhanced TNF-alpha activation of NK-kappaB. These results suggest a key role of mitochondria-derived reactive oxygen species (ROS) in mediating NF-kappaB activation in muscle. In addition, we found that TNF-alpha stimulated protein kinase C (PKC) activity. However, other signal transduction mediators including ceramide, Ca2+, phospholipase A2 (PLA2), and nitric oxide (NO) do not appear to be involved in the activation of NF-kappaB.

  18. Inhibition of tumor necrosis factor-alpha with anti-diabetic agents.

    Science.gov (United States)

    Fukuzawa, M; Satoh, J; Qiang, X; Miyaguchi, S; Sakata, Y; Nakazawa, T; Ikehata, F; Ohta, S; Toyota, T

    1999-03-01

    It has recently been indicated that tumor necrosis factor-alpha (TNF-alpha) production is increased under chronic hyperglycemia and TNF-alpha has harmful effects on insulin sensitivity and possibly on chronic diabetic complications. Therefore it will be favorable for diabetes treatment if anti-diabetic agents also have anti-TNF-alpha activities. In this study, we have investigated effects of hypoglycemic sulfonylureas (gliclazide and glibenclamide) and a thiazolidinedione (troglitazone) on lipopolysaccharide-induced TNF-alpha production, which was evaluated by immunoassay and bioassay, in vivo using mice and partly in vitro using human peripheral blood mononuclear cells. Gliclazide significantly inhibited TNF-alpha production in vivo and also in vitro at a concentration of 10(-3) mol/l. However, glibenclamide had neither effect on TNF-alpha production nor action. On the other hand, troglitazone inhibited action rather than production of TNF-alpha in vivo. In vitro troglitazone (10(-4) mol/l) significantly reduced cytolytic activity of TNF-alpha against LM cells. These results indicate that gliclazide and troglitazone have inhibitory effect on TNF-alpha.

  19. Modulation of tumor necrosis factor-alpha production with anti-hypertensive drugs.

    Science.gov (United States)

    Fukuzawa, M; Satoh, J; Ohta, S; Takahashi, K; Miyaguchi, S; Qiang, X; Sakata, Y; Nakazawa, T; Takizawa, Y; Toyota, T

    2000-06-01

    It is well known that some anti-hypertensive drugs affect insulin sensitivity and that tumor necrosis factor-alpha (TNF-alpha) is a mediator of obesity-associated insulin resistance. In this study, we have investigated the effect of anti-hypertensive drugs, calcium (Ca) channel blockers (amlodipine, manidipine and nicardipine), an alpha(1)-blocker (doxazosin), a beta(1)-blocker (metoprolol), and a thiazide diuretic (hydrochlorothiazide), on lipopolysaccharide (LPS)-induced TNF-alpha production. TNF-alpha production, measured with a bioassay and an immunoassay, was evaluated both in vivo and in vitro, by utilizing mice and a human peripheral blood mononuclear cell culture, respectively. Nicardipine, or amlodipine, manidipine and doxazosin significantly inhibited TNF-alpha production in mice at doses more than one or ten times higher than those used clinically, respectively. On the other hand, metoprolol increased TNF-alpha production at doses of more than 10 times those used clinically, whereas hydrochlorothiazide did not alter production of the cytokine. The in vivo effects of these drugs were not necessary parallel to the in vitro effects. Because high doses of these drugs in mice correspond to clinical doses and effects in human, these actions may be related to beneficial and/or harmful effects of these drugs on TNF-alpha mediated diseases, including insulin resistance.

  20. Analysis of Relationship between Tumor Necrosis Factor Alpha Gene (G308A Polymorphism) with Preterm Labor.

    Science.gov (United States)

    Jafarzadeh, Lobat; Danesh, Azar; Sadeghi, Marzieh; Heybati, Fateme; Hashemzadeh, Morteza

    2013-08-01

    Increased concentrations of tumor necrosis factor alpha (TNF-α) in blood and amniotic fluid are observed in women with preterm delivery (PTD) and TNF-α mutations at -308 position are associated with higher expression of this gene. Therefore, we compared the frequency of G308A transition in the promoter region of TNF-α gene of women and neonates delivered preterm with the normal subjects. This cross-sectional study was performed on 135 mothers who were referred for delivery. According to the gestational age, mothers and their neonates were allocated to the case (preterm, 64 subjects) and control (term, 71 subjects) groups. Using the polymerase chain reaction, restrictive fragment length polymorphism (RFLP), genotyping was performed on both maternal peripheral blood and cord blood samples to determine single nucleotide polymorphism in the promoter region of TNF-α gene at -308. Two mothers in the case group, one mother in the control group and one neonate in the case group had genotyping assays (GA) mutation. All other subjects had normal GG genotype. Frequency of GA mutation was not significantly different between two groups (P = 0.47). There is no significant association between PTD and either maternal or fetal TNF-α -308 polymorphism and frequency ofGAmutation is not significantly increased in mothers and neonates delivered preterm. It means that the presence of this mutation by itself does not modify the overall risk of PTD. Investigations on the combination of various polymorphisms indifferent genes are recommended to achieve more accurate results.

  1. The Role of Tumor Necrosis Factor- alpha and Resistin in Nonalcoholic Fatty Liver Disease

    International Nuclear Information System (INIS)

    Alkady, M.M.

    2011-01-01

    Nonalcoholic fatty liver disease (NAFLD) represents one of the most common liver diseases. It is strongly associated with obesity and insulin resistance and is thought to be a part of the metabolic syndrome. It can progress from simple fatty liver to steatohepatitis, cirrhosis and liver failure. Adipocytokines, synthesized in adipose tissue, are involved in the pathophysiology of many acute and chronic liver diseases. The aim of this study was to investigate the role of Tumor Necrosis Factor-alpha (TNF-alpha) and resistin in the pathogenesis of NAFLD and their correlation to the severity of the disease. Serum concentration of TNF-alpha and resistin were measured in 20 patients with NAFLD and 20 healthy controls with ELISA method. The results of this study revealed that serum levels of both adipokines were significantly elevated in NAFLD patients than controls (P<0.01). Moreover, they were significantly higher in patients with nonalcoholic steatohepatitis than in patients with simple fatty liver. There was a significant positive correlation between TNF-alpha, resistin and each of AST, ALT and HOMA. Similarly, the results showed a significant positive correlation between the two studied adipokines, TNF-alpha and resistin (P<0.001). We conclude that TNF-alpha and resistin have a role in the pathogenesis of NAFLD and they may be promising markers for the progressin to steatohepatitis and inhibition of their activities by drugs may be a new approach for the treatment of NAFLD

  2. Tumor necrosis factor alpha increases epithelial barrier permeability by disrupting tight junctions in Caco-2 cells.

    Science.gov (United States)

    Cui, W; Li, L X; Sun, C M; Wen, Y; Zhou, Y; Dong, Y L; Liu, P

    2010-04-01

    The objectives of this study were to determine the effect of tumor necrosis factor alpha (TNF-alpha) on intestinal epithelial cell permeability and the expression of tight junction proteins. Caco-2 cells were plated onto Transwell microporous filters and treated with TNF-alpha (10 or 100 ng/mL) for 0, 4, 8, 16, or 24 h. The transepithelial electrical resistance and the mucosal-to-serosal flux rates of the established paracellular marker Lucifer yellow were measured in filter-grown monolayers of Caco-2 intestinal cells. The localization and expression of the tight junction protein occludin were detected by immunofluorescence and Western blot analysis, respectively. SYBR-Green-based real-time PCR was used to measure the expression of occludin mRNA. TNF-alpha treatment produced concentration- and time-dependent decreases in Caco-2 transepithelial resistance and increases in transepithelial permeability to the paracellular marker Lucifer yellow. Western blot results indicated that TNF-alpha decreased the expression of phosphorylated occludin in detergent-insoluble fractions but did not affect the expression of non-phosphorylated occludin protein. Real-time RT-PCR data showed that TNF-alpha did not affect the expression of occludin mRNA. Taken together, our data demonstrate that TNF-alpha increases Caco-2 monolayer permeability, decreases occludin protein expression and disturbs intercellular junctions.

  3. Tumor necrosis factor alpha increases epithelial barrier permeability by disrupting tight junctions in Caco-2 cells

    Directory of Open Access Journals (Sweden)

    W. Cui

    2010-04-01

    Full Text Available The objectives of this study were to determine the effect of tumor necrosis factor alpha (TNF-α on intestinal epithelial cell permeability and the expression of tight junction proteins. Caco-2 cells were plated onto Transwell® microporous filters and treated with TNF-α (10 or 100 ng/mL for 0, 4, 8, 16, or 24 h. The transepithelial electrical resistance and the mucosal-to-serosal flux rates of the established paracellular marker Lucifer yellow were measured in filter-grown monolayers of Caco-2 intestinal cells. The localization and expression of the tight junction protein occludin were detected by immunofluorescence and Western blot analysis, respectively. SYBR-Green-based real-time PCR was used to measure the expression of occludin mRNA. TNF-α treatment produced concentration- and time-dependent decreases in Caco-2 transepithelial resistance and increases in transepithelial permeability to the paracellular marker Lucifer yellow. Western blot results indicated that TNF-α decreased the expression of phosphorylated occludin in detergent-insoluble fractions but did not affect the expression of non-phosphorylated occludin protein. Real-time RT-PCR data showed that TNF-α did not affect the expression of occludin mRNA. Taken together, our data demonstrate that TNF-α increases Caco-2 monolayer permeability, decreases occludin protein expression and disturbs intercellular junctions.

  4. Thermotherapy-induced reduction in glioma invasiveness is mediated by tumor necrosis factor-alpha.

    Science.gov (United States)

    Qin, L J; Zhang, T; Jia, Y S; Zhang, Y B; Zhang, Y X; Wang, H T

    2015-10-02

    Thermotherapy has been proven to be effective for the treatment of various tumors, including glioma. We determined whether tumor necrosis factor-alpha (TNF-α) is involved in the regulation of the biological processes of glioma development. Reverse transcription-polymerase chain reaction (RT-PCR) and immunocytochemistry were used to investigate the levels of TNF-α mRNA and heat shock factor-1 (HSF1) protein, respectively, in glioma cells. Radioimmunoassay was used to dynamically monitor the contents of TNF-α in the nutrient fluid of C6 cells after thermotherapy treatment. Crystal violet staining was used to determine glioma invasiveness. The most obvious increases in HSF1 protein and TNF-α mRNA in C6 cells were observed at 30 and 60 min after thermotherapy, respectively. In addition, the radioactivity of TNF-α in the culture fluid of the C6 cells reached a peak after 120 min of thermotherapy. In addition, glioma invasiveness decreased and the concentration of TNF-α reached a maximum after 120 min of thermotherapy. Our results show that the decrease in thermotherapy-mediated glioma invasiveness is due to the accelerated release of TNF-α, which could promote the release of HSF1 from neurospongioma cells.

  5. Tumor necrosis factor alpha maintains denervation-induced homeostatic synaptic plasticity of mouse dentate granule cells

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    Denise eBecker

    2013-12-01

    Full Text Available Neurons which lose part of their input respond with a compensatory increase in excitatory synaptic strength. This observation is of particular interest in the context of neurological diseases, which are accompanied by the loss of neurons and subsequent denervation of connected brain regions. However, while the cellular and molecular mechanisms of pharmacologically induced homeostatic synaptic plasticity have been identified to a certain degree, denervation-induced homeostatic synaptic plasticity remains not well understood. Here, we employed the entorhinal denervation in vitro model to study the role of tumor necrosis factor alpha (TNFα on changes in excitatory synaptic strength of mouse dentate granule cells following partial deafferentation. Our experiments disclose that TNFα is required for the maintenance of a compensatory increase in excitatory synaptic strength at 3/4 days postlesion (dpl, but not for the induction of synaptic scaling at 1 - 2 dpl. Furthermore, laser capture microdissection (LMD combined with quantitative PCR (qPCR demonstrates an increase in TNFα-mRNA levels in the denervated zone, which is consistent with our previous finding on a local, i.e., layer-specific increase in excitatory synaptic strength at 3 - 4 dpl. Immunostainings for the glial fibrillary acidic protein (GFAP and TNFα suggest that astrocytes are a source of TNFα in our experimental setting. We conclude that TNFα-signaling is a major regulatory system that aims at maintaining the homeostatic synaptic response of denervated neurons.

  6. Fusobacterium nucleatum infection of colonic cells stimulates MUC2 mucin and tumor necrosis factor alpha.

    Science.gov (United States)

    Dharmani, Poonam; Strauss, Jaclyn; Ambrose, Christian; Allen-Vercoe, Emma; Chadee, Kris

    2011-07-01

    The etiology of inflammatory bowel disease is not completely known, but it is influenced by the presence of normal gut microflora as well as yet-unrecognized pathogens. The anaerobic, Gram-negative bacterial species Fusobacterium nucleatum is a common resident of the human mouth and gut and varies in its pathogenic potential. In this study, we demonstrate that highly invasive F. nucleatum isolates derived from the inflamed guts of Crohn's disease patients evoked significantly greater MUC2 and tumor necrosis factor alpha (TNF-α) gene expression than minimally invasive strains isolated from the noninflamed gut in human colonic epithelial cells and in a rat ligated colonic loop model of infection. Only live F. nucleatum induced mucin secretion and TNF-α expression in direct contact with and/or during invasion of colonic cells. In rat colons, mucin secretion was augmented in response to a highly invasive F. nucleatum isolate but was unaffected by treatment with a minimally invasive strain. Taken together, these studies reveal that F. nucleatum may represent a challenging pathogen in the etiology of gut inflammatory diseases and highlight the importance of different pathotypes of candidate bacterial species in disease pathogenesis.

  7. Genetically engineered bacteriophage delivers a tumor necrosis factor alpha antagonist coating on neural electrodes

    International Nuclear Information System (INIS)

    Kim, Young Jun; Nam, Chang-Hoon; Jin, Young-Hyun; Stieglitz, Thomas; Salieb-Beugelaar, Georgette B

    2014-01-01

    This paper reports a novel approach for the formation of anti-inflammatory surface coating on a neural electrode. The surface coating is realized using a recombinant f88 filamentous bacteriophage, which displays a short platinum binding motif and a tumor necrosis factor alpha antagonist (TNF-α antagonist) on p3 and p8 proteins, respectively. The recombinant bacteriophages are immobilized on the platinum surface by a simple dip coating process. The selective and stable immobilization of bacteriophages on a platinum electrode is confirmed by quartz crystal microbalance with dissipation monitoring, atomic force microscope and fluorescence microscope. From the in vitro cell viability test, the inflammatory cytokine (TNF-α) induced cell death was prevented by presenting recombinant bacteriophage coating, albeit with no significant cytotoxic effect. It is also observed that the bacteriophage coating does not have critical effects on the electrochemical properties such as impedance and charge storage capacities. Thus, this approach demonstrates a promising anti-apoptotic as well as anti-inflammatory surface coating for neural implant applications. (paper)

  8. Plasma Levels of Tumor Necrosis Factor-Alpha and Interleukin-6 in Obsessive Compulsive Disorder

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    N. Konuk

    2007-01-01

    Full Text Available Aim. Recent research implicated place of an immune mechanism in the pathophysiology of obsessive-compulsive disorder (OCD. Despite increasing evidence involvement of cytokine release in OCD, results of the studies are inconsistent. The aim of this study was to evaluate the plasma levels of the cytokines; tumor necrosis factor-alpha (TNF-α and interleukin-6 (IL-6 in OCD patients. Methods. Plasma concentrations of TNF-α and IL-6 were measured in 31 drug-free outpatients with OCD, and 31-year age and sex-matched healthy controls. TNF-α and IL-6 concentrations in blood were determined by enzyme-linked immunosorbent assay (ELISA. Results. Both TNF-α and IL-6 levels showed statistically significant increases in OCD patients compared to controls (P<.000, P<.001, resp.. In addition, the age of onset was negatively correlated with TNF-α level (r=−.402, P=.025 and duration of illness was weakly correlated with IL-6 levels (r:.357; P:.048 in patients group. Conclusion. OCD patients showed increases in TNF-α and IL-6 levels compared to the healthy controls. This study provides evidence for alterations in the proinflamatory cytokines which suggest the involvement of the immune system in the pathophysiology of OCD.

  9. Tumor necrosis factor alpha of teleosts: in silico characterization and homology modeling

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    Tran Ngoc Tuan

    2016-10-01

    Full Text Available Tumor necrosis factor alpha (TNF- is known to be crucial in many biological activities of organisms. In this study, physicochemical properties and modeling of TNF- protein of fish was analyzed using in silico approach. TNF- proteins selected from fish species, including grass carp (Ctenopharyngodon idella, zebra fish (Danio rerio, Nile tilapia (Oreochromis niloticus, goldfish (Carassius auratus, and rainbow trout (Oncorhynchus mykiss were used in this study. Physicochemical characteristics with molecular weight, theoretical isoelectric point, extinction coefficient, aliphatic index, instability index, total number of negatively charged residues and positively charged residues, and grand average of hydropathicity were computed. All proteins were classified as transmembrane proteins. The “transmembrane region” and “TNF” domain were identified from protein sequences. The function prediction of proteins was also performed. Alpha helices and random coils were dominating in the secondary structure of the proteins. Three-dimensional structures were predicted and verified as good structures for the investigation of TNF- of fish by online server validation.

  10. Tumor Necrosis Factor-Alpha in Peripical Tissue Exudates of Teeth with Apical Periodontitis

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    Sonja Pezelj-Ribaric

    2007-01-01

    Full Text Available Aim. The aim of this study was to determine tumor necrosis factor-alpha (TNF-α levels in periapical exudates and to evaluate their relationship with radiological findings. Methodology. Periapical exudates were collected from root canals of 60 single-rooted teeth using absorbent paper points. TNF-α levels were determined by enzyme-linked immunosorbent assays. The samples were divided into three groups according to the periapical radiolucent area. Results. Nonparametric Kruskal-Wallis test revealed significant differences between TNF-α concentrations in control group (40, 57±28, 15 pg/mL and group with larger radiolucent areas (2365, 79±582, 95 pg/mL, as well as between control and canals with small radiolucent areas (507, 66±278, 97 (P<.05. Conclusions. The levels of TNF-α increase significantly in teeth with periapical pathosis, from smaller to bigger lesions. This research and its results have shown that objective analysis of the TNF-α levels enables establishment of a relationship between different concentrations of TNF-α and different radiological changes.

  11. Dissociative symptoms reflect levels of tumor necrosis factor alpha in patients with unipolar depression

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    Bizik G

    2014-04-01

    Full Text Available Gustav Bizik,1 Petr Bob,1 Jiri Raboch,1 Josef Pavlat,1 Jana Uhrova,2 Hana Benakova,2 Tomas Zima2 1Center for Neuropsychiatric Research of Traumatic Stress, Department of Psychiatry and UHSL, 2Department of Clinical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University, Prague, Czech Republic Abstract: Recent evidence indicates that the nature of interactions between the nervous system and immune system is important in the pathogenesis of depression. Specifically, alterations in pro-inflammatory cytokines have been related to the development of several psychological and neurobiological manifestations of depressive disorder, as well as to stress exposure. A number of findings point to tumor necrosis factor alpha (TNF-α as one of the central factors in these processes. Accordingly, in the present study, we test the hypothesis that specific influences of chronic stressors related to traumatic stress and dissociation are related to alterations in TNF-α levels. We performed psychometric measurement of depression (Beck Depression Inventory [BDI]-II, traumatic stress symptoms (Trauma Symptom Checklist [TSC]-40, and psychological and somatoform dissociation (Dissociative Experiences Scale [DES] and Somatoform Dissociation Questionnaire [SDQ]-20, respectively, and immunochemical measure of serum TNF-α in 66 inpatients with unipolar depression (mean age 43.1 ± 7.3 years. The results show that TNF-α is significantly related to DES (Spearman R=−0.42, P<0.01, SDQ-20 (Spearman R=−0.38, P<0.01, and TSC-40 (Spearman R=−0.41, P<0.01, but not to BDI-II. Results of the present study suggest that TNF-α levels are related to dissociative symptoms and stress exposure in depressed patients. Keywords: depression, dissociation, TNF-alpha, traumatic stress

  12. Labile anger during interferon alfa treatment is associated with a polymorphism in tumor necrosis factor alpha.

    Science.gov (United States)

    Lotrich, Francis E; Ferrell, Robert E; Rabinovitz, Mordechai; Pollock, Bruce G

    2010-07-01

    Inflammatory cytokines may influence both labile anger and depression. Both psychiatric conditions can occur during interferon alfa-based treatments. Evidence also indicates a central nervous system role for tumor necrosis factor alpha (TNF-alpha), whose expression may be increased by interferon alfa. A polymorphism in the promoter region of TNF-alpha has been associated with various inflammatory illnesses. We therefore hypothesized that this TNF-alpha polymorphism would influence susceptibility to psychiatric symptoms during interferon alfa therapy. One hundred five patients with hepatitis C, initially without active major depression (major depressive disorder), were treated with interferon alfa and then prospectively monitored using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, the Beck Depression Inventory II, the Anger Irritability and Assault Questionnaire, and circulating TNF-alpha levels. The A-308G polymorphism (rs1800629) was determined using the 5'-nuclease assay. Repeated-measure mixed-effect analyses compared changes in symptoms over time. Beck Depression Inventory II score increased during interferon alfa therapy (F = 6.2; P depression incidence (chi = 0.0; P = 0.99) or increased Beck Depression Inventory II (F = 1.2; P = 0.31). Labile anger was not predicted by the serotonin transporter polymorphism (F = 0.8; P = 0.59). During treatment with an exogenous cytokine, vulnerability to worsening labile anger-distinct from major depression-is associated with genetic variability in TNF-alpha. This has implications both for patients being treated with interferon alfa and our understanding of genetic vulnerability for different subtypes of dysphoric and mood disorders.

  13. High fat diet sensitizes fibromyalgia-like pain behaviors in mice via tumor necrosis factor alpha.

    Science.gov (United States)

    Tian, Dan; Tian, Miao; Zhang, Leilei; Zhao, Peng; Cui, Yunfeng; Li, Jinlong

    2018-01-01

    Fibromyalgia (FM) and obesity are closely related. However, little is known about how obesity contributes to FM. Importantly, adequate evidence has shown that tumor necrosis factor alpha (TNF-α) plays a critical role in obesity. Thus, we hypothesized that obesity-induced TNF-α release may potentiate FM-associated pain. To test this hypothesis, we investigated the role of TNF-α in the development of FM-like pain in a mouse model of acid saline injection-induced FM. Consistent with previous reports, we showed that repeated acid saline injections induced bilateral mechanical hyperalgesia, and this effect lasted for at least 4 days after acid saline injections. This phenomenon was associated with increased levels of TNF-α in plasma, muscles, and spinal cord. Furthermore, we found that 24 weeks of high fat diet treatment significantly potentiated acid saline-induced bilateral mechanical hyperalgesia. High fat diet-treated mice exhibited robustly increased levels of TNF-α in plasma, muscles, and spinal cord after acid saline injections compared with low fat diet-treated mice. Additionally, using immunofluorescence staining, we found that the number of TNF-α positive cells in dorsal root ganglion (DRG) was increased after acid saline injections, and high fat diet treatment further sensitized this increase. Finally, we reported that acid saline-induced FM-like pain behaviors were abolished in TNFRp55-/- mice, confirming the critical role of TNF-α in the development of FM-like pain. Taken together, our results suggested that high fat diet treatment may sensitize acid saline-induced FM-like pain via increasing TNF-α levels in plasma, muscles, and DRG.

  14. Estimation of salivary tumor necrosis factor-alpha in chronic and aggressive periodontitis patients.

    Science.gov (United States)

    Varghese, Sheeja S; Thomas, Hima; Jayakumar, N D; Sankari, M; Lakshmanan, Reema

    2015-09-01

    Periodontitis is a chronic bacterial infection characterized by persistent inflammation, connective tissue breakdown and alveolar bone destruction mediated by pro-inflammatory mediators. Tumor necrosis factor-alpha (TNF-α) is an important pro-inflammatory mediator that produced causes destruction of periodontal tissues. The aim of the study is to estimate the salivary TNF-α in chronic and aggressive periodontitis and control participants and further correlate the levels with clinical parameter such as gingival index (GI), plaque index (PI), probing pocket depth (PPD) and clinical attachment loss. The study population consisted of 75 subjects age ranging from 25 to 55 years attending the outpatient section of Department of Periodontics, Saveetha Dental College and Hospital. The study groups included Groups 1, 2, and 3 with participants with healthy periodontium (n = 25), generalized chronic periodontitis (n = 25) and generalized aggressive periodontitis (n = 25), respectively. Salivary samples from the participants were used to assess the TNF-α levels using enzyme-linked immunosorbent assay. GI and PI were found to be significantly higher in chronic and aggressive periodontitis compared to the controls. The mean TNF-α value in chronic periodontitis patients (12.92 ± 17.21 pg/ml) was significantly higher than in control subjects (2.15 ± 3.60 pg/ml). Whereas, in aggressive periodontitis patients the mean TNF-α (7.23 ± 7.67) were not significantly different from chronic periodontitis or healthy subjects. Among periodontitis participants, aggressive periodontitis subjects exhibited a significant positive correlation between the salivary TNF-α and PPD. Salivary TNF-α levels are significantly higher in chronic periodontitis than in healthy subjects, but there was no significant correlation with the clinical parameters.

  15. Induction of endogenous tumor necrosis factor-alpha: suppression of centrally stimulated gastric motility.

    Science.gov (United States)

    Hermann, G E; Tovar, C A; Rogers, R C

    1999-01-01

    Gastric stasis is frequently seen in conjunction with critical infectious illness, chronic inflammatory disorders, radiation sickness, and carcinogenesis. These conditions are associated with elevated circulating levels of the cytokine tumor necrosis factor-alpha (TNF-alpha). The present studies examined the relationship between endogenously produced TNF-alpha and the central neural mechanisms that augment gastric motility. Systemic lipopolysaccharide (LPS) was employed to induce TNF-alpha production in thiobutabarbital-anesthetized rats. Sixty minutes after intravenous LPS injection, gastric motility could not be stimulated by a potent centrally acting gastrokinetic stimulant, thyrotropin-releasing hormone (TRH). This failure to elicit gastric motility via central mechanisms coincided with high circulating levels of TNF-alpha. However, intravenous injections of bethanecol, a peripherally acting cholinergic agonist with direct gastrokinetic effects, were still able to elicit normal increases in gastric motility in the presence of TNF-alpha and LPS. Therefore, the inability to stimulate gastric motility via central TRH could not be attributed to the direct inhibitory effects of either LPS or TNF-alpha on the stomach. If the production of endogenous TNF-alpha was suppressed via the use of urethan as the anesthetic agent, then intravenous injections of LPS were no longer effective in suppressing gastric motility. Thus these effects on gastric motility are not directly attributable to LPS nor are they due to direct effects on the gastric smooth muscle. Our previous study demonstrated that microinjection of femtomole quantities of TNF-alpha in the brain stem dorsal vagal complex (DVC) can modulate gastric motility. This central TNF-alpha effect on gastric motility was dose dependent and required an intact vagal efferent pathway. The results from these two studies suggest that systemically produced TNF-alpha may gain access to the DVC to modulate gastric function.

  16. Pharmacokinetics and tissue distribution of recombinant human tumor necrosis factor-alpha in mice

    International Nuclear Information System (INIS)

    Ferraiolo, B.L.; Moore, J.A.; Crase, D.; Gribling, P.; Wilking, H.; Baughman, R.A.

    1988-01-01

    The serum pharmacokinetics and the major organs of accumulation of recombinant human tumor necrosis factor-alpha (rHuTNF) were determined in BDF1 mice after intravenous and intramuscular administration. Serum concentrations of immunoreactive protein were determined by enzyme-linked immunosorbent assay, and radioactivity was quantitated by beta and gamma scintigraphy. The serum pharmacokinetics of labeled and unlabeled rHuTNF were identical when administered by the intravenous route. After intravenous doses of 165 to 320 micrograms/kg, the clearance was 2.9-3.6 ml/hr, the initial volume of distribution was 1.4-1.6 ml (70-80 ml/kg), and the half-life was 18.5-19.2 min. Intramuscular administration of 320 micrograms/kg resulted in a peak serum concentration of 112 ng/ml. The time of the peak concentration was 1 hr, and the bioavailability of the intramuscular dose was 12%. The data suggest that the disposition of this protein may be biexponential. If this is the case, the terminal phase would appear to account for less than 1% of the total AUC. Since serum concentrations in the terminal phase are at the sensitivity limit of the assay, a single half-life is reported. 125I-Labeled and metabolically labeled 3H-rHuTNF were used to examine tissue distribution. After intravenous 125I-rHuTNF administration, the rank order of accumulation of the 125I-radiolabel in the major organs (per cent dose per organ over 1440 min) was: liver greater than kidney greater than lung greater than heart greater than spleen. This rank order of accumulation was confirmed by intravenous 3H-rHuTNF administration

  17. Tumor necrosis factor-alpha is a potential diagnostic biomarker for chronic neuropathic pain after spinal cord injury.

    Science.gov (United States)

    Xu, Jun; E, Xiaoqiang; Liu, Huiyong; Li, Feng; Cao, Yanhui; Tian, Jun; Yan, Jinglong

    2015-05-19

    Neuropathic pain (NP) is one of the most common complications after spinal cord injury (SCI), but no protein biomarkers has ever been introduced into clinical diagnosis. Previous studies implicated that toll-like receptor (TLR) 4 played a critical role in the development of NP in animal SCI models. Here, a total of 140 participants were recruited, 70 of them were SCI-NP subject and the rest 70 controls did not show neuropathic symptoms. TLR4 was upregulated significantly in SCI-NP patients compared with SCI-noNP subjects. Furthermore, we measured the concentrations of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), two TLR4 downstream pro-inflammatory cytokines, to assess their diagnostic values. Receiver operating characteristics (ROC) analysis revealed that TNF-α had great potential advantages to predict the progression of neuropathy, the risks of NP were strongly increased in SCI subjects with higher levels of TNF-α (odds ratio: 4.92; 95% confidence interval: 1.89-12.32). These results suggested neuro-immune activation contributed to the development of neuropathic disorder after SCI, and TNF-α could be a potential sensitive diagnostic biomarker for chronic neuropathic pain in SCI patients. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  18. Tumour necrosis factor-alpha contributes to improved cardiac ischaemic tolerance in rats adapted to chronic continuous hypoxia

    Czech Academy of Sciences Publication Activity Database

    Chytilová, Anna; Borchert, Gudrun H.; Mandíková-Alánová, Petra; Hlaváčková, Markéta; Kopkan, L.; Khan, M. A. H.; Imig, J. D.; Kolář, František; Neckář, Jan

    2015-01-01

    Roč. 241, č. 1 (2015), s. 97-108 ISSN 1748-1708 R&D Projects: GA ČR(CZ) GA13-10267S; GA ČR(CZ) GAP303/12/1162 Institutional support: RVO:67985823 Keywords : chronic hypoxia * ischaemia/reperfusion injury * reactive oxygen species * tumor necrosis factor - alpha Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 4.066, year: 2015

  19. Elevated levels of plasma tumor necrosis factor alpha in patients with pseudoexfoliation glaucoma

    Directory of Open Access Journals (Sweden)

    Kondkar AA

    2018-01-01

    Full Text Available Altaf A Kondkar,1 Taif A Azad,1 Faisal A Almobarak,1 Hatem Kalantan,1 Saleh A Al-Obeidan,1 Khaled K Abu-Amero1,2 1Glaucoma Research Chair, Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia; 2Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA Background: Tumor necrosis factor alpha (TNF-α is a pro-inflammatory cytokine, which plays a role in glaucomatous neurodegeneration. Based on the plausible role of inflammation in the pathogenesis of pseudoexfoliation glaucoma (PEG, we investigated whether there is any relationship between the levels of plasma TNF-α and PEG or any of its clinical indices in comparison to normal controls.Methods: The study was designed as a retrospective analysis. Plasma samples from 49 PEG patients and 88 non-glaucomatous controls were evaluated for TNF-α levels using an enzyme-linked immunosorbent assay (ELISA. The assay was performed in duplicates on a biochemical/ELISA analyzer.Results: The two study groups were similar in age, sex and systemic disease distribution. The mean TNF-α concentration was significantly higher in the PEG patients (5.54±4.58 pg/mL than in the control subjects (0.93±1.49 pg/mL; 95% confidence interval [CI] =3.50–5.72; p=0.000. The overall dose–response trend was significant (χ2=57.07, df=2; p=0.000. A moderate positive and significant correlation was seen between TNF-α level and cup/disc ratio, an important clinical index for PEG. Besides, binary logistic regression analysis showed that the risk of PEG was most significantly affected by TNF-α level as compared to no association with age and sex. In receiver operating characteristic analysis, the area under the curve was 0.777 (95% CI =0.682–0.872 and statistically significant (p=0.000.Conclusion: Elevated systemic levels of inflammatory marker, TNF-α, are associated with PEG and may possibly serve as a biomarker for undiagnosed early

  20. Tumor necrosis factor alpha rs1800629 polymorphism and risk of cervical lesions: a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Min Li

    Full Text Available BACKGROUND: Tumor necrosis factor- alpha (TNF-α is an inflammatory cytokine which may play important role on the immune response may control the progression of cervical lesions. There is a possible association between TNF-α rs1800629 G/A polymorphism and cervical lesions, but previous studies report conflicting results. We performed a meta-analysis to comprehensively assess the association between TNF-α rs1800629 polymorphism and cervical lesions risk. METHODS: Literature searches of Pubmed, Embase, Web of Science, and Wanfang databases were performed for all publications on the association between TNF-α rs1800629 polymorphism and cervical lesions through December 15, 2012. The pooled odds ratios (ORs with their 95% confidence interval (95%CIs were calculated to assess the strength of the association. RESULTS: Twenty individual case-control studies from 19 publications with a total of 4,146 cases and 4,731 controls were finally included into the meta-analysis. Overall, TNF-α rs1800629 polymorphism was significantly associated with increased risk of cervical lesions under two main genetic comparison models (For A versus G: OR 1.22, 95%CI 1.04-1.44, P = 0.017; for AA versus GG: OR 1.32, 95%CI 1.02-1.71, P = 0.034. Subgroup analysis by ethnicity further showed that there was a significant association between TNF-α rs1800629 polymorphism and increased risk of cervical lesions in Caucasians but not in Asians. Subgroup analysis by the types of cervical lesions showed that there was a significant association between TNF-α rs1800629 polymorphism and increased risk of cervical cancer (For A versus G: OR 1.24, 95%CI 1.05-1.47, P = 0.011; for AA versus GG: OR 1.31, 95%CI 1.01-1.70, P = 0.043; for AA/GA versus GG: OR 1.25, 95%CI 1.01-1.54, P = 0.039. CONCLUSION: The meta-analysis suggests that TNF-α rs1800629 polymorphism is associated with increased risk of cervical lesions, especially in Caucasians.

  1. Quality and completeness of utilisation data on biological agents across European countries: tumour necrosis factor alpha inhibitors as a case study.

    NARCIS (Netherlands)

    Hoebert, J.M.; Mantel-Teeuwisse, A.K.; Dijk, L. van; Laing, R.O.; Leufkens, H.G.M.

    2011-01-01

    PURPOSE: For optimal decision making on access to and regulations around biologicals availability of national utilisation data is a prerequisite. This study characterises the main categories of critical issues in collecting available national utilisation data on tumour necrosis factor alpha

  2. Association between hepatocellular carcinoma and tumor necrosis factor alpha polymorphisms in South Korea.

    Science.gov (United States)

    Shin, Suk Pyo; Kim, Nam Keun; Kim, Ju Hwan; Lee, Ju Ho; Kim, Jung Oh; Cho, Sung Hwan; Park, Hana; Kim, Mi Na; Rim, Kyu Sung; Hwang, Seong Gyu

    2015-12-14

    To investigate associations between the tumor necrosis factor alpha (TNF-α) -1031 T>C, -863 C>A, -857 C>T, -308 G>A, and -238 G>A polymorphisms and HCC in Korea. Hepatocellular carcinoma (HCC) cases were diagnosed at CHA Bundang Medical Center from June 1996 to August 2008. The association between TNF-α polymorphisms and HCC was analyzed in 157 HCC patients and 201 controls using a polymerase chain reaction-restriction fragment length polymorphism assay. We investigated five TNF-α polymorphisms, which are TNF-α -1031 T>C, -863 C>A, -857 C>T, -308 G>A, and -238 G>A. The TNF-α genotype frequencies, genotype combinations and haplotypes were analyzed to disclose the association with HCC. None of the TNF-α polymorphisms was significantly associated with HCC. However, nine genotype combinations had associations with increased likelihood of HCC. Among them, TNF-α -1031/-857/-238 TT/CC/GA (AOR = 18.849, 95%CI: 2.203-161.246, P = 0.007), TNF-α -1031/-308/-238 TT/GG/GA (AOR = 26.956, 95%CI: 3.071-236.584, P = 0.003), and TNF-α -1031/-238 TT/GA (AOR = 21.576, 95%CI: 2.581-180.394, P = 0.005) showed marked association with HCC. There were five haplotypes of TNF-α polymorphisms which were significantly associated with HCC. They are TNF-α -1031/-863/-857/-308/-238 T-C-C-G-A (OR = 25.824, 95%CI: 1.491-447.223, P = 0.0005), TNF-α -1031/-857/-308/-238 T-C-G-A (OR = 12.059, 95%CI: 2.747-52.950, P < 0.0001), TNF-α -1031/-857/-238 T-C-A (OR = 10.696, 95%CI: 2.428-47.110, P = 0.0001), TNF-α -1031/-308/-238 T-G-A (OR = 7.556, 95%CI: 2.173-26.280, P = 0.0002) and TNF-α -1031/-238 T-A (OR = 10.865, 95%CI: 2.473-47.740, P = 0.0001). Moreover, HCC Okuda stage III cases with the TNF-α -1031 CC genotype had better survival than those with the TT genotype (AOR = 5.795, 95%CI: 1.145-29.323). Although no single TNF-α polymorphism is associated with HCC in this study, some TNF-α genotype combinations and haplotypes are associated with HCC. In addition, HCC Okuda stage III cases

  3. 2000 Volvo Award winner in basic science studies: Exogenous tumor necrosis factor-alpha mimics nucleus pulposus-induced neuropathology. Molecular, histologic, and behavioral comparisons in rats.

    Science.gov (United States)

    Igarashi, T; Kikuchi, S; Shubayev, V; Myers, R R

    2000-12-01

    This study tested the hypothesis that the 17-kDa form of tumor necrosis factor-alpha is the pathophysiologic agent expressed by herniated nucleus pulposus in vivo that is primarily responsible for the histologic and behavioral manifestations of experimental sciatica associated with herniated lumbar discs. The authors determined the molecular weight and concentration of active tumor necrosis factor-alpha in rat herniated disc and used exogenous tumor necrosis factor-alpha at the same molecular weight to study its neuropathologic effect on rat nerve root and dorsal root ganglion preparations in vivo. Expressed by herniated nucleus pulposus in culture, tumor necrosis factor-alpha causes neuropathologic injury in nerve roots and neuropathic pain states in which mechanical allodynia is seen in response to peripheral stimuli. Western blotting was used to identify the molecular weight of the operative tumor necrosis factor-alpha protein form, and measures of optical density were used for semiquantitative determination of concentration. Plastic-embedded nerve roots and dorsal root ganglion were used for neuropathologic evaluation, and von Frey stimulation was used to quantify mechanical allodynia. The 17-kDa form of tumor necrosis factor-alpha is expressed by herniated nucleus pulposus at a concentration of approximately 0.48 ng per herniated rat lumbar disc. Exogenous tumor necrosis factor-alpha applied in vivo to rat nerve roots produced neuropathologic changes and behavior deficits that mimicked experimental studies with herniated nucleus pulposus applied to nerve roots. The data reinforce other evidence that tumor necrosis factor-alpha is involved in mechanisms of neuropathic pain.

  4. Impact of tobacco smoking on response to tumour necrosis factor-alpha inhibitor treatment in patients with ankylosing spondylitis

    DEFF Research Database (Denmark)

    Glintborg, Bente; Højgaard, Pil; Lund Hetland, Merete

    2016-01-01

    OBJECTIVES: To investigate the association between tobacco smoking and disease activity, treatment adherence and treatment responses in patients with AS treated with their first tumour necrosis factor-alpha inhibitor (TNFi) therapy in routine care. METHODS: Observational cohort study based...... AS patients included in the study, 1425(90%) had known smoking status (current/never/previous: 43%/41%/16%). The median follow-up time was 2.02 years (IQR 0.69-5.01). At baseline, current smokers compared with never smokers had longer disease duration (4 years (1-12)/2 years (0-10)), higher BASDAI (61 mm (47...

  5. Eugenol reduces acute pain in mice by modulating the glutamatergic and tumor necrosis factor alpha (TNF-α) pathways.

    Science.gov (United States)

    Dal Bó, Wladmir; Luiz, Ana Paula; Martins, Daniel F; Mazzardo-Martins, Leidiane; Santos, Adair R S

    2013-10-01

    Eugenol is utilized together with zinc oxide in odontological clinical for the cementation of temporary prostheses and the temporary restoration of teeth and cavities. This work explored the antinociceptive effects of the eugenol in different models of acute pain in mice and investigated its possible modulation of the inhibitory (opioid) and excitatory (glutamatergic and pro-inflammatory cytokines) pathways of nociceptive signaling. The administration of eugenol (3-300 mg/kg, p.o., 60 min or i.p., 30 min) inhibited 82 ± 10% and 90 ± 6% of the acetic acid-induced nociception, with ID₅₀ values of 51.3 and 50.2 mg/kg, respectively. In the glutamate test, eugenol (0.3-100 mg/kg, i.p.) reduced the response behavior by 62 ± 5% with an ID₅₀ of 5.6 mg/kg. In addition, the antinociceptive effect of eugenol (10 mg/kg, i.p.) in the glutamate test was prevented by the i.p. treatment for mice with naloxone. The pretreatment of mice with eugenol (10 mg/kg, i.p.) was able to inhibit the nociception induced by the intrathecal (i.t.) injection of glutamate (37 ± 9%), kainic (acid kainite) (41 ± 12%), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) (55 ± 5%), and substance P (SP) (39 ± 8%). Furthermore, eugenol (10 mg/kg, i.p.) also inhibited biting induced by tumor necrosis factor alpha (TNF-α, 65 ± 8%). These results extend our current knowledge of eugenol and confirm that it promotes significant antinociception against different mouse models of acute pain. The mechanism of action appears to involve the modulation of the opioid system and glutamatergic receptors (i.e., kainate and AMPA), and the inhibition of TNF-α. Thus, eugenol could represent an important compound in the treatment for acute pain. © 2012 The Authors Fundamental and Clinical Pharmacology © 2012 Société Française de Pharmacologie et de Thérapeutique.

  6. IgE-mediated basophil tumour necrosis factor alpha induces matrix metalloproteinase-9 from monocytes

    DEFF Research Database (Denmark)

    Falkencrone, Sidsel; Poulsen, Lars K.; Bindslev-Jensen, Carsten

    2013-01-01

    IgE-mediated activation of mast cells has been reported to induce the release of tumour necrosis alpha (TNF-α), which may display autocrine effects on these cells by inducing the generation of the tissue remodelling protease matrix metalloproteinase-9 (MMP-9). While mast cells and basophils have...

  7. Metabolic and vascular effects of tumor necrosis factor-alpha blockade with etanercept in obese patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Dominguez, Helena; Storgaard, Heidi; Rask-Madsen, Christian

    2005-01-01

    OBJECTIVE: The pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) impairs insulin action in insulin-sensitive tissues, such as fat, muscle and endothelium, and causes endothelial dysfunction. We hypothesized that TNF-alpha blockade with etanercept could reverse vascular and metabolic...... insulin resistance. METHOD AND RESULTS: Twenty obese patients with type 2 diabetes were randomized to etanercept treatment (25 mg subcutaneously twice weekly for 4 weeks) or used as controls in an open parallel study. Forearm blood flow and glucose uptake were measured during intra-arterial infusions...... of serotonin, sodium nitroprusside and insulin co-infused with serotonin. Beta-cell function was assessed with oral and intra-venous glucose tolerance tests and whole-body insulin sensitivity by hyperinsulinemic euglycemic clamps. Plasma levels of C-reactive protein and interleukin-6 decreased significantly...

  8. Individual medicine in inflammatory bowel disease: monitoring bioavailability, pharmacokinetics and immunogenicity of anti-tumour necrosis factor-alpha antibodies

    DEFF Research Database (Denmark)

    Bendtzen, Klaus; Ainsworth, Mark; Steenholdt, Casper

    2009-01-01

    Antibody constructs targeting tumour necrosis factor-alpha (TNF) have become important in the management of several chronic immunoinflammatory diseases. Four recombinant anti-TNF drugs are currently approved for clinical use in patients with various chronic inflammatory diseases, three of which...... are effective in chronic inflammatory bowel disease. These proteins can dramatically lower disease activity and, in some patients, induce remission. Unfortunately, however, not all patients respond favourably to anti-TNF antibodies. For example, patients suffering from Crohn's disease do not benefit from...... for circulating levels of functional anti-TNF drugs and ADAs is therefore warranted so that treatment can be tailored to the individual patient (individual medicine or personal medicine) in order that effective and economical long-term therapy can be given with minimal risks to the patients....

  9. Salivary and serum interleukin 1 beta, interleukin 6 and tumor necrosis factor alpha in patients with leukoplakia and oral cancer.

    Science.gov (United States)

    Brailo, Vlaho; Vucicevic-Boras, Vanja; Lukac, Josip; Biocina-Lukenda, Dolores; Zilic-Alajbeg, Iva; Milenovic, Aleksandar; Balija, Melita

    2012-01-01

    The aim of study was to compare salivary and serum concentrations of interleukin 1 beta (IL-1β), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) in patients with oral leukoplakia, oral cancer and healthy controls. Eighty eight patients (28 with oral cancer, 29 leukoplakia, and 31 healthy controls) were included in this study. Cytokine concentrations were measured by commercial enzyme linked immunoassay. Salivary IL-1β and IL-6 were significantly higher in oral cancer patients than in patients with leukoplakia and control group (pcancer patients. Patients with oral cancer have elevated levels of inflammatory cytokines in their saliva. Whether this elevation can be used for monitoring the malignant transformation of oral leukoplakia remains to be answered by further follow up studies.

  10. Increased plasma levels of tumor necrosis factor-alpha in asymptomatic/"indeterminate" and Chagas disease cardiomyopathy patients

    Directory of Open Access Journals (Sweden)

    Renata Cristina Ferreira

    2003-04-01

    Full Text Available We compared plasma tumor necrosis factor-alpha (TNF-alpha levels among asymptomatic/"indeterminate" Chagas disease patients (ASY and patients across the clinical spectrum of chronic Chagas disease cardiomyopathy (CCC. Idiopathic dilated cardiomyopathy (DCM patients and normal controls (NC were included as controls. ASY Chagas disease patients had significantly higher plasma TNF-alpha levels than NC. TNF-alpha levels among severe CCC patients with significant left ventricular (LV dysfunction were similar to those of DCM patients, showing average 2-fold higher levels than CCC patients without LV dysfunction and ASY patients, and 8-fold higher levels than NC. In Chagas disease, chronic TNF-a production prior to heart failure may play a role in CCC progression.

  11. Salivary and serum interleukin 1 beta, interleukin 6 and tumor necrosis factor alpha in patients with leukoplakia and oral cancer

    Science.gov (United States)

    Vucicevic-Boras, Vanja; Lukac, Josip; Biocina-Lukenda, Dolores; Zilic-Alajbeg, Iva; Milenovic, Aleksandar; Balija, Melita

    2012-01-01

    Objectives: The aim of study was to compare salivary and serum concentrations of interleukin 1 beta (IL-1β), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) in patients with oral leukoplakia, oral cancer and healthy controls. Study design: Eighty eight patients (28 with oral cancer, 29 leukoplakia, and 31 healthy controls) were included in this study. Cytokine concentrations were measured by commercial enzyme linked immunoassay. Results: Salivary IL-1β and IL-6 were significantly higher in oral cancer patients than in patients with leukoplakia and control group (poral cancer patients. Conclusions: Patients with oral cancer have elevated levels of inflammatory cytokines in their saliva. Whether this elevation can be used for monitoring the malignant transformation of oral leukoplakia remains to be answered by further follow up studies. Key words: Cytokines, oral, leukoplakia, cancer. PMID:21743397

  12. Characterization of a canine tetranucleotide microsatellite marker located in the first intron of the tumor necrosis factor alpha gene.

    Science.gov (United States)

    Watanabe, Masashi; Tanaka, Kazuaki; Takizawa, Tatsuya; Segawa, Kazuhito; Neo, Sakurako; Tsuchiya, Ryo; Murata, Michiko; Murakami, Masaru; Hisasue, Masaharu

    2014-01-01

    A polymorphic tetranucleotide (GAAT)n microsatellite in the first intron of the canine tumor necrosis factor alpha (TNFA) gene was characterized in this study; 139 dogs were analyzed: 22 Beagles, 26 Chihuahuas, 20 Miniature Dachshunds, 24 Miniature Poodles, 22 Pembroke Welsh Corgis and 25 Shiba Inus. We detected the presence of the 4 alleles (GAAT)5, (GAAT)6, (GAAT)7 and (GAAT)8, including 9 of the 10 expected genotypes. The expected heterozygosity (He) and the polymorphic information content (PIC) value of this microsatellite locus varied from 0.389 to 0.749 and from 0.333 to 0.682, respectively, among the 6 breeds. The allelic frequency differed greatly among breeds, but this microsatellite marker was highly polymorphic and could be a useful marker for the canine TNFA gene.

  13. Transcutaneous cervical vagal nerve stimulation modulates cardiac vagal tone and tumor necrosis factor-alpha.

    Science.gov (United States)

    Brock, C; Brock, B; Aziz, Q; Møller, H J; Pfeiffer Jensen, M; Drewes, A M; Farmer, A D

    2017-05-01

    The vagus nerve is a central component of cholinergic anti-inflammatory pathways. We sought to evaluate the effect of bilateral transcutaneous cervical vagal nerve stimulation (t-VNS) on validated parameters of autonomic tone and cytokines in 20 healthy subjects. 24 hours after t-VNS, there was an increase in cardiac vagal tone and a reduction in tumor necrosis factor-α in comparison to baseline. No change was seen in blood pressure, cardiac sympathetic index or other cytokines. These preliminary data suggest that t-VNS exerts an autonomic and a subtle antitumor necrosis factor-α effect, which warrants further evaluation in larger controlled studies. © 2016 John Wiley & Sons Ltd.

  14. Endogenous endophthalmitis in a rheumatoid patient on tumor necrosis factor alpha blocker

    Directory of Open Access Journals (Sweden)

    Agarwal Pankaj

    2007-01-01

    Full Text Available The development of anti-tumor necrosis factor (TNF therapies is a milestone in the therapy of rheumatic diseases. It is of concern whether all potential undesired complications of therapy have been evaluated within clinical trials which have led to treatment approval. Specialists prescribing TNF blockers should be aware of the unusual and severe complications that can occur. We describe a case of endogenous endophthalmitis in a rheumatoid patient on TNF alpha blocker.

  15. Systemic lupus erythematosus induced by anti-tumour necrosis factor alpha therapy: a French national survey

    OpenAIRE

    De Bandt, Michel; Sibilia, Jean; Le Lo?t, Xavier; Prouzeau, Sebastian; Fautrel, Bruno; Marcelli, Christian; Boucquillard, Eric; Siame, Jean Louis; Mariette, Xavier; ,

    2005-01-01

    The development of drug-induced lupus remains a matter of concern in patients treated with anti-tumour necrosis factor (TNF) alpha. The incidence of such adverse effects is unknown. We undertook a retrospective national study to analyse such patients. Between June and October 2003, 866 rheumatology and internal medicine practitioners from all French hospital centres prescribing anti-TNF in rheumatic diseases registered on the website of the 'Club Rhumatismes et Inflammation' were contacted by...

  16. Suppression of interleukin-1[beta] and tumour necrosis factor-[alpha] biosynthesis by cadmium in in vitro activated human peripheral blood mononuclear cells

    Energy Technology Data Exchange (ETDEWEB)

    Theocharis, S.E. (Dept. of Experimental Pharmacology, School of Medicine, Univ. of Athens (Greece) First Dept. of Internal Medicine, School of Medicine, Univ. of Athens, Laikon Hospital (Greece)); Panayiotidis, P.G. (First Dept. of Internal Medicine, School of Medicine, Univ. of Athens, Laikon Hospital (Greece)); Souliotis, V.L. (National Hellenic Research Foundation, Inst. of Biological Research and Biotechnology, Athens (Greece))

    1994-12-01

    Cadmium is a highly toxic element responsible for acute and chronic toxicity in man. There is evidence that cadmium induces pathophysiological effects by modulating components of the immune system. Cytokines are being increasingly recognized as essential mediators of normal and pathologic immune responses. Cadmium at concentrations varying from 1.0x10[sup -4] to 3.3x10[sup -6] M inhibited the phytohemagglutinin induced production of interleukin-1[beta] and tumour necrosis factor-[alpha], in in vitro activated human peripheral blood mononuclear cells. The messenger RNA levels of interleukin-1[beta] and tumour necrosis factor-[alpha] were examined during a 24-h culture period, at different time points. The decreased messenger RNA levels at the time points of the maximum expression of interleukin-1[beta] and tumour necrosis factor-[alpha] indicate that cadmium suppresses their production at the transcriptional level. (orig.)

  17. Alopecia secondary to anti-tumor necrosis factor-alpha therapy*

    Science.gov (United States)

    Ribeiro, Lara Beatriz Prata; Rego, Juliana Carlos Gonçalves; Estrada, Bruna Duque; Bastos, Paula Raso; Piñeiro Maceira, Juan Manuel; Sodré, Celso Tavares

    2015-01-01

    Biologic drugs represent a substantial progress in the treatment of chronic inflammatory immunologic diseases. However, its crescent use has revealed seldom reported or unknown adverse reactions, mainly associated with anti-tumor necrosis factor (anti-TNF). Psoriasiform cutaneous reactions and few cases of alopecia can occur in some patients while taking these drugs. Two cases of alopecia were reported after anti-TNF therapy. Both also developed psoriasiform lesions on the body. This is the second report about a new entity described as 'anti-TNF therapy-related alopecia', which combines clinical and histopathological features of both alopecia areata and psoriatic alopecia. The recognition of these effects by specialists is essential for the proper management and guidance of these patients. PMID:25830994

  18. Tumor necrosis factor-alpha antagonism improves vasodilation during hyperinsulinemia in metabolic syndrome.

    Science.gov (United States)

    Tesauro, Manfredi; Schinzari, Francesca; Rovella, Valentina; Melina, Domenico; Mores, Nadia; Barini, Angela; Mettimano, Marco; Lauro, Davide; Iantorno, Micaela; Quon, Michael J; Cardillo, Carmine

    2008-07-01

    Obesity is associated with chronic inflammation due to overproduction of proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha. We assessed the effects of TNF-alpha neutralization by infliximab on vascular reactivity during hyperinsulinemia in obesity-related metabolic syndrome. Vascular responses to intra-arterial infusion of acetylcholine (ACh) and sodium nitroprusside (SNP) were assessed in patients with metabolic syndrome, before and after administration of infliximab. Patients had blunted vasodilator responses to ACh and SNP during hyperinsulinemia compared with control subjects; a potentiation of the responsiveness to both ACh and SNP, however, was observed in patients following infliximab. The antioxidant vitamin C improved the vasodilator response to ACh in patients with metabolic syndrome, but its effect was not further enhanced by concurrent administration of infliximab. TNF-alpha neutralization ameliorates vascular reactivity in metabolic syndrome during hyperinsulinemia, likely in relation to decreased oxidative stress, thereby suggesting an involvement of inflammatory cytokines in vascular dysfunction of these patients.

  19. Tumor necrosis factor-alpha inhibition and VATER association: a causal relationship.

    Science.gov (United States)

    Carter, John D; Valeriano, Joanne; Vasey, Frank B

    2006-05-01

    Inflammatory conditions that may require the use of a tumor necrosis factor-a (TNF-a) antagonist often involve women of child-bearing age. TNF-a antagonists are presumed to be safe in pregnancy based on animal data. However, this has never been formally studied in prospective trials involving humans. We describe a patient with psoriasis and psoriatic arthritis who took etanercept 50 mg subcutaneously (SQ) twice weekly throughout her pregnancy. She gave birth to a child with VATER association. Animal and human data exist to suggest a possible causal relationship between the mother's use of etanercept and the child's development of VATER association. We propose that the TNF antagonists, specifically etanercept, be used with caution in pregnant women. Patient registries of women who take TNF-a antagonists during pregnancy also need to be followed to see if there is an increase in the birth defects that are part of VATER association.

  20. Immunomagnetic separation of tumor necrosis factor alpha. II. In situ procedure for the human gingival space.

    Science.gov (United States)

    Rossomando, E F; White, L B; Hadjimichael, J

    1992-11-27

    An in situ procedure has been developed for the separation of tumor necrosis factor (TNF) alpha directly from the fluid in the human gingival space. Paramagnetic beads coated with anti-TNF monoclonal antibodies were introduced into the gingival space of the subject with a polypropylene-tipped calibrated delivery system and retrieved using a permanent magnet designed to fit into the space. After retrieval, the amount of immunoadsorbed TNF was quantified using an immunochemical assay called the "cluster assay". The results indicate that following the appropriate preparation of the site, over 95% of the beads could be recovered. With this method we found that 62% of those cavities sampled contained TNF and that the values ranged from 0.10 to 13.0 ng/ml with a mean value of 1.7 ng/ml. A comparison of these values with those obtained from the same space using other methods suggests that the immunomagnetic method was more effective in retrieval of TNF. Because the separation is performed in situ we have named the procedure "chromatobiosis".

  1. Activated astrocytes induce nitric oxide synthase-2 in cerebral endothelium via tumor necrosis factor alpha.

    Science.gov (United States)

    Shafer, R A; Murphy, S

    1997-12-01

    Astrocytes under pathological conditions become activated and produce a variety of cytokines and low molecular weight signal molecules. Previously we demonstrated that activated astrocytes release nitric oxide which can downregulate the expression of nitric oxide synthase (NOS)-2 in co-cultured cerebral endothelium, and also release a transcriptionally regulated factor that can induce NOS-2 expression in endothelium (Borgerding and Murphy: J Neurochem 65:1342, 1995). The activity of this NOS-2-inducing factor was impeded by inhibitors of tyrosine kinases and NF-kappaB activation. Tumor necrosis factor (TNF alpha) alone, or in combination with IL-6, induced NOS-2 expression in endothelial cells. A neutralizing antibody against TNF alpha attenuated the NOS-2 expression in endothelial cells exposed to activated astrocytes. These results imply that cytokine-activated astrocytes release TNF alpha which can induce NOS-2 expression in endothelium and suggest that activated astrocytes within the CNS may induce expression of NOS-2 in cells of the adjacent microvasculature. The ensuing alterations in blood-brain barrier properties may be either beneficial or detrimental.

  2. PROGNOSTIC VALUE OF TUMOR NECROSIS FACTOR-ALPHA IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    E. N. Zotina

    2016-01-01

    Full Text Available The prognostic value of tumor necrosis factor-alfa (TNFα, a pro-inflammatory cytokine was studied in 140 patients with a newly diagnosed chronic lymphocytic leukemia (CLL. TNFα contents in blood serum was determined using ELISA method. A significant increase of serum TNFα was shown in patients with newly diagnosed CLL, as compared to healthy individuals. Dependence of the cytokine concentration on clnical stage and course of disease was revealed: the highest levels of serum TNFα were registered in patients with advanced disease and/or CLL progression. Distinct correlations were revealed between the studied cytokine amounts and clinical laboratory parameters reflecting the cell proliferative activity and tumor clone size. Immunochemotherapy was accompanied by a significant reduction of TNFα levels. According to the data from multivariate regression analysis. TNFα level of at the time of the diagnosis was an independent predictor of overall survival. Hence, TNFα plays an important role in CLL pathogenesis and may be used as an additional predictive factor for CLL outcomes.

  3. Tumor necrosis factor alpha inhibits in vitro bovine embryo development through a prostaglandin mediated mechanism

    Directory of Open Access Journals (Sweden)

    Jackson Lauren R

    2012-03-01

    Full Text Available Abstract Mastitis or other infectious diseases have been related to reduced fertility in cattle. Inflammatory cytokines such as tumor necrosis factor α (TNFα are released in response to infection and may have negative effects on embryo development. In the current study the effect of exposure to TNFα on the development of in vitro fertilized bovine embryos was examined. Indomethacin, a prostaglandin synthesis inhibitor, was used to determine if blockade of prostaglandin synthesis would alter the effects of TNFα. Ovaries were obtained from a local abattoir and immature COC were isolated from 2-10 mm follicles, in vitro matured and fertilized. After fertilization, groups of presumptive zygotes were randomly placed into either control development medium, medium containing 25 ng/mL TNFα or medium containing 25 ng/mL TNFα plus 1 μg/mL indomethacin. The proportion of blastocysts formed was assessed at day 7 of culture. Fewer embryos exposed to TNFα alone reached the blastocyst stage (17.5 ± 2.4%, P

  4. Erythropoietin protects myocardin-expressing cardiac stem cells against cytotoxicity of tumor necrosis factor-{alpha}

    Energy Technology Data Exchange (ETDEWEB)

    Madonna, Rosalinda [The Center for Cardiovascular Biology and Atherosclerosis Research, The University of Texas Health Science Center at Houston, Texas (United States); Institute of Cardiology, and Center of Excellence on Aging, ' G. d' Annunzio' University, Chieti (Italy); Shelat, Harnath; Xue, Qun; Willerson, James T. [The Center for Cardiovascular Biology and Atherosclerosis Research, The University of Texas Health Science Center at Houston, Texas (United States); The Texas Heart Institute at St. Luke' s Episcopal Hospital, Houston, Texas (United States); De Caterina, Raffaele [Institute of Cardiology, and Center of Excellence on Aging, ' G. d' Annunzio' University, Chieti (Italy); Geng, Yong-Jian, E-mail: yong-jian.geng@uth.tmc.edu [The Center for Cardiovascular Biology and Atherosclerosis Research, The University of Texas Health Science Center at Houston, Texas (United States); The Texas Heart Institute at St. Luke' s Episcopal Hospital, Houston, Texas (United States)

    2009-10-15

    Cardiac stem cells are vulnerable to inflammation caused by infarction or ischemic injury. The growth factor, erythropoietin (Epo), ameliorates the inflammatory response of the myocardium to ischemic injury. This study was designed to assess the role of Epo in regulation of expression and activation of the cell death-associated intracellular signaling components in cardiac myoblasts stimulated with the proinflammatory cytokine tumor necrosis factor (TNF)-{alpha}. Cardiac myoblasts isolated from canine embryonic hearts characterized by expression of myocardin A, a promyogenic transcription factor for cardiovascular muscle development were pretreated with Epo and then exposed to TNF-{alpha}. Compared to untreated cells, the Epo-treated cardiac myoblasts exhibited better morphology and viability. Immunoblotting revealed lower levels of active caspase-3 and reductions in iNOS expression and NO production in Epo-treated cells. Furthermore, Epo pretreatment reduced nuclear translocation of NF-{kappa}B and inhibited phosphorylation of inhibitor of kappa B (I{kappa}B) in TNF-{alpha}-stimulated cardiac myoblasts. Thus, Epo protects cardiac myocyte progenitors or myoblasts against the cytotoxic effects of TNF-{alpha} by inhibiting NF-{kappa}B-mediated iNOS expression and NO production and by preventing caspase-3 activation.

  5. Isolated limb perfusion with tumor necrosis factor alpha and melphalan for locally advanced soft tissue sarcoma : Three time periods at risk for amputation

    NARCIS (Netherlands)

    van Ginkel, Robert J.; Thijssens, Katja M. J.; Pras, Elisabeth; van der Graaf, Winette T. A.; Suurmeijer, Albert J. H.; Hoekstra, Harald J.

    Background: The aim of this study was to investigate the long-term limb salvage rate and overall survival after isolated limb perfusion (ILP) with tumor necrosis factor alpha and melphalan for locally advanced soft tissue sarcoma (STS). Methods: From 1991 to 2003, 73 patients (36 men, 37 women,

  6. Isolated limb perfusion with tumor necrosis factor alpha and melphalan for locally advanced soft tissue sarcoma: three time periods at risk for amputation.

    NARCIS (Netherlands)

    Ginkel, R.J. van; Thijssens, K.M.; Pras, E.; Graaf, W.T.A. van der; Suurmeijer, A.J.H.; Hoekstra, H.J.

    2007-01-01

    BACKGROUND: The aim of this study was to investigate the long-term limb salvage rate and overall survival after isolated limb perfusion (ILP) with tumor necrosis factor alpha and melphalan for locally advanced soft tissue sarcoma (STS). METHODS: From 1991 to 2003, 73 patients (36 men, 37 women,

  7. Value of continuous leakage monitoring with radioactive iodine-131-labeled human serum albumin during hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan

    NARCIS (Netherlands)

    van Ginkel, RJ; Limburg, PC; Piers, DA; Hoekstra, HJ; Schraffordt Koops, H.

    Background: The aim of this study was to analyze the value of continuous leakage monitoring with radioactive iodine-131-labeled human serum albumin (RISA) in patients treated with hyperthermic isolated limb perfusion with tumor necrosis factor-alpha (TNFalpha) and melphalan. Methods: Forty-eight

  8. Combined cytotoxic effects of tumor necrosis factor-alpha with various cytotoxic agents in tumor cell lines that are drug resistant due to mutated p53

    NARCIS (Netherlands)

    Sleijfer, S; Le, T. K. P.; de Jong, S.; Timmer-Bosscha, H; Withoff, S; Mulder, NH

    Several studies suggest that tumor necrosis factor-alpha (TNF) is able to overcome drug resistance in tumors. Whether TNF is able to do so in tumor cell lines that are drug resistant due to a mutation in the tumor suppressor gene p53 is unclear. Therefore, we studied the in vitro cytotoxic effects

  9. Tumor necrosis factor alpha is associated with insulin-mediated suppression of free fatty acids and net lipid oxidation in HIV-infected patients with lipodystrophy

    DEFF Research Database (Denmark)

    Haugaard, Steen B; Andersen, Ove; Pedersen, SB

    2006-01-01

    Tumor necrosis factor alpha (TNF-alpha) stimulates lipolysis in man. We examined whether plasma TNF-alpha is associated with the degree by which insulin suppresses markers of lipolysis, for example, plasma free fatty acid (FFA) and net lipid oxidation (LIPOX) rate in HIV-infected patients...

  10. Modulator effects of interleukin-1beta and tumor necrosis factor-alpha on AMPA-induced excitotoxicity in mouse organotypic hippocampal slice cultures

    DEFF Research Database (Denmark)

    Bernardino, Liliana; Xapelli, Sara; Silva, Ana P

    2005-01-01

    The inflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha (TNF-alpha) have been identified as mediators of several forms of neurodegeneration in the brain. However, they can produce either deleterious or beneficial effects on neuronal function. We investigated the effects of th...

  11. Reactivation of pulmonary tuberculosis (TBC) with the use of antagonist of the tumor necrosis factor alpha (FNTα) in rheumatoid arthritis: On purpose of a case

    International Nuclear Information System (INIS)

    Martinez V, Jose B; Medina V, Yimy F; Parga, Roberto; Restrepo, Jose Felix; Iglesias G, Antonio; Rondon, Federico

    2005-01-01

    Woman 56 years old, with history of rheumatoid arthritis who develops reactivation of pulmonary tuberculosis (TBC) after 1 year of treatment with biological therapy (antagonist of the tumor necrosis factor alpha). It is discussed pathophysiologic mechanisms, diagnostic approach, treatment of TBC and some recommendations for the use of biological therapy in patients with rheumatic disease

  12. Systemic lupus erythematosus induced by anti-tumour necrosis factor alpha therapy: a French national survey.

    Science.gov (United States)

    De Bandt, Michel; Sibilia, Jean; Le Loët, Xavier; Prouzeau, Sebastian; Fautrel, Bruno; Marcelli, Christian; Boucquillard, Eric; Siame, Jean Louis; Mariette, Xavier

    2005-01-01

    The development of drug-induced lupus remains a matter of concern in patients treated with anti-tumour necrosis factor (TNF) alpha. The incidence of such adverse effects is unknown. We undertook a retrospective national study to analyse such patients. Between June and October 2003, 866 rheumatology and internal medicine practitioners from all French hospital centres prescribing anti-TNF in rheumatic diseases registered on the website of the 'Club Rhumatismes et Inflammation' were contacted by email to obtain the files of patients with TNF-induced systemic lupus erythematosus. Twenty-two cases were collected, revealing two aspects of these manifestations. Ten patients (six patients receiving infliximab, four patients receiving etanercept) only had anti-DNA antibodies and skin manifestations one could classify as 'limited skin lupus' or 'toxidermia' in a context of autoimmunity, whereas 12 patients (nine patients receiving infliximab, three patients receiving etanercept) had more complete drug-induced lupus with systemic manifestations and at least four American Congress of Rheumatology criteria. One patient had central nervous system manifestations. No patients had lupus nephritis. The signs of lupus occurred within a mean of 9 months (range 3-16 months) in patients treated with infliximab and within a mean of 4 months (range 2-5 months) in patients treated with etanercept. In all cases after diagnosis was determined, anti-TNF was stopped and specific treatment introduced in eight patients: two patients received intravenous methylprednisolone, four patients received oral steroids (15-35 mg/day), and two patients received topical steroids. Lupus manifestations abated within a few weeks (median 8 weeks, standard deviation 3-16) in all patients except one with longer-lasting evolution (6 months). At that time, cautious estimations (unpublished data from Schering Plough Inc. and Wyeth Inc.) indicated that about 7700 patients had been exposed to infliximab and 3000 to

  13. Inhibitory effect of nicotinamide on in vitro and in vivo production of tumor necrosis factor-alpha.

    Science.gov (United States)

    Fukuzawa, M; Satoh, J; Muto, G; Muto, Y; Nishimura, S; Miyaguchi, S; Qiang, X L; Toyota, T

    1997-10-01

    Nicotinamide, a pellagra-preventive factor, has multiple functions such as inhibition of poly-ADP-ribose synthetase, inhibition of inducible nitric oxide synthase, free radical scavenging and suppression of major histocompatibility complex class II expression and ICAM-1 expression on endothelial cells. In addition to these, we have found an inhibitory effect of nicotinamide on production of tumor necrosis factor-alpha (TNF-alpha) in vitro and in vivo. Lipopolysaccharide (LPS)-induced in vitro TNF-alpha production by human peripheral blood mononuclear cells, measured by enzyme-linked immunosorbent assay (ELISA), was significantly inhibited with more than 1 x 10(-3) mol/l of nicotinamide, while interleukin-1-beta was not inhibited and interleukin-6 was slightly inhibited even with 10(-2) mol/l. Oral administration of nicotinamide with more than 62.5 mg/kg also significantly inhibited LPS-induced serum TNF-alpha production measured by ELISA and bioassay in Balb/c mice. Thus, nicotinamide has an inhibitory effect on TNF-alpha production that may be beneficial to TNF-alpha-mediated diseases.

  14. Garlic (Allium sativum) stimulates lipopolysaccharide-induced tumor necrosis factor-alpha production from J774A.1 murine macrophages.

    Science.gov (United States)

    Sung, Jessica; Harfouche, Youssef; De La Cruz, Melissa; Zamora, Martha P; Liu, Yan; Rego, James A; Buckley, Nancy E

    2015-02-01

    Garlic (Allium sativum) is known to have many beneficial attributes such as antimicrobial, antiatherosclerotic, antitumorigenetic, and immunomodulatory properties. In the present study, we investigated the effects of an aqueous garlic extract on macrophage cytokine production by challenging the macrophage J774A.1 cell line with the garlic extract in the absence or presence of lipopolysaccharide (LPS) under different conditions. The effect of allicin, the major component of crushed garlic, was also investigated. Using enzyme-linked immunosorbent assay and reverse transcriptase-quantitative polymerase chain reaction, it was found that garlic and synthetic allicin greatly stimulated tumor necrosis factor-alpha (TNF-α) production in macrophages treated with LPS. The TNF-α secretion levels peaked earlier and were sustained for a longer time in cells treated with garlic and LPS compared with cells treated with LPS alone. Garlic acted in a time-dependent manner. We suggest that garlic, at least partially via its allicin component, acts downstream from LPS to stimulate macrophage TNF-α secretion. © 2014 The Authors. Phytotherapy Research published by John Wiley & Sons, Ltd.

  15. An update on the use of tumor necrosis factor alpha inhibitors in the treatment of ankylosing spondylitis.

    Science.gov (United States)

    Osman, Mohammed S; Maksymowych, Walter P

    2017-02-01

    Ankylosing spondylitis is a chronic immune-mediated disease affecting the sacroiliac joints and the spine manifesting with new bone formation and osteopenia. Over the past decade, tumour necrosis factor alpha (TNF-α) inhibitors (TNFi) have become the cornerstone for therapy in improving functional outcomes, and decreasing disease activity in patients with a marginal benefit from non-steroidal anti-inflammatory (NSAID) therapy. At this time, it remains to be determined whether these agents decrease new bone formation, although some studies have recently suggested that. Areas covered: In this review we discuss the factors that favour a good response to these agents both initially and during maintenance, and some of the more recent studies outlining strategies for dose reduction. Expert commentary: Finally, we discuss the importance of using more objective tools for disease activity, such as magnetic resonance imaging, as a complementary tool for clinical assessments in both predicting responses to treatment but also in selecting patients most suited for targeted therapy.

  16. Alcohol extracts of Echinacea inhibit production of nitric oxide and tumor necrosis factor-alpha by macrophages in vitro.

    Science.gov (United States)

    Zhai, Zili; Haney, Devon; Wu, Lankun; Solco, Avery; Murphy, Patricia A; Wurtele, Eve S; Kohut, Marian L; Cunnick, Joan E

    2007-09-01

    It has been suggested that Echinacea has anti-inflammatory activity in vivo. Nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), and interleukin-1beta are important mediators in the inflammatory response. The effect of alcohol extracts of E. angustifolia (EA), E. pallida (EPA) and E. purpurea (EP) on the production of these inflammatory mediators in both LPS-stimulated RAW 264.7 macrophages in vitro and murine peritoneal exudate cells (PECs) in vivo were investigated. As macrophages produce these inflammatory mediators in response to pathogenic infection, parallel cultures of macrophages were studied for phagocytosis and intracellular killing of Salmonella enterica. EPA and EP in vitro inhibited NO production and TNF-α release in a dose-dependent manner. RAW 264.7 cells treated with EA or EP showed decreased killing over 24 h, although EA enhanced bacterial phagocytosis. Upon bacterial infection, RAW 264.7 cells produce high levels of NO; however, an Echinacea-mediated decrease in NO production was observed. Echinacea alcohol extracts administered orally at 130 mg/kg per day for seven days had a weak effect on NO production and phagocytosis by LPS-stimulated PECs. The results indicated that all Echinacea species significantly decreased inflammatory mediators in vitro, however, only EA and EP reduced bacterial killing. Oral administration of Echinacea alcohol extracts did not adversely affect the development and anti-bacterial function of inflammatory PECs in vivo, however, NO production was decreased during bacterial infection of PECs.

  17. Establishment and evaluation of a transgenic mouse model of arthritis induced by overexpressing human tumor necrosis factor alpha

    Directory of Open Access Journals (Sweden)

    Ge Li

    2016-04-01

    Full Text Available Tumor necrosis factor alpha (TNFα plays a key role in the pathogenesis of rheumatoid arthritis (RA. Blockade of TNFα by monoclonal antibody has been widely used for the therapy of RA since the 1990s; however, its mechanism of efficacy, and potential safety concerns of the treatment are still not fully understood. This study sought to establish a transgenic arthritic mouse model by overexpressing human TNFα (hTNFα and to apply this model as a means to evaluate therapeutic consequences of TNFα inhibitors. The transgenic mouse line (TgTC with FVB background was generated by incorporating 3′-modified hTNFα gene sequences. A progressively erosive polyarthritis developed in the TgTC mice, with many characteristics observed in human rheumatoid arthritis, including polyarticular swelling, impairment of movement, synovial hyperplasia, and cartilage and bone erosion. Gene expression analysis demonstrated that hTNFα is not only expressed in hyperplastic synovial membrane, but also in tissues without lesions, including brain, lung and kidney. Treatment of the TgTC mice with anti-hTNFα monoclonal antibodies (mAb significantly decreased the level of hTNFα in the diseased joint and effectively prevented development of arthritis in a dose-dependent response fashion. Our results indicated that the TgTC mice represent a genetic model which can be used to comprehensively investigate the pathogenesis and therapeutics of TNFα-related diseases.

  18. Requirement of FADD, NEMO, and BAX/BAK for Aberrant Mitochondrial Function in Tumor Necrosis Factor Alpha-Induced Necrosis▿

    Science.gov (United States)

    Irrinki, Krishna M.; Mallilankaraman, Karthik; Thapa, Roshan J.; Chandramoorthy, Harish C.; Smith, Frank J.; Jog, Neelakshi R.; Gandhirajan, Rajesh Kumar; Kelsen, Steven G.; Houser, Steven R.; May, Michael J.; Balachandran, Siddharth; Madesh, Muniswamy

    2011-01-01

    Necroptosis represents a form of alternative programmed cell death that is dependent on the kinase RIP1. RIP1-dependent necroptotic death manifests as increased reactive oxygen species (ROS) production in mitochondria and is accompanied by loss of ATP biogenesis and eventual dissipation of mitochondrial membrane potential. Here, we show that tumor necrosis factor alpha (TNF-α)-induced necroptosis requires the adaptor proteins FADD and NEMO. FADD was found to mediate formation of the TNF-α-induced pronecrotic RIP1-RIP3 kinase complex, whereas the IκB Kinase (IKK) subunit NEMO appears to function downstream of RIP1-RIP3. Interestingly, loss of RelA potentiated TNF-α-dependent necroptosis, indicating that NEMO regulates necroptosis independently of NF-κB. Using both pharmacologic and genetic approaches, we demonstrate that the overexpression of antioxidants alleviates ROS elevation and necroptosis. Finally, elimination of BAX and BAK or overexpression of Bcl-xL protects cells from necroptosis at a later step. These findings provide evidence that mitochondria play an amplifying role in inflammation-induced necroptosis. PMID:21746883

  19. Comparison of the Intravenous and Epidural Administration of Tumor Necrosis Factor-alpha Antagonists in an Experimental Rat Pain Model

    Science.gov (United States)

    Beyaz, Serbülent Gökhan; İnanmaz, Mustafa Erkan; Ergönenç, Tolga; Palabıyık, Onur; Tomak, Yakup; Tuna, Ayça Taş

    2017-01-01

    Introduction: Inflammatory cytokines secreted from the nucleus pulposus are thought to lead to lumbar nerve root compression-like symptoms. Tumor necrosis factor-alpha (TNF-α), an inflammatory cytokine, likely plays an important role in lumbar disc hernia-related leg pain. In this experimental study, we compared the effectiveness of TNF-α antagonists administered through the intravenous or epidural route in lumbar spine pathologies. Materials and Methods: After ethics committee approval had been obtained, 24 Sprague Dawley male rats aged 70–90 days and weighing 250–300 g each were allocated to four groups. In Group I, only the surgical procedure was performed; in Group II, 1 ml of saline solution was administered into the epidural field; in Group III, 10 mg/kg of infliximab was administered into the coccygeal vein; and in Group IV (epidural group), 25 mg of etanercept was administered into the epidural region. Results: When the left leg pull values were analyzed on day 14, whereas there was not a significant difference among the three groups, a decreasing difference was observed in Group IV (P discopathy, TNF-α antagonists administered epidurally led to earlier recovery from radiculopathy-related allodynia compared to intravenous administration. PMID:29284846

  20. Pathophysiological roles of microvascular alterations in pulmonary inflammatory diseases: possible implications of tumor necrosis factor-alpha and CXC chemokines

    Directory of Open Access Journals (Sweden)

    Kanami Orihara

    2008-10-01

    Full Text Available Kanami Orihara, Akio MatsudaDepartment of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, JapanAbstract: Chronic obstructive pulmonary disease (COPD and bronchial asthma are common respiratory diseases that are caused by chronic infl ammation of the airways. Although these diseases are mediated by substantially distinct immunological reactions, especially in mild cases, they both show increased numbers of neutrophils, increased production of tumor necrosis factor-alpha (TNF-α and poor responses to corticosteroids, particularly in patients with severe diseases. These immunological alterations may contribute strongly to airway structural changes, commonly referred to as airway remodeling. Microvascular alterations, a component of airway remodeling and caused by chronic inflammation, are observed and appear to be clinically involved in both diseases. It has been well established that vascular endothelial growth factor (VEGF plays important roles in the airway microvascular alterations in mild and moderate cases of both diseases, but any role that VEGF might play in severe cases of these diseases remains unclear. Here, we review recent research findings, including our own data, and discuss the possibility that TNF-α and its associated CXC chemokines play roles in microvascular alterations that are even more crucial than those of VEGF in patients with severe COPD or asthma.Keywords: TNF-α, CXC chemokines, corticosteroid, pulmonary microvessels, COPD, asthma

  1. Baseline tumour necrosis factor alpha levels predict the necessity for dose escalation of infliximab therapy in patients with rheumatoid arthritis

    Science.gov (United States)

    Takeuchi, Tsutomu; Miyasaka, Nobuyuki; Tatsuki, Yoshihiko; Yano, Toshiro; Yoshinari, Toru; Abe, Tohru; Koike, Takao

    2011-01-01

    Objectives To investigate the possible role of baseline plasma tumour necrosis factor alpha levels (baseline-TNF) on the clinical response to infliximab in patients with rheumatoid arthritis (RA). Methods Patients with RA refractory to methotrexate received 3, 6, or 10 mg/kg of infliximab every 8 weeks, in a randomised, double-blind manner: the RISING study. Clinical response (disease activity score in 28 joints based on C-reactive protein or American College of Rheumatology core set) at week 54 and serum infliximab levels were compared in three patient groups with low, intermediate, or high baseline-TNF (TNF-low, TNF-int, or TNF-high). Results In TNF-low patients, the clinical response to different doses of infliximab was comparable, whereas TNF-int patients exhibited a dose-dependent trend. In contrast, TNF-high patients (approximately 13% of the total patients) had a clinical response to 10 mg/kg significantly better than the response to 3 and 6 mg/kg of infliximab. In TNF-high patients, the median trough serum levels of infliximab were below the detection limit (infliximab in patients with a high baseline-TNF. A higher dose of infliximab may be necessary in these patients, whereas lower doses of infliximab are sufficient for those with a low baseline-TNF. Baseline-TNF may be a useful measure for personalising the treatment of RA using infliximab. PMID:21478189

  2. [Role of serum leptin and tumor necrosis factor-alpha in malnutrition of male chronic obstructive pulmonary disease patients].

    Science.gov (United States)

    Yang, Yi-meng; Sun, Tie-ying; Liu, Xin-min

    2005-12-18

    To explore the function of serum leptin in COPD patients with malnutrition, and to investigate the relationship between leptin and TNF-alpha. A total of 81 subjects (47 COPD patients and 34 control subjects) participated in this study. The 47 COPD patients were divided into 2 groups: group COPD I (patients without malnutrition during stable disease, n=29), group COPDII (patients with malnutrition during stable disease, n=18). To eliminate the effect of sex differences, all the patients and controls were male. Body mass index (BMI), percent ideal body weight (IBWå), triceps skin-fold thickness (TSF), mid-upper arm circumference (MAC), mid-upper arm muscle circumference(MAMC),serum leptin and tumor necrosis factor-alpha(TNF-alpha) levels, serum prealbumin (PA), serum transferrin (TF), serum albumin(Alb),total lymphocytes count (TLC), forced expiratory volume in one second (FEV(1)), maximal inspiration pressure(MIP)and maximal expiration pressure(MEP)were measured in all participants. Leptin levels were measured by radioimmunoassay. TNF-alpha levels were measured by ELISA. The between group difference and correlation of these parameters were analysed. (1) Serum leptin levels were significantly lower in group COPDII (4.07+/-3.42 microg/L) than in group COPD I (9.72+/-6.67 microg/L) and controls (8.21+/- 5.41 microg/L, PCOPD I (7.25+/- 2.08 ng/L). (3) There was no significant correlation between leptin and TNF-alpha in any group. Leptin was not involved in anorexia and weight loss of COPD patients. There was no significant correlation between TNF-alpha and leptin during the regulation of the energy balance in COPD patients.

  3. Pentoxifylline inhibits tumor necrosis factor-alpha (TNF alpha)-induced T-lymphoma cell adhesion to endothelioma cells.

    Science.gov (United States)

    Weiss, J M; Vanscheidt, W; Pilarski, K A; Weyl, A; Peschen, M; Schöpf, E; Vestweber, D; Simon, J C

    1995-05-01

    Pentoxifylline, a methylxanthine derivative, has been shown to inhibit T-cell-mediated cutaneous immune response by yet ill-understood mechanisms. Because cell adhesion to endothelial cells is a critical step in the initiation of such immune responses, we analyzed whether pentoxifylline would affect this process. To address this issue, adhesion of mouse T-lymphoma cells (TK-1) to mouse endothelioma cells (eEnd.2), either untreated or stimulated with tumor necrosis factor-alpha (TNF alpha), was studied. Pentoxifylline reduced the ability of endothelioma cells stimulated with different concentrations of TNF alpha, but not of untreated endothelioma cells, to bind T-lymphoma cells in dose-dependent (10(-5)-10(-3) M) fashion. Selective incubation of either endothelioma cells or T-lymphoma cells revealed that pentoxifylline acted exclusively on the endothelioma cells, even when added after TNF alpha stimulation. We questioned whether pentoxifylline suppressed T-lymphoma cell/endothelioma cell interactions by interfering with adhesion molecules expressed by either cell. However, as determined by flow cytometry, pentoxifylline did not alter TNF alpha-induced upregulation of intercellular adhesion molecule-1 or vascular cellular adhesion molecule-1 on endothelioma cells nor did it affect constitutive CD11a, CD18, or alpha 4-integrin expression on T-lymphoma cells, suggesting that rather than affecting quantitative expression of these adhesion molecules, pentoxifylline might modulate their avidity. We conclude that pentoxifylline in therapeutically achievable concentrations is a potent inhibitor of TNF alpha-induced T-lymphoma cell adhesion to endothelioma cells. This finding may account, at least in part, for the recently discovered anti-inflammatory action of pentoxifylline.

  4. Alteration of serum tumor necrosis factor-alpha level in gestational diabetes mellitus and correlation with insulin resistance

    International Nuclear Information System (INIS)

    Zou Gang; Li Cuiyin; Shao Hao; Lu Zeyuan; Lai Liping; Liu Lan; Hu Xiaorong

    2009-01-01

    Objective: To explore the dynamic of tumor necrosis factor-alpha (TNF-α)and its correlation with insulin resistance (IR)during different stages of gestational diabetes mellitus (GDM). Methods: Thirty-two subjects with GDM and 31 cases of normal pregnant women nonnal glucose tolerance, NGT were enrolled in the study, serum TNF-α and insulin were determined by radioimmunoassay. The plasma glucose was measured by using glucose oxidase. Tests repeated for each group according different stages of prenatal 25-28 weeks, 29-32 weeks, 37-38 weeks and postpartum 6-8 weeks. IR was assessed by the homeostasis model of assessment for insulin resistance index (HOMA-IR). Results: (1)Serum TNF-α levels in CDM and NGT group rose with gestational age, and both significantly decreased at postpartum. (2) Serum TNF-α levels in GDM of above-mentioned four stages respectively were (7.05±0.67) ng/L, (7.11± 0.75) ng/L, (7.36±0.79) ng/L, (5.46±0.37) ng/L respectively. All significantly increased than those in the same stage group (t=7.81, 7.05, 7.15, P<0.01). (3) Maternal serum TNF-α levels were in positive correlation with HOMA-IR in GDM (r=0.571, P<0.05). Conclusions: Serum TNF-α levels in GDM rose with gestational age, but significantly decreased at postpartum. The dynamic changes of serum TNF-α contribute to occurrence of insulin resistance. (authors)

  5. Manipulation of flaxseed inhibits tumor necrosis factor-alpha and interleukin-6 production in ovarian-induced osteoporosis.

    Science.gov (United States)

    Abdelkarem, Hala M; Abd El-Kader, Madeha M; Kasem, Seham A

    2011-04-01

    To evaluate the potential effects of whole flaxseed (FS), and/or flax oil (FO) incorporation into the diet on the level of pro-inflammatory cytokines in ovariectomized (OVX) rats model of osteoporosis. This study was performed in the Food Science & Agriculture Collage, King Saud University, Kingdom of Saudi Arabia from October to December 2009. Forty-eight, 3-month-old female Sprague-Dawley rats were randomly divided into 6 groups: Group 1 - sham + control diet; Group 2 - OVX rats + basal diet; Group 3 - OVX + 20% whole FS; Group 4 - OVX rats + 40% FS; Group 5 - OVX rats + 5% FO; Group 6 - OVX rats + 10% FO. All OVX rats underwent bilateral ovariectomy. The experiment was continued for 2 months. Serum bone alkaline phosphatase (B-ALP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), calcium (Ca), phosphorous (P), and magnesium (Mg) were measured. A significant increase of serum IL-6 and TNF-alpha concentrations were observed between OVX rats when compared with Group 1, while there was no significant difference in the activity of B-ALP, serum Ca, P, and Mg among all groups. A remarkable significant decrease of serum levels of IL-6 and TNF-alpha was observed in the group of rats that were fed with FS (Groups 3 and 4) and FO (Groups 5 and 6). This study suggests that FS and FO might be useful in the prevention of estrogen-deficiency induced osteoporosis via decreasing osteoclastogenesis. Further studies are needed to demonstrate their efficacy in humans by using bioactive components of FS, and to clarify their mechanism of action.

  6. Tumour necrosis factor-alpha infusion produced insulin resistance but no change in the incretin effect in healthy volunteers.

    Science.gov (United States)

    Nielsen, Signe Tellerup; Lehrskov-Schmidt, Louise; Krogh-Madsen, Rikke; Solomon, Thomas P J; Lehrskov-Schmidt, Lars; Holst, Jens Juul; Møller, Kirsten

    2013-11-01

    Type 2 diabetes mellitus (T2DM) is associated with peripheral insulin resistance, impaired incretin effect, and increased plasma levels of tumour necrosis factor-alpha (TNF-α). Although TNF-α infusion at a dose that induces systemic inflammation in healthy volunteers has been demonstrated to induce peripheral insulin resistance, the influence of this cytokine on the incretin effect is unknown. We investigated whether systemic inflammation induced by TNF-α infusion in healthy volunteers alters the incretin hormone response to oral and intravenous glucose loads in a crossover study design with ten healthy male volunteers (mean age 24 years, mean body mass index 23.7 kg/m(2) ). The study consisted of four study days: days 1 and 2, 6-h infusion of saline; days 3 and 4, 6-h infusion of TNF-α; days 1 and 3, 4-h oral glucose tolerance test; and days 2 and 4, 4-h corresponding intravenous isoglycaemic glucose tolerance test. Glucose tolerance tests were initiated after 2 h of saline/TNF-α infusion. Plasma concentrations of TNF-α, interleukin 6, glucose, incretin hormones, and cortisol, and serum concentrations of C-peptide and insulin were measured throughout the study days. Insulin sensitivity was estimated by the Matsuda index and homeostasis model assessment of insulin resistance (HOMA-IR). Prehepatic insulin secretion rates were calculated. TNF-α infusion induced symptoms of systemic inflammation; increased plasma levels of cortisol, TNF-α, and interleukin 6; and increased the HOMA-IR. The secretion of incretin hormones as well as the incretin effect remained unchanged. In healthy young male volunteers, acute systemic inflammation induced by infusion of TNF-α is associated with insulin resistance with no change in the incretin effect. Copyright © 2013 John Wiley & Sons, Ltd.

  7. Quantitative assessment of the influence of tumor necrosis factor alpha polymorphism with gastritis and gastric cancer risk.

    Science.gov (United States)

    Li, Ming; Wang, Yinping; Gu, Yahong

    2014-02-01

    Tumor necrosis factor alpha (TNFA) is an important molecule in inflammatory, infectious, and tumoral processes. Inflammation is one of the early phases in the development of gastric cancer (GC). Therefore, several studies have examined the association of polymorphism in TNFA with gastritis and GC risk. A functional polymorphism, -308G>A (rs1800629), which is located in the promoter of TNFA gene, has been suggested to alter the production of TNF-α and influence cancer risk. To date, a number of studies have been carried out to investigate the relationship between the polymorphism and gastritis or GC susceptibility, but the results were conflicting. To investigate this inconsistency, we performed a meta-analysis of 36 studies for TNFA -308G>A polymorphism to evaluate the effect of TNFA on genetic susceptibility for gastritis and GC. An overall random-effects per-allele odds ratio of 1.16 (95 % confidence interval 1.04-1.29, P = 0.008) was found for the polymorphism. Significant results were also observed using dominant or recessive genetic models. In the subgroup analyses by ethnicity, significant results were found in Caucasians, whereas no significant associations were found among East Asians and other ethnic populations. No associations between the polymorphism and gastritis were observed. In addition, our data indicate that TNFA is involved in GC susceptibility and confers its effect primarily in diffuse type of tumors. Besides, -308G>A polymorphism was found to be significantly associated with both cardiac and noncardiac tumors. This meta-analysis demonstrated that the TNFA -308G>A polymorphism is a risk factor for developing GC, but the associations vary in different ethnic populations.

  8. Anti-tumor necrosis factor-alpha-loaded microspheres as a prospective novel treatment for Crohn's disease fistulae.

    Science.gov (United States)

    Foong, Keen Shawn; Patel, Rishni; Forbes, Alastair; Day, Richard M

    2010-10-01

    Antibodies to tumor necrosis factor alpha (TNF-α) have been successful in treating perianal fistulae in Crohn's disease, but current modes of delivery are limited. Microspheres are currently being assessed as scaffolds for tissue engineering and drug delivery devices. The aim of this study was to produce anti-TNF-α antibody-encapsulated microspheres using thermally induced phase separation (TIPS) and to characterize their behavior. Anti-TNF-α antibody was encapsulated into the microspheres (100 mg infliximab/g poly[lactide-co-glycolide] w/w) using a novel technique combining a vibration encapsulator unit with a TIPS process, using either lyophilized particulate antibody or an aqueous solution of antibody. Microspheres were incubated in phosphate-buffered saline for collection of supernatant and assessment of degradation. The amount and biological activity of the encapsulated antibody released from the microspheres was assessed by enzyme-linked immunosorbent assay and its ability to neutralize recombinant human (rh)TNF-α in vitro with a cytotoxicity assay. An in vitro wound scratch assay was used to assess the effect of released antibody on fibroblast migration. Ultrastructural characteristics of the different microspheres were characterized by scanning electron microscopy. Highly porous microspheres released anti-TNF-α antibody under zero-order kinetics and inhibited the cytotoxic activity of rhTNF-α, producing a significant increase in cell viability compared with cells treated with rhTNF-α alone. This effect was most pronounced with microspheres fabricated by blending lyophilized particulate anti-TNF-α antibody into the polymer solution, which also significantly reduced the release of lactate dehydrogenase. Anti-TNF-α antibody encapsulated into highly porous microspheres was released in a controlled manner and exhibited biological activity against TNF-α. The technique used to produce TIPS microspheres is rapid and provides high encapsulation efficiency

  9. Preliminary characterisation of tumor necrosis factor alpha and interleukin-10 responses to Chlamydia pecorum infection in the koala (Phascolarctos cinereus.

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    Marina Mathew

    Full Text Available Debilitating infectious diseases caused by Chlamydia are major contributors to the decline of Australia's iconic native marsupial species, the koala (Phascolarctos cinereus. An understanding of koala chlamydial disease pathogenesis and the development of effective strategies to control infections continue to be hindered by an almost complete lack of species-specific immunological reagents. The cell-mediated immune response has been shown to play an influential role in the response to chlamydial infection in other hosts. The objective of this study, hence, was to provide preliminary data on the role of two key cytokines, pro-inflammatory tumour necrosis factor alpha (TNFα and anti-inflammatory interleukin 10 (IL10, in the koala Chlamydia pecorum response. Utilising sequence homology between the cytokine sequences obtained from several recently sequenced marsupial genomes, this report describes the first mRNA sequences of any koala cytokine and the development of koala specific TNFα and IL10 real-time PCR assays to measure the expression of these genes from koala samples. In preliminary studies comparing wild koalas with overt chlamydial disease, previous evidence of C. pecorum infection or no signs of C. pecorum infection, we revealed strong but variable expression of TNFα and IL10 in wild koalas with current signs of chlamydiosis. The description of these assays and the preliminary data on the cell-mediated immune response of koalas to chlamydial infection paves the way for future studies characterising the koala immune response to a range of its pathogens while providing reagents to assist with measuring the efficacy of ongoing attempts to develop a koala chlamydial vaccine.

  10. Preliminary characterisation of tumor necrosis factor alpha and interleukin-10 responses to Chlamydia pecorum infection in the koala (Phascolarctos cinereus).

    Science.gov (United States)

    Mathew, Marina; Beagley, Kenneth W; Timms, Peter; Polkinghorne, Adam

    2013-01-01

    Debilitating infectious diseases caused by Chlamydia are major contributors to the decline of Australia's iconic native marsupial species, the koala (Phascolarctos cinereus). An understanding of koala chlamydial disease pathogenesis and the development of effective strategies to control infections continue to be hindered by an almost complete lack of species-specific immunological reagents. The cell-mediated immune response has been shown to play an influential role in the response to chlamydial infection in other hosts. The objective of this study, hence, was to provide preliminary data on the role of two key cytokines, pro-inflammatory tumour necrosis factor alpha (TNFα) and anti-inflammatory interleukin 10 (IL10), in the koala Chlamydia pecorum response. Utilising sequence homology between the cytokine sequences obtained from several recently sequenced marsupial genomes, this report describes the first mRNA sequences of any koala cytokine and the development of koala specific TNFα and IL10 real-time PCR assays to measure the expression of these genes from koala samples. In preliminary studies comparing wild koalas with overt chlamydial disease, previous evidence of C. pecorum infection or no signs of C. pecorum infection, we revealed strong but variable expression of TNFα and IL10 in wild koalas with current signs of chlamydiosis. The description of these assays and the preliminary data on the cell-mediated immune response of koalas to chlamydial infection paves the way for future studies characterising the koala immune response to a range of its pathogens while providing reagents to assist with measuring the efficacy of ongoing attempts to develop a koala chlamydial vaccine.

  11. Serum concentrations of interleukin-1 alpha, interleukin-6 and tumor necrosis factor-alpha in neonatal sepsis and meningitis

    International Nuclear Information System (INIS)

    Fida, Nadia M.; Fadelallah, Mohamed F.; Al-Mughales, Jamil A.

    2006-01-01

    To investigate whether serum levels of interleukin-1alpha (IL-1alpha), IL-6, tumor necrosis factor alpha (TNF-alpha), C-reactive protein (CRP) are useful in the diagnosis of neonatal sepsis and meningitis and differentiate them. Blood samples were collected from 35 full term neonates with suspected infection who admitted to the Neonatology Unit, Pediatric Department, King Abdul-Aziz University Hospital, Jeddah, Saudi Arabia during January 2002 - June 2003. On the basis of laboratory and bacteriological results, newborns were classified into: sepsis (n=28), meningitis (n=7), and healthy controls (n=16). Sepsis groups were further subdivided according to culture results into: group 1 = proven sepsis (n=6), group 2 = clinical sepsis (n=14), and group 3 = possible-infected (n=8). Serum levels of IL-1alpha, IL-6, TNF-alpha were measured using Enzyme-Linked Immunosorbent Assay while CRP by nephelometer: In sepsis and meningitis patients, serum levels of CRP (p<0.01, p<0.05,) and IL-1alpha (p<0.001, p<0.05) were elevated than controls. C-reactive protein levels elevated in proven sepsis (p<0.001) and IL-1alpha elevated in all subgroups of sepsis (groups 1, 2, 3) compared with (p<0.05, p<0.001, p<0.01) controls. Interleukin-6, TNF-alpha showed no significant differences between studied groups. In sepsis and meningitis, IL-1alpha had a highest sensitivity (89%, 86%), and negative predictive values (89% and 93%). Interleukin-1alpha and CRP increased in neonatal sepsis and meningitis, but cannot differentiate between them. Interleukin-1alpha had a highest sensitivity in prediction of neonatal infection and its assessment may improve accuracy of diagnosis. (author)

  12. Serum tumor necrosis factor-alpha concentrations are negatively correlated with serum 25(OHD concentrations in healthy women

    Directory of Open Access Journals (Sweden)

    Heffernan Mary E

    2008-07-01

    Full Text Available Abstract Background Circulating 25 hydroxyvitamin D (25 (OHD, an accurate measure of vitamin D status, is markedly greater in individuals with increased exposure to ultraviolet B (UVB light via sunlight or the use of artificial UV light. Aside from the known relationship between vitamin D and bone, vitamin D has also been implicated in immune function and inflammation. Furthermore, a mass of evidence is accumulating that vitamin D deficiency could lead to immune malfunction. Our overall objective was to study the relationship between vitamin D status (as determined by serum 25(OH D concentrations and inflammatory markers in healthy women. Methods This observational study included 69 healthy women, age 25–82 years. Women with high UVB exposure and women with minimal UVB exposure were specifically recruited to obtain a wide-range of serum 25(OHD concentrations. Health, sun exposure and habitual dietary intake information were obtained from all subjects. Body composition was determined by dual-energy-x-ray absorptiometry. A fasting blood sample was collected in the morning and analyzed for serum 25(OHD, parathyroid hormone (iPTH, estradiol (E2, cortisol, and inflammatory markers [tumor necrosis factor -alpha (TNF-α, interleukin-6 and -10 (IL-6, IL-10, and C-reactive protein (CRP]. Results Women with regular UVB exposure (Hi-D had serum 25(OHD concentrations that were significantly higher (p p Conclusion Serum 25(OHD status is inversely related to TNF-α concentrations in healthy women, which may in part explain this vitamin's role in the prevention and treatment of inflammatory diseases. Results gleaned from this investigation also support the need to re-examine the biological basis for determining optimal vitamin D status.

  13. Induction of NKG2D ligands by gamma radiation and tumor necrosis factor-alpha may participate in the tissue damage during acute graft-versus-host disease.

    Science.gov (United States)

    Gannagé, Monique; Buzyn, Agnès; Bogiatzi, Sofia I; Lambert, Marion; Soumelis, Vassili; Dal Cortivo, Liliane; Cavazzana-Calvo, Marina; Brousse, Nicole; Caillat-Zucman, Sophie

    2008-03-27

    Immunopathology of acute graft-versus-host disease (aGVHD) involves secretion of proinflammatory cytokines with subsequent expression of danger signals by injured host tissues. This explanation, however, does not explain the cluster of aGVHD target organs (skin, gut, and liver). NKG2D ligands (MICA/B and ULBP1-3 proteins) are stress-induced molecules that act as danger signals to alert NK and alphabeta or gammadelta CD8 T cells through engagement of the activating NKG2D receptor. We observed a strong and reversible induction of MICA/B expression in skin and liver sections during aGVHD. Tumor necrosis factor-alpha and gamma-radiation up-regulated expression of MICA/B and ULBP proteins in vitro on skin and intestine epithelial cell lines and ex vivo in normal skin explants. This NKG2D-ligand induction was regulated by a complex interplay between NFkB and JNK activation pathways. Our data suggest that NKG2D ligand induction might participate in the amplification loop that leads to tissue damage during aGVHD.

  14. The roles of tumor necrosis factor-alpha in colon tight junction protein expression and intestinal mucosa structure in a mouse model of acute liver failure

    Directory of Open Access Journals (Sweden)

    Lv Sa

    2009-09-01

    Full Text Available Abstract Background Spontaneous bacterial peritonitis (SBP is a common clinical disease and one of the most severe complications of acute liver failure (ALF. Although the mechanism responsible for SBP is unclear, cytokines play an important role. The aim of this study was to investigate the effects of tumor necrosis factor-alpha (TNF-α on the structure of the intestinal mucosa and the expression of tight junction (Zona Occludens 1; ZO-1 protein in a mouse model of ALF. Methods We induced ALF using D-galactosamine/lipopolysaccharide (GalN/LPS or GalN/TNF-α and assessed the results using transmission electron microscopy, immunohistochemistry, Western blotting, ELISA and real-time quantitative PCR. The effects of administration of anti-TNF-α IgG antibody or anti-TNF-α R1 antibody before administration of GalN/LPS or GalN/TNF-α, respectively, on TNF-α were also assessed. Results Morphological abnormalities in the intestinal mucosa of ALF mice were positively correlated with serum TNF-α level. Electron microscopic analysis revealed tight junction (TJ disruptions, epithelial cell swelling, and atrophy of intestinal villi. Gut bacteria invaded the body at sites where TJ disruptions occurred. Expression of ZO-1 mRNA was significantly decreased in both ALF models, as was the level of ZO-1 protein. Prophylactic treatment with either anti-TNF-α IgG antibody or anti-tumor necrosis factor-a receptor1 (anti-TNF-α R1 antibody prevented changes in intestinal tissue ultrastructure and ZO-1 expression. Conclusion TNF-α affects the structure of the intestinal mucosa, decreases expression of ZO-1, and affects the morphology of the colon in a mouse model of ALF. It also may participate in the pathophysiological mechanism of SBP complicated to ALF.

  15. The repeatability of interleukin-6, tumor necrosis factor-alpha, and C-reactive protein in COPD patients over one year

    DEFF Research Database (Denmark)

    Kolsum, Umme; Roy, Kay; Starkey, Cerys

    2009-01-01

    BACKGROUND: Many of the systemic manifestations of chronic obstructive pulmonary disease (COPD) are mediated through increased systemic levels of inflammatory proteins. We assessed the long term repeatability of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein......(i)) and the Bland-Altman method. Pearson correlations were used to determine the relationships between the systemic markers at both visits. RESULTS: There was moderate repeatability with a very high degree of statistical significance (p...

  16. The repeatability of interleukin-6, tumor necrosis factor-alpha, and C-reactive protein in COPD patients over one year

    DEFF Research Database (Denmark)

    Kolsum, Umme; Roy, Kay; Starkey, Cerys

    2009-01-01

    BACKGROUND: Many of the systemic manifestations of chronic obstructive pulmonary disease (COPD) are mediated through increased systemic levels of inflammatory proteins. We assessed the long term repeatability of Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein......(i)) and the Bland-Altman method. Pearson correlations were used to determine the relationships between the systemic markers at both visits. RESULTS: There was moderate repeatability with a very high degree of statistical significance (p...

  17. Effects of MS-8209, an Amphotericin B Derivative, on Tumor Necrosis Factor Alpha Synthesis and Human Immunodeficiency Virus Replication in Macrophages

    OpenAIRE

    Clayette, Pascal; Martin, Marc; Beringue, Vincent; Dereuddre-Bosquet, Nathalie; Adjou, Karim T.; Seman, Michel; Dormont, Dominique

    2000-01-01

    Amphotericin B derivatives, such as MS-8209, have been evaluated as a therapeutic approach to human immunodeficiency virus (HIV) infection. We show that MS-8209, like amphotericin B, increases tumor necrosis factor alpha (TNF-α) mRNA expression and TNF-α production and consequently HIV replication in human macrophages. These effects confirm the pharmacological risk associated with the administration of amphotericin B or its derivatives to HIV-infected patients.

  18. Effects of MS-8209, an amphotericin B derivative, on tumor necrosis factor alpha synthesis and human immunodeficiency virus replication in macrophages.

    Science.gov (United States)

    Clayette, P; Martin, M; Beringue, V; Dereuddre-Bosquet, N; Adjou, K T; Seman, M; Dormont, D

    2000-02-01

    Amphotericin B derivatives, such as MS-8209, have been evaluated as a therapeutic approach to human immunodeficiency virus (HIV) infection. We show that MS-8209, like amphotericin B, increases tumor necrosis factor alpha (TNF-alpha) mRNA expression and TNF-alpha production and consequently HIV replication in human macrophages. These effects confirm the pharmacological risk associated with the administration of amphotericin B or its derivatives to HIV-infected patients.

  19. Intervertebral disc cells produce tumor necrosis factor alpha, interleukin-1beta, and monocyte chemoattractant protein-1 immediately after herniation: an experimental study using a new hernia model.

    Science.gov (United States)

    Yoshida, Masakazu; Nakamura, Takafumi; Sei, Akira; Kikuchi, Taro; Takagi, Katsumasa; Matsukawa, Akihiro

    2005-01-01

    A new hernia model that simulates human disc herniations was developed in rabbits. The herniated discs were examined by gross appearance and histology and production of tumor necrosis factor alpha, interleukin-1beta, and monocyte chemoattractant protein-1 was investigated. To clarify the early mechanism of spontaneous herniated disc resorption. Macrophage infiltration in herniated discs is essential for disc resorption. However, surgically removed human herniated disc tissues and existing animal hernia models are not suitable for analyzing the mechanism of macrophage infiltration. Recently, we have demonstrated that intervertebral disc cells are capable of producing monocyte chemoattractant protein-1, a potent macrophage chemoattractant, after stimulation with tumor necrosis factor alpha and interleukin-1beta. Intervertebral disc herniations were surgically developed in rabbits using a new technique. The herniated discs were excised at appropriate time intervals after the surgery, and the size and histologic findings were examined. Expressions of tumor necrosis factor alpha, interleukin-1beta, and monocyte chemoattractant protein-1 in herniated discs were investigated immunohistochemically. A new rabbit model of disc herniation was established. The herniated discs spontaneously reduced in size by 12 weeks postsurgery. Infiltrating cells, mainly composed of macrophages, were observed from day 3. Immunohistochemically, intervertebral disc cells in the herniated discs produced tumor necrosis factor alpha and interleukin-1beta on day 1, followed by monocyte chemoattractant protein-1 on day 3. The new hernia model appears to be very useful for studying herniated disc resorption. Intervertebral disc cells may produce inflammatory cytokines/chemokine immediately after the onset of disc herniation, possibly triggering subsequent macrophage infiltration that leads to disc resorption.

  20. Proinflammatory cytokines tumor necrosis factor-alpha and interferon-gamma alter tight junction structure and function in the rat parotid gland Par-C10 cell line.

    Science.gov (United States)

    Baker, Olga J; Camden, Jean M; Redman, Robert S; Jones, Jonathan E; Seye, Cheikh I; Erb, Laurie; Weisman, Gary A

    2008-11-01

    Sjögren's syndrome (SS) is an autoimmune disorder characterized by inflammation and dysfunction of salivary glands, resulting in impaired secretory function. The production of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) is elevated in exocrine glands of patients with SS, although little is known about the effects of these cytokines on salivary epithelial cell functions necessary for saliva secretion, including tight junction (TJ) integrity and the establishment of transepithelial ion gradients. The present study demonstrates that chronic exposure of polarized rat parotid gland (Par-C10) epithelial cell monolayers to TNF-alpha and IFN-gamma decreases transepithelial resistance (TER) and anion secretion, as measured by changes in short-circuit current (I(sc)) induced by carbachol, a muscarinic cholinergic receptor agonist, or UTP, a P2Y(2) nucleotide receptor agonist. In contrast, TNF-alpha and IFN-gamma had no effect on agonist-induced increases in the intracellular calcium concentration [Ca(2+)](i) in Par-C10 cells. Furthermore, treatment of Par-C10 cell monolayers with TNF-alpha and IFN-gamma increased paracellular permeability to normally impermeant proteins, altered cell and TJ morphology, and downregulated the expression of the TJ protein, claudin-1, but not other TJ proteins expressed in Par-C10 cells. The decreases in TER, agonist-induced transepithelial anion secretion, and claudin-1 expression caused by TNF-alpha, but not IFN-gamma, were reversible by incubation of Par-C10 cell monolayers with cytokine-free medium for 24 h, indicating that IFN-gamma causes irreversible inhibition of cellular activities associated with fluid secretion in salivary glands. Our results suggest that cytokine production is an important contributor to secretory dysfunction in SS by disrupting TJ integrity of salivary epithelium.

  1. Evaluation of Cucurbita maxima extract against scopolamine-induced amnesia in rats: implication of tumour necrosis factor alpha.

    Science.gov (United States)

    Jawaid, Talha; Shakya, Ashok K; Siddiqui, Hefazat Hussain; Kamal, Mehnaz

    2014-01-01

    Cucurbita maxima (CM) seed oil is commonly used in Indian folk medicine to treat various ailments. We have investigated the effect of CM seed oil on memory impairment induced by scopolamine in rats. Male adult Wistar rats were administered scopolamine 1 mg/kg body weight, i.p. or 1.25 mg/kg body weight, s.c. to induce memory impairment. The nootropic agent piracetam 100 mg/kg body weight, i.p. and CM seed oil 100 and 200 mg/kg body weight, p.o. were administered daily for five consecutive days. The memory function was evaluated in the Morris water maze (MWM) test, the social recognition test (SRT), the elevated plus maze (EPM) test, and the pole climbing test (PCT). Acetylcholinesterase (AChE) activity and oxidative stress parameters were estimated in the cortex, hippocampus, and cerebellum of the brains after completion of the behavioural studies. The effects of scopolamine on the levels of the tumour necrosis factor alpha (TNF-α) transcript were also investigated. Scopolamine caused memory impairment in all the behavioural paradigms along with a significant increase in the AChE activity and oxidative stress in the brain. Scopolamine also caused a significant increase in the expression of TNF-α in the hippocampus. CM seed oil exhibited antiamnesic activity as indicated by a significant reduction in the latency time in the MWM test and decreased social interaction during trial 2 in the SRT. Further, treatment with CM seed oil significantly decreased the AChE activity and malondialdehyde levels and increased the glutathione level in brain regions. CM seed oil also significantly decreased the expression of TNF-α in the hippocampus. The effect of CM seed oil on behavioural and biochemical parameters was comparable to that observed in rats treated with piracetam. These results indicate that CM seed oil may exert antiamnesic activity which may be attributed to the inhibition of AChE and inflammation as well as its antioxidant activity in the brain.

  2. Working life and physical activity in ankylosing spondylitis pre and post anti-tumor necrosis factor-alpha therapy.

    Science.gov (United States)

    Prince, David S; McGuigan, Louis E; McGirr, Ellen E

    2014-02-01

    To assess effects of ankylosing spondylitis (AS) on working life and physical activity in Australia; to quantify changes in working life and physical activity that occur after anti-tumor necrosis factor-alpha (TNF-α) treatment; and to assess efficacy of anti-TNF-α therapy for AS in an Australian context. This is a multi-centre observational study of people with AS on anti-TNF-α therapy. All participants satisfied the New York Modified Criteria and had active and refractory disease at anti-TNF-α therapy commencement. Participation involved a standardized interview, a metrology assessment, assessment of disease remission and medical record review. Interviews and patients' records were used to compare working life (employment, sick leave and productivity) and physical activity (participation rate, hours/week, and physical intensity) between the pre-AS, post-AS and post-anti-TNF-α therapy periods. Fifty-two patients took part. Participants were on average 44.8 years old, predominately male (86.5%) and had been on anti-TNF-α therapy for 29 months; 39% were in partial remission and 75% had 50% reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Responders to anti-TNF-α therapy were 10.5 years younger than non-responders (P = 0.004). Post-anti-TNF-α therapy participants gained 6.6 h/week of work (P = 0.02), and productivity improved 31% (P treatment. Physical activity participation increased from 71% to 85% (P = 0.039) and activity intensity increased by 33% (P = 0.002) post-treatment. Participants gained 1.8 h/week of sport (P = 0.001) and 2.2 h/week of recreational physical activity (P Treatment with anti-TNF-α therapy results in significant improvement in these parameters. © 2012 The Authors International Journal of Rheumatic Diseases © 2012 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

  3. Association of Polymorphism Harbored by Tumor Necrosis Factor Alpha Gene and Sex of Calf with Lactation Performance in Cattle

    Directory of Open Access Journals (Sweden)

    N. S. Yudin

    2013-10-01

    Full Text Available In a majority of mammals, male infants have heavier body mass and grow faster than female infants. Accordingly, male offspring nursing requires a much greater maternal energy contribution to lactation. It is possible that the maternal-fetal immunoendocrine dialog plays an important role in female preparation for lactation during pregnancy. Immune system genes are an integral part of gene regulatory networks in lactation and tumor necrosis factor alpha (TNFα is a proinflammatory cytokine that also plays an important role in normal mammary gland development. The aim of this study was to evaluate the influence of the sex of calf and/or the -824A/G polymorphism in the promoter region of TNFα gene on milk performance traits in Black Pied cattle over the course of lactation. We also studied the allele frequency differences of -824A/G variants across several cattle breeds, which were bred in different climatic conditions. The G allele frequency decreased gradually over the course of lactation events in the Black Pied dairy cattle because of a higher culling rate of cows with the G/G genotype (p<0.001. In contrast to the genotypes A/A and A/G, cows with G/G genotype showed significant variability of milk and milk fat yield subject to sex of delivered calf. Milk yield and milk fat yield were significantly higher in the case of birth of a bull calf than with a heifer calf (p<0.03. The G allele frequency varies from 48% to 58% in Grey Ukrainian and Black Pied cattle to 77% in aboriginal Yakut cattle. Our results suggest that the TNFα -824A/G gene polymorphism may have an influence on the reproductive efforts of cows over the course of lactation events depending on the sex of progeny. Allocation of resources according to sex of the calf allows optimizing the energy cost of lactation. This may be a probable reason for high G allele frequency in Yakut cattle breeding in extreme environmental conditions. Similarly, the dramatic fall in milk production after

  4. Molecular cloning and functional characterization of the human platelet-derived growth factor alpha receptor gene promoter

    NARCIS (Netherlands)

    Afink, G. B.; Nistér, M.; Stassen, B. H.; Joosten, P. H.; Rademakers, P. J.; Bongcam-Rudloff, E.; van Zoelen, E. J.; Mosselman, S.

    1995-01-01

    Expression of the platelet-derived growth factor alpha receptor (PDGF alpha R) is strictly regulated during mammalian development and tumorigenesis. The molecular mechanisms involved in the specific regulation of PDGF alpha R expression are unknown, but transcriptional regulation of the PDGF alpha R

  5. Tumor necrosis factor alpha inhibits the suppressive effect of regulatory T cells on the hepatitis B virus-specific immune response.

    Science.gov (United States)

    Stoop, Jeroen N; Woltman, Andrea M; Biesta, Paula J; Kusters, Johannes G; Kuipers, Ernst J; Janssen, Harry L A; van der Molen, Renate G

    2007-09-01

    Chronicity of hepatitis B virus (HBV) infection is characterized by a weak immune response to the virus. CD4+CD25+ regulatory T cells (Treg) are present in increased numbers in the peripheral blood of chronic HBV patients, and these Treg are capable of suppressing the HBV-specific immune response. The aim of this study was to abrogate Treg-mediated suppression of the HBV-specific immune response. Therefore, Treg and a Treg-depleted cell fraction were isolated from peripheral blood of chronic HBV patients. Subsequently, the suppressive effect of Treg on the response to HBV core antigen (HBcAg) and tetanus toxin was compared, and the effect of exogenous tumor necrosis factor alpha (TNF-alpha), interleukin-1-beta (IL-1beta), or neutralizing antibodies against interleukin-10 (IL-10) or transforming growth factor beta (TGF-beta) on Treg-mediated suppression was determined. The results show that Treg of chronic HBV patients had a more potent suppressive effect on the response to HBcAg compared with the response to tetanus toxin. Neutralization of IL-10 and TGF-beta or exogenous IL-1beta had no effect on Treg-mediated suppression of the anti-HBcAg response, whereas exogenous TNF-alpha partially abrogated Treg-mediated suppression. Preincubation of Treg with TNF-alpha demonstrated that TNF-alpha had a direct effect on the Treg. No difference was observed in the type II TNF receptor expression by Treg from chronic HBV patients and healthy controls. Treg-mediated suppression of the anti-HBV response can be reduced by exogenous TNF-alpha. Because chronic HBV patients are known to produce less TNF-alpha, these data implicate an important role for TNF-alpha in the impaired antiviral response in chronic HBV.

  6. Tumor necrosis factor alpha protects against lethal West Nile virus infection by promoting trafficking of mononuclear leukocytes into the central nervous system.

    Science.gov (United States)

    Shrestha, Bimmi; Zhang, Bo; Purtha, Whitney E; Klein, Robyn S; Diamond, Michael S

    2008-09-01

    West Nile virus (WNV) is a neurotropic flavivirus that has emerged globally as a significant cause of viral encephalitis in humans, especially in immunocompromised individuals. Previous studies have shown essential protective roles for antiviral cytokines (e.g., alpha interferon [IFN-alpha] and IFN-gamma) against WNV in mice. However, studies using cell culture offer conflicting answers regarding whether tumor necrosis factor alpha (TNF-alpha) has an anti-WNV function. To test the biological significance of TNF-alpha against WNV in vivo, experiments were performed with TNF receptor-1 (TNF-R1)-deficient and TNF-alpha-depleted C57BL/6 mice. TNF-R1(-/-) mice had enhanced mortality and decreased survival time after WNV infection compared to congenic wild-type mice. Consistent with this, administration of a neutralizing anti-TNF-alpha monoclonal antibody also decreased survival after WNV infection. Relatively small differences in viral burdens in peripheral tissues of TNF-R1(-/-) mice were observed, and this occurrence correlated with a modest antiviral effect of TNF-alpha on primary macrophages but not dendritic cells. In contrast, the viral titers detected in the central nervous systems of TNF-R1(-/-) mice were significantly increased compared to those of wild-type mice, although TNF-alpha did not have a direct antiviral effect in primary neuron cultures. Whereas no defect in priming of adaptive B- and T-cell responses in TNF-R1(-/-) mice was observed, there were significant reductions in accumulations of CD8+ T cells and macrophages in the brain. Our data are most consistent with a model in which interaction of TNF-alpha with TNF-R1 protects against WNV infection by regulating migration of protective inflammatory cells into the brain during acute infection.

  7. The role of serum leptin and tumor necrosis factor-alpha in malnutrition of male chronic obstructive pulmonary disease patients.

    Science.gov (United States)

    Yang, Yi-meng; Sun, Tie-ying; Liu, Xin-min

    2006-04-20

    Leptin is a protein mainly secreted by adipocytes, and the major function of leptin was its role in body weight regulation. It is suggested that increased levels of circulating leptin may contribute to anorexia in pathologic conditions including chronic obstructive pulmonary disease (COPD). Recent studies have provided evidence for a link between leptin and proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha). This study aimed to explore the role of serum leptin in the malnutrition of COPD patients, and to observe the changes of serum leptin levels during acute exacerbation, also to investigate relationship between leptin and TNF-alpha. Seventy-two COPD patients and 34 control subjects participated in this study. Seventy-two COPD patients were divided into 3 groups: group COPD IA (patients without malnutrition during acute exacerbation, n = 25), group COPD IB (patients without malnutrition during stable disease, n = 29), group COPD II (patients with malnutrition during stable disease, n = 18). To eliminate the effect of sex differences, all patients and controls were male. Body mass index (BMI), percent ideal body weight (IBW%), triceps skin-fold thickness (TSF), mid-upper arm circumference (MAC), mid-upper arm muscle circumference (MAMC), serum leptin and TNF-alpha levels, serum prealbumin (PA), serum transferrin (TF), serum albumin (Alb), total lymphocytes count (TLC), forced expiratory volume in one second (FEV(1)), maximal inspiration pressure (MIP) and maximal expiration pressure (MEP) were measured in all participants. Leptin levels were measured by radioimmunoassay. TNF-alpha levels were measured by ELISA. The between group difference and correlation of these parameters were analyzed. Serum leptin levels were significantly lower in group COPD II [(4.07 +/- 3.42) ng/ml] than in group COPD IB [(9.72 +/- 6.67) ng/ml] and controls [(8.21 +/- 5.41) ng/ml] (P leptin levels between group COPD IA [(10.82 +/- 6.40) ng/ml], group COPD IB [(9

  8. Influence of butter and of corn, coconut and fish oils on the effects of recombinant human tumour necrosis factor-alpha in rats.

    Science.gov (United States)

    Mulrooney, H M; Grimble, R F

    1993-01-01

    1. Tumour necrosis factor-alpha is produced in response to inflammatory stimuli. Fish oil can suppress the production and actions of cytokines. Little information is available on the effects of other fats on cytokine biology. We compared the effects of fats, with a wide range of fatty acid characteristics, on the effects of tumour necrosis factor-alpha on protein and zinc metabolism in rats. 2. Weanling rats were fed for 8 weeks on diets containing 10% fat in the form of corn, fish or coconut oils or butter before an intraperitoneal injection of recombinant human tumour necrosis factor-alpha was given. Measurements were made 24h after the injection. 3. In rats fed corn oil, food intake was reduced by 62% and rates of protein synthesis were increased by 86, 32 and 39% in the liver, lung and kidney, respectively. Zinc concentrations increased by 23% in the liver but decreased by 10% in the kidney. Plasma caeruloplasmin and complement C3 levels increased by 25% and 28%, respectively, and plasma albumin level decreased by 24%. 4. Fish oil prevented the increase in hepatic protein synthesis and changed the response of protein synthesis in lung and kidney to a decrease. Changes in hepatic and renal zinc concentrations were prevented. The response of the plasma caeruloplasmin level was unaltered but those of the plasma complement C3 and albumin concentrations were prevented. 5. Coconut oil and butter, although similarly low in linoleic acid, differed in their modulatory effects. With the exception of the rise in the plasma complement C3 concentration, all responses were prevented or greatly inhibited in rats fed butter.(ABSTRACT TRUNCATED AT 250 WORDS)

  9. Polymorphisms in the tumor necrosis factor-alpha gene at position -308 and the inducible 70 kd heat shock protein gene at position +1267 in multifetal pregnancies and preterm premature rupture of fetal membranes.

    Science.gov (United States)

    Kalish, Robin B; Vardhana, Santosh; Gupta, Meruka; Perni, Sriram C; Chasen, Stephen T; Witkin, Steven S

    2004-10-01

    The purpose of this study was to determine the relationship between preterm premature rupture of membranes, tumor necrosis factor-alpha, and heat shock protein-70 gene polymorphisms in multifetal gestations. Buccal swabs from 101 mother-neonate pairs of multifetal pregnancies were tested for single nucleotide polymorphisms at position -308 of the tumor necrosis factor-alpha gene and +1267 of the heat shock protein-70 gene. Pregnancy outcome data were obtained subsequently. Tumor necrosis factor-alpha allele 2 carriage by the first-born occurred in 10 of 27 pregnancies (37.0%) that resulted in preterm premature rupture of membranes compared with 6 of 67 pregnancies (9.0%) without preterm premature rupture of membranes ( P = .002). The allele frequency of tumor necrosis factor-alpha allele 2 and heat shock protein-70 allele 2 in the first born was higher in pregnancies that were complicated by preterm premature rupture of membranes (18.5% vs 4.5%; P = .003; and 57.7% vs 41.3%; P = .04, respectively). There was no relationship between tumor necrosis factor-alpha allele 2 or heat shock protein-70 allele 2 carriage by the second fetus or mother and preterm premature rupture of membranes. Tumor necrosis factor-alpha allele 2 and/or heat shock protein-70 allele 2 carriage by the first-born fetus is associated with preterm premature rupture of membranes in multifetal pregnancies.

  10. Systemic administration of an anti-tumor necrosis factor-alpha monoclonal antibody protects against endotoxin-induced uveitis in rats

    OpenAIRE

    Ge, Qingman; Wang, Shaocheng; Zheng, Yuezhong

    2016-01-01

    Objective: This study was to evaluate the effect of systemic injection of an anti-tumor necrosis factor alpha (TNF-?) monoclonal antibody (mAb) on endotoxin-induced uveitis (EIU). Materials and Methods: Fifty-six male Wistar rats (6?8 weeks old) were randomly divided into three groups: EIU, anti-TNF-? mAb + EIU, and control. EIU was induced by injecting Escherichia coli O55:B5 lipopolysaccharide (LPS) into the hind footpad of the rats (150 ?g/rat). The anti-TNF-? mAb (1 ?g/kg) was administrat...

  11. An inhibitory effect of tumor necrosis factor-alpha antagonist to gene expression in monocrotalineinduced pulmonary hypertensive rats model

    Directory of Open Access Journals (Sweden)

    Jung Hyun kwon

    2013-03-01

    Full Text Available Purpose: Tumor necrosis factor (TNF-?#6185;s thought to contribute to pulmonary hypertension. We aimed to investigate the effect of infliximab (TNF-?#6177;ntagonist treatment on pathologic findings and gene expression in a monocrotaline-induced pulmonary hypertension rat model. Methods: Six-week-old male Sprague-Dawley rats were allocated to 3 groups: control (C, single subcutaneous injection of normal saline (0.1 mL/kg; monocrotaline (M, single subcutaneous injection of monocrotaline (60 mg/kg; and monocrotaline + infliximab (M+I, single subcutaneous injection of monocrotaline plus single subcutaneous injection of infliximab (5 mg/kg. The rats were sacrificed after 1, 5, 7, 14, or 28 days. We examined changes in pathology and gene expression levels of TNF-?#6188;endothelin-1 (ET-1 , endothelin receptor A (ERA , endothelial nitric oxide synthase (eNOS , matrix metalloproteinase (MMP 2, and tissue inhibitor of matrix metalloproteinase (TIMP . Results: The increase in medial wall thickness of the pulmonary arteriole in the M+I group was significantly lower than that in the M group on day 7 after infliximab treatment (P&lt;0.05. The number of intraacinar muscular arteries in the M+I group was lower than that in the M group on days 14 and 28 (P &lt; 0.05. Expression levels of TNF-?#6944;ET-1, ERA, and MMP2 were significantly lower in the M+I group than in the M group on day 5, whereas eNOS and TIMP expressions were late in the M group (day 28. Conclusion: Infliximab administration induced early changes in pathological findings and expression levels of TNF-?#6944;and MMP2 in a monocrotaline-induced pulmonary hypertension rat model.

  12. Association of apoptosis with the inhibition of extracellular signal-regulated protein kinase activity in the tumor necrosis factor alpha-resistant ovarian carcinoma cell line UCI 101.

    Science.gov (United States)

    Yazlovitskaya, E M; Pelling, J C; Persons, D L

    1999-05-01

    Tumor necrosis factor-alpha (TNF alpha) can function as both an autocrine and a paracrine growth factor and may therefore play a role in ovarian tumor progression. TNF alpha initiates multiple cellular responses, many of which are mediated through the mitogen-activated protein kinase pathways, which transduce signals from the TNF alpha receptors through the cytoplasm to the nucleus, resulting in regulation of gene expression. We examined the role of c-jun N-terminal kinase 1 (JNK1) and extracellular signal-regulated protein kinase (ERK) 1 and 2 in the cellular growth response to TNF alpha in the ovarian carcinoma cell line UCI 101. JNK1 activity was increased to a maximum level ninefold above the basal level after 10-20 min of treatment with 10 ng/mL TNF alpha. A maximum threefold induction of ERK1/2 activity was observed after 1 min of treatment. At concentrations up to 100 ng/mL, TNF alpha had neither a stimulatory nor an inhibitory effect on growth of UCI 101 cells. However, inhibition of TNF alpha-induced ERK1/2 activity by the MAP/ERK kinase 1 inhibitor PD 98059 resulted in 60% inhibition of cell growth in TNF alpha-treated UCI 101 cells. This decrease in cell growth was accompanied by apoptosis, as demonstrated by the presence of a 180-bp DNA ladder. Thus, the inhibition of TNF alpha-induced ERK1/2 activity was associated with induction of apoptosis in the TNF alpha-resistant cell line UCI 101. Inhibition of TNF alpha-induced ERK1/2 activity was accompanied by a subsequent transient increase in TNF alpha-induced JNK1 activity. The significance of this increase with respect to apoptosis induction remains to be determined. These findings demonstrated that ERK1/2 activity can modulate cellular sensitivity to TNF alpha and suggested that the balance between the levels of ERK1/2 and JNK1 activation may be critical in the cellular growth response to TNF alpha.

  13. Phase I study of bryostatin 1: assessment of interleukin 6 and tumor necrosis factor alpha induction in vivo. The Cancer Research Campaign Phase I Committee.

    Science.gov (United States)

    Philip, P A; Rea, D; Thavasu, P; Carmichael, J; Stuart, N S; Rockett, H; Talbot, D C; Ganesan, T; Pettit, G R; Balkwill, F

    1993-11-17

    Many oncogenes have been shown to code for growth factor receptors that are involved in regulation of cell growth and proliferation and can activate transcription via protein kinase C. Bryostatin 1, a partial agonist of protein kinase C, has demonstrated potent antitumor activity in vitro and in vivo in human tumor xenografts. The aim of this phase I study was to determine the optimal dosage and toxicity profile of bryostatin 1 and its influence on cytokine release in vivo. Three successive cohorts consisting of 35 patients with various malignant tumors were treated with bryostatin 1 by intravenous infusion over 1 hour as follows: cohort A--35 micrograms/m2 (three patients) or 50 micrograms/m2 (eight patients) once every 2 weeks; cohort B--25 micrograms/m2 once a week (eight patients); and cohort C--25 micrograms/m2 once a week for 3 weeks, with no treatment during the 4th week (16 patients). Plasma levels of tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) were measured by immunoradiometric assay and by radioimmunoassay, respectively. The dose-limiting toxicity was grade 3 or 4 myalgia in four of 11 patients in cohort A, in two of eight in cohort B, and in none of 16 in cohort C. Occurrence of myalgia was dose related. There was no significant myelosuppression, apart from a small and transient fall in platelet count. Six patients experienced acute but transient skin flushing, dyspnea, hypotension, and bradycardia, probably related to the bryostatin 1 vehicle. TNF-alpha and IL-6 were detected in plasma at 2 and 24 hours after treatment, respectively, and the levels were dose related (P = .02). Two patients with metastatic malignant melanoma had partial remission after three or four cycles of therapy; remission lasted 6 weeks and 10+ months, respectively. The dose-limiting toxicity of bryostatin 1 was myalgia. Plasma IL-6 and TNF-alpha concentrations were increased within 24 hours of therapy. Antitumor activity against malignant melanoma was observed

  14. A randomized, double-blind, placebo-controlled study of tumor necrosis factor-alpha blockade in severe persistent asthma

    NARCIS (Netherlands)

    Wenzel, Sally E.; Barnes, Peter J.; Bleecker, Eugene R.; Bousquet, Jean; Busse, William; Dahlén, Sven-Erik; Holgate, Stephen T.; Meyers, Deborah A.; Rabe, Klaus F.; Antczak, Adam; Baker, James; Horvath, Ildiko; Mark, Zsuzsanna; Bernstein, David; Kerwin, Edward; Schlenker-Herceg, Rozsa; Lo, Kim Hung; Watt, Rosemary; Barnathan, Elliot S.; Chanez, Pascal; Chanez, P.; Tunon-de-Lara, M.; Antczak, A.; Pierzchala, W.; Bukowczan, Z.; Trawinska, E.; Baker, J.; Wenzel, S. E.; Katial, R.; Bernstein, D.; Kerwin, E.; Bensch, G.; Castro, M.; Noonan, M.; Nayak, A.; Chupp, G.; Kline, J.; Busse, W.; Kavuru, M. S.; Lang, D.; Wolfe, R.; Baughman, R.; Korenblat, P.; Mansfield, L.; Bleecker, E.; Lisberg, E.; Liu, M.; Panettieri, R.; Spangenthal, S.; Bel, E. H.

    2009-01-01

    RATIONALE: The treatment effect of golimumab, a human monoclonal antibody against tumor necrosis factor (TNF)-alpha, in severe persistent asthma is unknown. OBJECTIVES: To assess the safety and efficacy of golimumab in a large population of patients with uncontrolled, severe persistent asthma.

  15. Activity and tissue-specific expression of lipases and tumor-necrosis factor alpha in lean and obese cats.

    NARCIS (Netherlands)

    Hoenig, M.; McGoldrick, J.B.; Beer, M. de; Demacker, P.N.M.; Ferguson, D.C.

    2006-01-01

    Post-heparin plasma activity of lipoprotein lipase (LPL) and hepatic lipase (HL), and fat and muscle activity of LPL were measured in neutered lean and obese cats. Lipoprotein lipase, hormone-sensitive lipase (HSL), and tumor necrosis factor a (TNF) mRNA were measured in muscle and fat tissue with

  16. The effect of chronic periodontitis on serum levels of tumor necrosis factor-alpha in Alzheimer disease.

    Science.gov (United States)

    Farhad, Shirin Zahra; Amini, Shahram; Khalilian, Amir; Barekatain, Majid; Mafi, Morvarid; Barekatain, Mehrdad; Rafei, Ehsan

    2014-09-01

    Despite the outbreak in dental science, oral and dental complications in Alzheimer are of the unsolved problems. It is assumed that tumor necrosis factor-α, which is a key factor in Alzheimer, has a relation with periodontal complications in patients with Alzheimer disease. The present study evaluated the effect of chronic periodontitis on serum levels of tumor necrosis factor-α in Alzheimer disease. This case-control study was performed on 80 patients with Alzheimer disease seeking medical care at Nour Hospital, Isfahan, Iran. Eighty patients with Alzheimer disease between 40 and 70 years old attended this study. Forty had chronic periodontitis (case group), and 40 patients had healthy periodontium (control group). Blood sample was taken, and serum levels of tumor necrosis factor-α were measured by means of an ELISA Reader device. Independent T-Test was used to analyze data, and P patients with Alzheimer and periodontitis was approximately three folds higher than the patients only with Alzheimer, and this difference was statistically significant (P patient with Alzheimer and chronic periodontitis and patients with Alzheimer disease and healthy periodontium. Tumor necrosis factor-α level in serum may act as a diagnostic marker of periodontal disease in patients with Alzheimer disease.

  17. Maturation of human dendritic cells by monocyte-conditioned medium is dependent upon trace amounts of lipopolysaccharide inducing tumour necrosis factor alpha

    DEFF Research Database (Denmark)

    Nersting, Jacob; Svenson, Morten; Andersen, Vagn

    2003-01-01

    We investigated the ability of monocyte-conditioned medium (MCM), generated by monocytes cultured on plastic-immobilised immunoglobulin, to stimulate maturation of human monocyte-derived dendritic cells (DC). Earlier reports suggest that MCM is a strong inducer of irreversible DC maturation......, whereas we find, that adding a small amount of lipopolysaccharide (LPS) to the MCM-generating cultures is required for the production of a DC-stimulatory MCM. Moreover, compared with addition of LPS directly to the DC cultures, stimulation via MCM cultures increases by several fold the DC......-stimulatory potency of LPS. Maturation by this procedure is mediated mainly by tumour necrosis factor alpha secreted from monocytes during the medium-conditioning period....

  18. A low concentration of ethanol reduces the chemiluminescence of human granulocytes and monocytes but not the tumor necrosis factor alpha production by monocytes after endotoxin stimulation

    DEFF Research Database (Denmark)

    Parlesak, Alexandr; Diedrich, J. P.; Schäfer, Christian

    1998-01-01

    necrosis factor alpha (TNF-alpha) from Mphi. Further, the efficiency of ethanol to inactivate chemically generated ROS was tested. Significant stimulation of ROS release occurred at endotoxin concentrations of 1 ng/ml or higher in both PMNs and Mphi. Ethanol significantly suppressed the formation of ROS...... identical (6 to 8 ng/ml) in both PMNs and Mphi, independent of the presence of ethanol. In contrast to ROS formation, ethanol had no effect on the amount of TNF-alpha produced by endotoxin-stimulated Mphi. Ethanol was shown to be unable to decrease the levels of chemically generated ROS under physiological......The ability of polymorphonuclear neutrophils (PMNs) and monocytes (Mphi) to produce reactive oxygen species (ROS) has been related closely to their potential in the killing of microorganisms. Ethanol has been shown to impair the generation of ROS in these phagocytes after stimulation with some...

  19. Interleukin-1beta and tumor necrosis factor-alpha are expressed by different subsets of microglia and macrophages after ischemic stroke in mice

    DEFF Research Database (Denmark)

    Clausen, Bettina H; Lambertsen, Kate L; Babcock, Alicia A

    2008-01-01

    BACKGROUND: Interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) are expressed by microglia and infiltrating macrophages following ischemic stroke. Whereas IL-1beta is primarily neurotoxic in ischemic stroke, TNF-alpha may have neurotoxic and/or neuroprotective effects. We...... artery occlusion in mice, validating the results by the use of bone marrow chimeric mice. RESULTS: We found that IL-1beta and TNF-alpha were expressed in largely segregated populations of CD11b+CD45dim microglia and CD11b+CD45high macrophages, with cells expressing both cytokines only rarely. The number...... of Gr1+ granulocytes producing IL-1beta or TNF-alpha was very low, and we observed no IL-1beta- or TNF-alpha-expressing T cells or astrocytes. CONCLUSION: Taken together, the results show that IL-1beta and TNF-alpha are produced by largely segregated populations of microglia and macrophages after...

  20. Increased severity of experimental autoimmune encephalomyelitis, chronic macrophage/microglial reactivity, and demyelination in transgenic mice producing tumor necrosis factor-alpha in the central nervous system

    DEFF Research Database (Denmark)

    Taupin, V; Renno, T; Bourbonnière, L

    1997-01-01

    Tumor necrosis factor-alpha (TNF-alpha) is an inflammatory cytokine implicated in a number of autoimmune diseases. Apoptotic cell death is induced by TNF-alpha in vitro, and has been suggested as one cause of autoimmune pathology, including autoimmune demyelinating diseases where oligodendrocytes...... are a target of immune attack. TNF-alpha also regulates macrophage activity which could contribute to autoimmune inflammation. We have expressed TNF-alpha at disease-equivalent levels in the central nervous system of transgenic mice, using a myelin basic protein (MBP) promoter. These mice were normal...... and showed no spontaneous pathology, but they developed experimental autoimmune encephalomyelitis (EAE) with greater severity than nontransgenic controls when immunized with MBP in adjuvant. Unlike nontransgenic controls, EAE then progressed to a nonabating demyelinating disease. Macrophage...

  1. The effect of clomethiazole on plasma concentrations of interleukin-6, -8, -1beta, tumor necrosis factor-alpha, and neutrophil adhesion molecule expression during experimental extracorporeal circulation.

    LENUS (Irish Health Repository)

    Harmon, D

    2012-02-03

    Clomethiazole (CMZ), a neuroprotective drug, has antiinflammatory actions. We investigated the effects of CMZ administration on plasma concentrations of interleukin (IL)-6, IL-8, IL-1beta, tumor necrosis factor-alpha, and neutrophil adhesion molecule expression during experimental extracorporeal circulation. Five healthy volunteers each donated 500 mL of blood, which was subsequently divided into equal portions. Identical extracorporeal circuits were simultaneously primed with donated blood (250 mL) and circulated for 2 h at 37 degrees C. CMZ was added to 1 of the circuits of each pair to achieve a total plasma concentration of 40 micro mol\\/L. Blood samples were withdrawn at (i) donation, (ii) immediately after addition of CMZ, and at (iii) 30, 60, 90, and 120 min after commencing circulation. Plasma concentrations of IL-6, IL-8, and tumor necrosis factor-alpha were less in the CMZ group compared with control after 60 min of circulation (2.2 [0.3] versus 3.2 [0.4], 14.9 [4.8] versus 21.9 [18.4], 63.3 [43.5] versus 132.2 [118.9] pg\\/mL, respectively, P < 0.05). After 120 min of circulation, neutrophils from CMZ-treated circuits showed significantly less CD18 expression compared with control (237.5 [97.4] versus 280.5 [111.5], P = 0.03). The addition of CMZ to experimental extracorporeal circuits decreases the inflammatory response. This effect may be of clinical benefit by decreasing inflammatory-mediated neurological injury during cardiopulmonary bypass. IMPLICATIONS: Enhancement of gamma-aminobutyric acid(A)-mediated effects by clomethiazole (CMZ) and associated neuroprotection has been established in animal models of cerebral ischemia. In an ex vivo study, we demonstrated antiinflammatory activity of CMZ in experimental extracorporeal circulation. This represents a potential neuroprotective mechanism of CMZ in patients undergoing coronary artery bypass surgery.

  2. Canadian Association of Gastroenterology Clinical Practice Guidelines: The use of tumour necrosis factor-alpha antagonist therapy in Crohn’s disease

    Science.gov (United States)

    Sadowski, Daniel C; Bernstein, Charles N; Bitton, Alain; Croitoru, Ken; Fedorak, Richard N; Griffiths, Anne

    2009-01-01

    BACKGROUND: Guidelines regarding the use of infliximab in Crohn’s disease were previously published by the Canadian Association of Gastroenterology in 2004. However, recent clinical findings and drug developments warrant a review and update of these guidelines. OBJECTIVE: To review and update Canadian guidelines regarding the use of tumour necrosis factor-alpha antibody therapy in both luminal and fistulizing Crohn’s disease. METHODS: A consensus group of 25 voting participants developed a series of recommendation statements that addressed pertinent clinical questions and gaps in existing knowledge. An iterative voting and feedback process was used in advance of the consensus meeting in conjunction with a systematic literature review to refine the voting statements. These statements were brought to a formal consensus meeting held in Montreal, Quebec (March 2008), wherein each statement underwent discussion, reformulation, voting and subsequent revision until group consensus was obtained (at least 80% agreement). OUTCOME: The 47 voting statements addressed three themes: induction therapy, maintenance therapy and safety issues. As a result of the iterative process, 23 statements achieved consensus and were submitted for publication. CONCLUSION: In the past five years, tumour necrosis factor-alpha antagonist therapy has become a cornerstone in the management of moderate-to-severe Crohn’s disease refractory to conventional treatment algorithms. The evidentiary base supporting the use of these drugs in Crohn’s disease is substantial and strengthened by results from long-term clinical and molecular studies. However, significant gaps in knowledge exist, particularly with regard to treatment failure. Confidence in the safety of these drugs is increasing, provided that therapy is administered in a clinical setting in which potential complications can be readily recognized and treated. PMID:19319383

  3. Predicting death from tumour necrosis factor-alpha and interleukin-6 in 80-year-old people

    DEFF Research Database (Denmark)

    Bruunsgaard, H; Ladelund, S; Pedersen, A N

    2003-01-01

    % of the variability in IL-6 and effects of the two cytokines were independent of each other as well as of other traditional risk factors for death [smoking, blood pressure, physical exercise, total cholesterol, co-morbidity, body mass index (BMI) and intake of anti-inflammatory drugs]. These findings indicate......Ageing is associated with low-grade inflammation and markers such as IL-6 possess prognostic value. Tumour necrosis-alpha (TNF-alpha) initiates the inflammatory cascade and has been linked to several age-associated disorders. It remains, however, unknown if TNF-alpha is associated with mortality......-alpha and IL-6 on survival in the following 6 years. A total of 133 participants died during this follow-up period. TNF-alpha was associated with mortality in men, but not in women, whereas low-grade elevations in IL-6 were associated strongly with mortality in both sexes. TNF-alpha explained only 7...

  4. Predicting death from tumour necrosis factor-alpha and interleukin-6 in 80-year-old people

    DEFF Research Database (Denmark)

    Bruunsgaard, H; Ladelund, S; Pedersen, A N

    2003-01-01

    Ageing is associated with low-grade inflammation and markers such as IL-6 possess prognostic value. Tumour necrosis-alpha (TNF-alpha) initiates the inflammatory cascade and has been linked to several age-associated disorders. It remains, however, unknown if TNF-alpha is associated with mortality...... in old populations. The aim of the present study was to investigate if serum levels of TNF-alpha were associated with all-cause mortality independently of interleukin (IL)-6 in a prospective study of 333 relatively healthy 80-year-old people. A Cox regression model was used to explore effects of TNF......% of the variability in IL-6 and effects of the two cytokines were independent of each other as well as of other traditional risk factors for death [smoking, blood pressure, physical exercise, total cholesterol, co-morbidity, body mass index (BMI) and intake of anti-inflammatory drugs]. These findings indicate...

  5. Predicting death from tumour necrosis factor-alpha and interleukin-6 in 80-year-old people

    DEFF Research Database (Denmark)

    Bruunsgaard, H.; Ladelund, S.; Pedersen, Agnes Nadelmann

    2003-01-01

    Ageing is associated with low-grade inflammation and markers such as IL-6 possess prognostic value. Tumour necrosis-alpha (TNF-alpha ) initiates the inflammatory cascade and has been linked to several age-associated disorders. It remains, however, unknown if TNF-alpha is associated with mortality...... in old populations. The aim of the present study was to investigate if serum levels of TNF-alpha were associated with all-cause mortality independently of interleukin (IL)-6 in a prospective study of 333 relatively healthy 80-year-old people. A Cox regression model was used to explore effects of TNF......% of the variability in IL-6 and effects of the two cytokines were independent of each other as well as of other traditional risk factors for death [smoking, blood pressure, physical exercise, total cholesterol, co-morbidity, body mass index (BMI) and intake of anti-inflammatory drugs]. These findings indicate...

  6. High circulating levels of tumor necrosis factor-alpha in centenarians are not associated with increased production in T lymphocytes

    DEFF Research Database (Denmark)

    Sandmand, Marie; Bruunsgaard, Helle; Kemp, Kåre

    2003-01-01

    BACKGROUND: Aging is characterized by increased inflammatory activity reflected by increased plasma levels of proinflammatory cytokines, concomitant with an altered cytokine profile of T lymphocytes. High plasma levels of tumor necrosis factor (TNF)-alpha are strongly associated with morbidity...... and mortality in elderly humans. However, the cellular source and mechanisms for the increased circulating TNF-alpha levels are unknown. OBJECTIVE: The aim of the present study was to investigate if high plasma levels of TNF-alpha are associated with increased production of TNF-alpha by T lymphocytes in elderly...... humans. METHODS: TNF-alpha production by CD4+ and CD8+ T lymphocytes was measured by flow cytometry following stimulation with phorbol 12-myristate 13-acetate and ionomycin in 28 young controls, 14, 81-year-olds and 25 centenarians. RESULTS: Plasma levels of TNF-alpha increased with increasing age...

  7. Tumour necrosis factor-alpha-induced protein 8 (TNFAIP8) expression associated with cell survival and death in cancer cell lines infected with canine distemper virus.

    Science.gov (United States)

    Garcia, J A; Ferreira, H L; Vieira, F V; Gameiro, R; Andrade, A L; Eugênio, F R; Flores, E F; Cardoso, T C

    2017-06-01

    Oncolytic virotherapy is a novel strategy for treatment of cancer in humans and companion animals as well. Canine distemper virus (CDV), a paramyxovirus, has proven to be oncolytic through induction of apoptosis in canine-derived tumour cells, yet the mechanism behind this inhibitory action is poorly understood. In this study, three human mammary tumour cell lines and one canine-derived adenofibrosarcoma cell line were tested regarding to their susceptibility to CDV infection, cell proliferation, apoptosis, mitochondrial membrane potential and expression of tumour necrosis factor-alpha-induced protein 8 (TNFAIP8). CDV replication-induced cytopathic effect, decrease of cell proliferation rates, and >45% of infected cells were considered death and/or under late apoptosis/necrosis. TNFAIP8 and CDVM gene expression were positively correlated in all cell lines. In addition, mitochondrial membrane depolarization was associated with increase in virus titres (p < 0.005). Thus, these results strongly suggest that both human and canine mammary tumour cells are potential candidates for studies concerning CDV-induced cancer therapy. © 2015 John Wiley & Sons Ltd.

  8. Response of tumour necrosis factor alpha (TNF ) in blood and spleen mice that vaccinated with P.berghei radiation

    International Nuclear Information System (INIS)

    Darlina; Tur R; Teja K

    2015-01-01

    Tumor necrosis factor is a glycoprotein derived from helper T lymphocytes that play an important role in the body's response against malaria infection. However, TNF-α has double play that is on appropriate levels will provide protection and healing, while at excessive levels which may be a response to hyperparasitemia. Thus investigated the expression of TNF alpha secreted blood lymphocytes and spleen cells the mice that's infected with 1 x 10 7 P.berghei infectious or inactivated by radiation. Levels of TNF alpha serum and spleen cell culture medium was monitored on days 2, 7, 14 post infection. Monitoring of parasite growth every two days for 60 days. Determination of TNF alpha levels were measure using ELISA. The results showed parasitaemia mice infected with 175 Gy irradiated parasites have pre patent period of 16 days longer than the control (non-irradiated parasites) with low parasitaemia. TNF alpha concentration that secreted spleen cells of mice vaccinated higher than control mice. Concentration of TNF alpha that secreted blood lymphocyte of mice vaccinated lower than control mice. It was concluded that the secretion of TNF alpha by blood lymphocytes caused more pathogenic factors of the parasite, while the secretion of TNF alpha in spleen due to an immune response against the parasite. (author)

  9. Tumor necrosis factor alpha and alpha-1 antitrypsin gene variants in Serbian pediatric arterial ischemic stroke patients

    Directory of Open Access Journals (Sweden)

    Đorđević Valentina

    2013-01-01

    Full Text Available The etiology of arterial ischemic stroke (AIS in children is complex, and different from that in adults. Although rare, stroke in children is an important cause of mortality and morbidity. There is increasing evidence that genetic factors, including inflammation mediators, have a role in occurrence and outcome of stroke. We have chosen to assess the role of polymorphism -308G/A in the promoter of tumor necrosis factor α (TNFα gene and S and Z mutations in alpha 1-antitrypsin (AAT gene in the etiology of stroke in children. TNFα polymorphism affects plasma levels of this proinflamatory cytokine, and this could contribute to stroke pathology. It has been shown that increased AAT concentration may present a risk for AIS in children. Since S and Z mutations in AAT gene reduce its levels in plasma they could have a protective role in pediatric stroke. In this study twenty six children with AIS and 100 unrelated individuals from Serbian general population were investigated by PCR/RFLP for these gene variations. No statistically significant difference was observed between patients and general population in distribution of genotypes for -308G/A TNFα polymorphism, so its contributory role in the etiology of stroke was not evident in our group of patients. None of the tested AAT gene mutations were found in patients, which is in concordance with the proposed protective role of deficient AAT variants. AIS is a multifactorial disease, with many genes having a modest role in its pathophysiology, so further analyses of their combined effect are needed to elucidate genetic risk factors in the etiology and outcome of stroke in pediatric patients.

  10. Interleukin-8 production in response to tumor necrosis factor-alpha by cholesteatoma keratinocytes in cell culture.

    Science.gov (United States)

    Hilton, Christopher W; Ondrey, Frank G; Wuertz, Beverley R; Levine, Samuel C

    2011-02-01

    Keratinocytes harvested from acquired cholesteatoma and grown in cell culture will demonstrate increased interleukin-8 (IL-8) production in response to tumor necrosis factor (TNF)-alpha as compared with a control keratinocyte cell line. Immunohistochemical studies have identified IL-8 and TNF-alpha, mediators of bony destruction, in tissue samples of cholesteatoma. TNF-alpha stimulates IL-8 production in healthy epidermal keratinocyte cell lines. It is not known whether TNF-alpha stimulates IL-8 production in cultured cholesteatoma keratinocytes. Prospective controlled tissue culture experiment. Tissue from an acquired cholesteatoma was dissociated and grown in keratinocyte serum-free media for 8 weeks. Cholesteatoma keratinocytes and a control cell line of skin epidermal keratinocytes were treated with TNF-alpha. Conditioned media were harvested; production of IL-8 was measured by enzyme-linked immunosorbent assay, and cell counts were performed. At a zero concentration of TNF-alpha, mean production of IL-8 by cholesteatoma keratinocytes was 39,809 pg/mL/24hr/1 × 10(6) cells versus 1,907 pg/mL/24hr/1 × 10(6) cells from skin epidermal keratinocytes, a statistically significant difference (P alpha and a 2.44-fold increase in response to 20 pg/mL of TNF-alpha. The skin epidermal keratinocyte cell line demonstrated a 1.07- and 1.13-fold increase to respective concentrations of TNF-alpha. Cholesteatoma keratinocytes appear to retain cell signaling characteristics in vitro that distinguish them from skin epidermal keratinocytes. This finding may indicate that cholesteatoma keratinocytes undergo a change in behavior in vivo that is preserved after the cells are removed from the inflammatory environment of the middle ear. Copyright © 2011 The American Laryngological, Rhinological, and Otological Society, Inc.

  11. Tumour necrosis factor alpha inhibitor therapy and rehabilitation for the treatment of ankylosing spondylitis: a systematic review.

    Science.gov (United States)

    Lubrano, Ennio; Spadaro, Antonio; Amato, Giorgio; Benucci, Maurizio; Cavazzana, Ilaria; Chimenti, Maria Sole; Ciancio, Giovanni; D Alessandro, Giuseppe; Angelis, Rossella De; Lupoli, Salvatore; Lurati, Alfredo Maria; Naclerio, Caterina; Russo, Romualdo; Semeraro, Angelo; Tomietto, Paola; Zuccaro, Carmelo; De Marco, Gabriele

    2015-04-01

    To systematically review the evidence for a synergistic effect of combining rehabilitation with biological anti-tumour necrosis factor (TNF) therapy in patients with ankylosing spondylitis (AS). Data were analysed to identify the most effective rehabilitation programmes, the best endpoints for effectiveness, and patient subgroups most likely to benefit from combination therapy. Systematic MEDLINE and Embase searches were performed to identify studies evaluating rehabilitation programmes and biological therapy in patients with AS. Evidence was categorised by study type, and efficacy, adverse effects and other outcomes were summarised. Of the 75 studies identified, 13 investigated the combination of a rehabilitation programme with TNF inhibitor therapy, while the remainder studied rehabilitation with standard therapy (often not specified). Data from these few studies suggest that combined rehabilitation plus anti-TNF therapy is more effective in terms of symptom severity, disease activity, disability and quality-of-life indices versus biologic alone or rehabilitation with standard medical therapy, or, in non-comparative studies, compared with baseline. The most effective rehabilitation appears to be supervised or in-patient programmes with an educational component. Available data do not provide guidance on most appropriate endpoints or identify patients most likely to benefit from combination therapy. Combined, TNF inhibitor and rehabilitation therapy appear to have a synergistic effect, possibly due to increased adherence to exercise. Exercise regimes are more effective if supervised and include an education component. Further randomized, controlled trials comparing endpoints and investigating longer-term benefits of combining TNF inhibitors with rehabilitation in different AS subgroups are needed. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor alpha inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial

    NARCIS (Netherlands)

    Smolen, Josef S.; Kay, Jonathan; Doyle, Mittie K.; Landewé, Robert; Matteson, Eric L.; Wollenhaupt, Jürgen; Gaylis, Norman; Murphy, Frederick T.; Neal, Jeffrey S.; Zhou, Yiying; Visvanathan, Sudha; Hsia, Elizabeth C.; Rahman, Mahboob U.; Ahern, Michael John; Hall, Stephen; Nash, Peter Thomas; Graninger, Winfried; Ebner, Wolfgang; Machold, Klaus; Zamani, Omid; Atkins, Christopher; Beaulieu, André; Bell, Mary; Fitzcharles, Mary Ann; Keystone, Edward; Khraishi, Majed; McKendry, Robert J. R.; Rahman, Proton; Thomason, Glen T. D.; Thorne, J. Carter; Bookman, Arthur; Faraawi, Rafat; Hannonen, Pekka; Leirisalo-Repo, Marjetta; Järvinen, Pentti; Braun, Jürgen; Burmester, Gerd; Fiehn, Christoph; Gruenke, Mathias; Bäuerle, Michael; Hauer, Rolf-Walter; Kellner, Herbert; Rubbert, Andrea; Schewe, Stefan; Sieper, Joachim; Tony, Hans-Peter; Kekow, Jörn; Ching, Daniel Wai Tho; Jones, Peter Brian Barrie; Singh, Gagrath Pradeep

    2009-01-01

    Tumour necrosis factor alpha (TNFalpha) inhibitors are frequently used to treat rheumatoid arthritis, but whether use of a different TNFalpha inhibitor can improve patient response is unknown. We assess the efficacy and safety of the TNFalpha inhibitor golimumab in patients with active rheumatoid

  13. Release of tumor necrosis factor alpha and interleukin 6 during antibiotic killing of Escherichia coli in whole blood: influence of antibiotic class, antibiotic concentration, and presence of septic serum

    NARCIS (Netherlands)

    Prins, J. M.; Kuijper, E. J.; Mevissen, M. L.; Speelman, P.; van Deventer, S. J.

    1995-01-01

    The concentration and accessibility of endotoxin can increase following antibiotic killing of gram-negative bacteria. There are indications that antibiotics may differ in this respect. We measured endotoxin levels in RPMI 1640 and tumor necrosis factor alpha (TNF-alpha) and interleukin-6 production

  14. Lipopolysaccharide-induced cytokine production in peripheral blood mononuclear cells : Intracellular localization of tumor necrosis factor alpha and interleukin 1 beta detected with a three-color immunofluorescence technique

    NARCIS (Netherlands)

    deBont, ESJM; Niemarkt, AE; Tamminga, RYJ; Kimpen, JLL; Kamps, WA; deLeij, LHMF

    1996-01-01

    Lipopolysaccharide (LPS) can induce monocytes to produce various cytokines such as tumor necrosis factor alpha (TNF alpha) and interleukin 1 beta (IL-1 beta). In the present study, the kinetics of both intracellular and extra cellular accumulation of TNF alpha and IL-1 beta in LPS stimulated

  15. Relationship of tumor necrosis factor alpha genotypes with various biochemical parameters of normal, over weight and obese human subjects

    International Nuclear Information System (INIS)

    Raza, M.; Chaudhary, B.; Shakoori, A.R.

    2008-01-01

    Tumor Necrosis Factor (TNF-alpha) is expressed primarily in adipocytes and elevated levels of this cytokine have been associated with obesity. The purpose of this investigation was to test whether the TNF-alpha -308 polymorphism were associated with insulin resistance or obesity related traits in non-diabetic and diabetic patients visiting Sheikh Zayed Hospital, Lahore, Fatima Hospital and Irfan Clinic in Sargodha. In non diabetic subjects the AA allele carriers, compared with homozygous G allele carriers had significantly lower (28%) triglyceride values and 15% higher HDL yal ues, whereas other parameters tested 81id not show any significant variation. In diabetic patients the AA allele carriers, compared with GG allele carriers, besides having 31 % higher FBS and 26% higher creatinine, had 20% higher cholesterol and 34% higher triglycerides. The HDL values were 14% less, compared to GG allele carriers. In normal subjects (BMI 22.85:1:0.25 kgim2), the AA allele carriers showed 132%, 125%, 65% and 112% higher triglycerides, cholesterol and LDL values compared with GG allele carriers. The HDL and creatinine did not show any significant change. In the overweight subjects (BMI: 27.17+-0.17 kgim/sup 2/) all these values were lower than in AA allele carriers compared with GG allele carriers. The AA allele carries had FBS, triglycerides, cholesterol and LDL 28%, 48%, 14% and 14% lower than in the GG allele' carriers, respectively. In obese subjects, (BMI: 36.73+-0.78kgm/sup 2/), however, the FBS, triglycerides, cholesterol and creatinine values were 5%, 8%, 7% and 14% higher in AA allele carries compared to GG allele carriers, respectively. The LDL content was 8% lower in AA allele carrier as compared with the respective GG allele carriers, It is concluded that replacement of G at -308 with A leads to reduced risk for cardiovascular disease in non-diabetic subject, whereas in diabetic patients this mutation-increases the risk of CVD. Using BMI as index of obesity, it was

  16. Tumor necrosis factor-alpha and interleukin -6 as diagnostic markers of diabetic complications in children with type I diabetes mellitus

    International Nuclear Information System (INIS)

    El-Nashar, N.A.; Moawad, A.T.; Nassar, E.M.

    2010-01-01

    This study aimed to determine the role of cellular auto immunity and its humoral mediators in pathogenesis and following up of type I diabetes mellitus (TIDM). Therefore, serum concentrations of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), glycemic control, body mass index, duration of the disease and microalbuminuria in children with TIDM were evaluated. This study was conducted on 30 patients suffered from type I diabetes mellitus (TIDM), 14 males and 16 females with mean age of 11.40 ±3.67 years and 20 apparently healthy children served as control (10 male and 10 female). Children with TIDM were classified according to duration: diabetic children for 5 years or less duration (n= 15, duration means: 2.74 ± 1.34 years) and diabetic children > 5 years (n=15, duration means: 7.35 ± 1.49 years); according to glycemic control: children with good glycemic control (n=16, HbAIc: 7.82 ± 2.70) and diabetic children with poor glycemic control (n=14, HbAIc: 10.49 ± 2.72) and according to complication: diabetic children without complications (n= 20) and diabetic children with microvascular or neurological complications (n= 10, nephritic, retinal or neurological complications). Patients and controls were subjected to careful history, clinical examination and laboratory investigations. The following investigations were done for all children; random blood glucose, Glycated hemoglobin (HbAIc %), microalbuminuria and kidney function tests. Serum tumour necrosis factor-alpha (TNF-alpha) and serum interleukin-6 (IL-6) were measured using immuno-enzymometric assay (ELISA). Patients with TIDM with duration more than 5 years, with poor glycemic control and with complications had higher serum glucose levels, higher HbAIc%, higher level of blood urea nitrogen (BUN), serum creatinine, microalbuminuria and elevated serum TNF-alpha (p<0.0001) and IL-6 (p<0.0001) in comparison to the same diabetic patients with 5 years duration or less, with good glycemic control

  17. Expression of tumor necrosis factor-alpha-mediated genes predicts recurrence-free survival in lung cancer.

    Directory of Open Access Journals (Sweden)

    Baohua Wang

    Full Text Available In this study, we conducted a meta-analysis on high-throughput gene expression data to identify TNF-α-mediated genes implicated in lung cancer. We first investigated the gene expression profiles of two independent TNF-α/TNFR KO murine models. The EGF receptor signaling pathway was the top pathway associated with genes mediated by TNF-α. After matching the TNF-α-mediated mouse genes to their human orthologs, we compared the expression patterns of the TNF-α-mediated genes in normal and tumor lung tissues obtained from humans. Based on the TNF-α-mediated genes that were dysregulated in lung tumors, we developed a prognostic gene signature that effectively predicted recurrence-free survival in lung cancer in two validation cohorts. Resampling tests suggested that the prognostic power of the gene signature was not by chance, and multivariate analysis suggested that this gene signature was independent of the traditional clinical factors and enhanced the identification of lung cancer patients at greater risk for recurrence.

  18. Tumor necrosis factor-alpha-induced reduction of glomerular filtration rate in rats with fulminant hepatic failure.

    Science.gov (United States)

    Wang, Jing-Bo; Wang, Dong-Lei; Wang, Hai-Tao; Wang, Zhao-Han; Wen, Ying; Sun, Cui-Ming; Zhao, Yi-Tong; Wu, Jian; Liu, Pei

    2014-07-01

    The mechanism of renal failure during fulminant hepatic failure (FHF) or end-stage of liver disease is not fully understood. The present study aims to delineate the mechanisms of decreased glomerular filtration rate (GFR) in acute hepatic failure. A rat model of renal insufficiency in severe liver injury was established by lipopolysaccharide (LPS) plus D-galactosamine (GalN) exposure. GFR was evaluated by continuous infusion of fluorescein isothiocyanate-inulin with implanted micro-osmotic pumps. GalN/LPS intoxication resulted in severe hepatocyte toxicity as evidenced by liver histology and biochemical tests, whereas renal morphology remained normal. GFR was reduced by 33% of the controls 12 h after GalN/LPS exposure, accompanied with a decreased serum sodium levels, a marked increase in serum TNF-α and ET-1 levels as well as significantly upregulated renal type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) expression. The upregulated IP3R1 expression was abrogated by the treatment of anti-TNF-α antibodies, but not by 2-aminoethoxydiphenylborate (2-APB), which blocks the inositol 1,4,5-trisphosphate signaling pathway. Treatments with either TNF-α antibodies or 2-APB also significantly improved the compromised GFR, elevated serum urea nitrogen and creatinine levels, and reversed the decrease in glomerular inulin space and the increase in glomerular calcium content in GalN/LPS-exposed rats. The extent of acute liver injury as reflected by serum ALT levels was much more attenuated by anti-TNF-α antibodies than by 2-APB. Liver histology further confirmed that anti-TNF-α antibodies conferred better protection than 2-APB in GalN/LPS-exposed rats. LPS-elicited TNF-α over-production is responsible for decreased GFR through IP3R1 overexpression, and the compromised GFR resulted in the development of acute renal failure in rats with FHF.

  19. Inflammatory cascades driven by tumor necrosis factor-alpha play a major role in the progression of acute liver failure and its neurological complications.

    Directory of Open Access Journals (Sweden)

    Anne Chastre

    Full Text Available Acute liver failure (ALF due to ischemic or toxic liver injury is a clinical condition that results from massive loss of hepatocytes and may lead to hepatic encephalopathy (HE, a serious neuropsychiatric complication. Although increased expression of tumor necrosis factor-alpha (TNF-α in liver, plasma and brain has been observed, conflicting results exist concerning its roles in drug-induced liver injury and on the progression of HE. The present study aimed to investigate the therapeutic value of etanercept, a TNF-α neutralizing molecule, on the progression of liver injury and HE in mice with ALF resulting from azoxymethane (AOM hepatotoxicity.Mice were administered saline or etanercept (10 mg/kg; i.p. 30 minutes prior to, or up to 6 h after AOM. Etanercept-treated ALF mice were sacrificed in parallel with vehicle-treated comatose ALF mice and controls. AOM induced severe hepatic necrosis, leading to HE, and etanercept administered prior or up to 3 h after AOM significantly delayed the onset of coma stages of HE. Etanercept pretreatment attenuated AOM-induced liver injury, as assessed by histological examination, plasma ammonia and transaminase levels, and by hepatic glutathione content. Peripheral inflammation was significantly reduced by etanercept as shown by decreased plasma IL-6 (4.1-fold; p<0.001 and CD40L levels (3.7-fold; p<0.001 compared to saline-treated ALF mice. Etanercept also decreased IL-6 levels in brain (1.2-fold; p<0.05, attenuated microglial activation (assessed by OX-42 immunoreactivity, and increased brain glutathione concentrations.These results indicate that systemic sequestration of TNF-α attenuates both peripheral and cerebral inflammation leading to delayed progression of liver disease and HE in mice with ALF due to toxic liver injury. These results suggest that etanercept may provide a novel therapeutic approach for the management of ALF patients awaiting liver transplantation.

  20. Changes in gene expression of tumor necrosis factor alpha and interleukin 6 in a canine model of caerulein-induced pancreatitis.

    Science.gov (United States)

    Song, Ruhui; Yu, Dohyeon; Park, Jinho

    2016-07-01

    Acute pancreatitis is an inflammatory process that frequently involves peripancreatic tissues and remote organ systems. It has high morbidity and mortality rates in both human and veterinary patients. The severity of pancreatitis is generally determined by events that occur after acinar cell injury in the pancreas, resulting in elevated levels of various proinflammatory mediators, such as interleukin (IL) 1β and 6, as well as tumor necrosis factor alpha (TNF-α). When these mediators are excessively released into the systemic circulation, severe pancreatitis occurs with systemic complications. This pathophysiological process is similar to that of sepsis; thus, there are many striking clinical similarities between patients with septic shock and those with severe acute pancreatitis. We induced acute pancreatitis using caerulein in dogs and measured the change in the gene expression of proinflammatory cytokines. The levels of TNF-α and IL-6 mRNA peaked at 3 h, at twice the baseline levels, and the serum concentrations of amylase and lipase also increased. Histopathological examination revealed severe hyperemia of the pancreas and hyperemia in the duodenal villi and the hepatic sinusoid. Thus, pancreatitis can be considered an appropriate model to better understand the development of naturally occurring sepsis and to assist in the effective treatment and management of septic patients.

  1. Expression of anti-tumor necrosis factor alpha (TNFα) single-chain variable fragment (scFv) in Spirodela punctata plants transformed with Agrobacterium tumefaciens.

    Science.gov (United States)

    Balaji, Parthasarathy; Satheeshkumar, P K; Venkataraman, Krishnan; Vijayalakshmi, M A

    2016-05-01

    Therapeutic antibodies against tumor necrosis factor alpha (TNFα) have been considered effective for some of the autoimmune diseases such as rheumatoid arthritis, Crohn's diseases, and so on. But associated limitations of the current therapeutics in terms of cost, availability, and immunogenicity have necessitated the need for alternative candidates. Single-chain variable fragment (scFv) can negate the limitations tagged with the anti-TNFα therapeutics to a greater extent. In the present study, Spirodela punctata plants were transformed with anti-TNFα through in planta transformation using Agrobacterium tumefaciens strain, EHA105. Instead of cefotaxime, garlic extract (1 mg/mL) was used to remove the agrobacterial cells after cocultivation. To the best of our knowledge, this report shows for the first time the application of plant extracts in transgenic plant development. 95% of the plants survived screening under hygromycin. ScFv cDNA integration in the plant genomic DNA was confirmed at the molecular level by PCR. The transgenic protein expression was followed up to 10 months. Expression of scFv was confirmed by immunodot blot. Protein expression levels of up to 6.3% of total soluble protein were observed. β-Glucuronidase and green fluorescent protein expressions were also detected in the antibiotic resistant plants. The paper shows the generation of transgenic Spirodela punctuata plants through in planta transformation. © 2015 International Union of Biochemistry and Molecular Biology, Inc.

  2. Polymorphism in the tumor necrosis factor-alpha gene (TNFA -308 G/A is not associated with susceptibility to chronic periodontitis in a Brazilian population

    Directory of Open Access Journals (Sweden)

    Paula Cristina Trevilatto

    2016-02-01

    Full Text Available Objective: Tumor necrosis factor-alpha (TNF-α is a major mediator of the immune-inflammatory response and may play an important role in the pathogenesis and progression of chronic periodontitis. Polymorphisms in the promoter of the TNFA gene have been associated with some types of inflammatory diseases. The present study investigated the association between a single-nucleotide polymorphism (SNP of the TNFA (G-308A gene and chronic periodontitis in Brazilians. Methods: One hundred and thirteen (113 over 25 years were divided according to the severity level of periodontal disease: 44 healthy individuals (control group, 31 subjects with moderate and 38 patients with severe periodontitis. Genomic DNA was obtained from epithelial cells. The samples were analyzed for TNFA (G-308A polymorphism using polymerase chain reaction-restriction fragment length polymorphism techniques. The significance of the differences in the genotype frequencies of the polymorphism was assessed by Chi-square test (p<0.05. Results: No significant differences in the genotype distribution and allele frequency were found between control and groups with periodontitis. Conclusion: It was concluded that TNFA (-308 polymorphism was not associated with chronic periodontitis. Other polymorphisms in this or/and other genes of the host inflammatory response might be involved in determining susceptibility to periodontitis in the study population.

  3. Polymorphisms of Tumor Necrosis Factor Alpha in Moroccan Patients with Gastric Pathology: New Single-Nucleotide Polymorphisms in TNF-α−193 (G/A

    Directory of Open Access Journals (Sweden)

    A. Essadik

    2015-01-01

    Full Text Available Polymorphisms in tumor necrosis factor alpha (TNF-α gene are emerging as key determinants of gastric diseases. The TNF-α−308 (G/A and TNF-α−238 (G/A single-nucleotide polymorphisms SNPs are the most extensively studied. However, all these studies are conducted in Caucasian and Asian populations. Thus, for the first time in Africa, we sought to investigate whether polymorphisms in TNF-α gene were associated with the development of gastric pathology in Morocco. Two SNPs located in the promoter region (positions −308 and −238 in TNF-α gene were genotyped in 244 individuals (170 patients and 74 healthy controls. Odds ratios (ORs and 95% confidence intervals (CI were estimated using logistic regression analysis. The TNF-α−238 (G/A genotype was significantly associated with a high risk of gastritis and gastric cancer (GC (P=0.001 and P=0.002, resp.. Furthermore, a new polymorphism located in the promoter region at position −193 in TNF-α gene was identified. The distribution of this SNP was markedly different in patients suffering from ulcers. The association between TNF-α−193 (G/A genotype and high risk of ulcer was significant (P=0.03. These results suggest that the TNF-α−193 (G/A allele has a protective function against gastric cancer by developing ulcer.

  4. ASTAXANTHIN MENURUNKAN KADAR VASCULAR ENDOTHELIAL GROWTH FACTOR, TUMOR NECROSIS FACTOR ALPHA, INTERLEUKIN-6, DAN NITRIC OXIDE PADA NONPROLIFERATIVE DIABETIC RETINOPATHY RINGAN: UJI KLINIS TERKENDALI

    Directory of Open Access Journals (Sweden)

    Ni Made Laksmi Utari

    2015-01-01

    Full Text Available Diabetic Retinopathy (DR merupakan komplikasi mikrovaskular pada Diabetes Mellitus (DM dan penyebab kebutaan paling sering pada usia produktif. Hiperglikemia menyebabkan terjadinya reaksiinflamasi dan stres oksidatif  dalam patogenesis DR dipaparkan oleh beberapa peneliti, namun peran antioksidan dalam mengurangi progresifitas DR masih menjadi perdebatan. Penelitian ini bertujuanuntuk mengetahui pemberian astaxanthin 8 mg dapat menurunkan kadar Vascular Endothelial Growth Factor (VEGF, Tumor Necrosis Factor-alpha (TNF-á, Interleukin-6 (IL-6 dan Nitric Oxide (NO padapenderita Non Proliferative Diabetic Retinopathy (NPDR ringan. Penelitian clinical trial dengan perluasan Randomized, Double Blinded, Placebo-Control, Pre and Posttest Group Design ini dilaksanakanpada bulan Juli 2013 - Desember 2013 di Poliklinik Mata RSUP Sanglah Denpasar Bali. Jumlah sampel yang memenuhi kriteria eligibilitas sebanyak 40 pasien NPDR ringan terbagi menjadi 20 pasien  sebagai kelompok perlakuan yang diberikan astaxanthin 8 mg dan 20 pasien NPDR ringan yang diberikan plasebo sebagai kelompok kontrol. Pengambilan sampel darah vena untuk pemeriksaan dilakukan sebelum dan setelah pemberian astaxanthin 8 mg serta plasebo selama 4 minggu. Perbedaan kadar rerata VEGF, TNF-á, IL-6 dan NO dianalisis dengan uji-t jika distribusi data normal dan uji Mann-whitney jika distribusi data tidak  normal. Hasil penelitian ini diharapkan dapat memberikaninformasi mengenai hubungan VEGF, TNF-á, IL-6, dan NO dalam perkembangan NPDR ringan serta manfaat pemberian astaxanthin dalam perkembangan NPDR ringan. [MEDICINA 2014;45:31-37

  5. The change of serum tumor necrosis factor alpha in patients with type 1 diabetes mellitus: A systematic review and meta-analysis.

    Directory of Open Access Journals (Sweden)

    Yong-Chao Qiao

    Full Text Available The aim of this study was used meta-analysis to investigate changes of serum tumor necrosis factor-alpha (TNF-α in patients with type 1 diabetes mellitus (T1DM.Relevant literatures were identified from PubMed, Cochrane Library, CNKI, WanFang and Chinese-Cqvip databases (published from January 1, 1999 to September 30, 2016. Eligible reports were included for pooled analysis of serum TNF-α level and subgroup analysis was performed in relation with age, disease duration and ethnicity.A total of 23 articles (1631 T1DM cases, 1429 healthy controls were included for this meta-analysis. Compared with the controls, the patients had significantly increased serum TNF-α level (P < 0.001. Similar results were also found among all subgroup analysis of different age, disease duration and ethnicity (with the exception of Asian (all P < 0.05. Regression analysis indicated that age (P = 0.680, disease duration (P = 0.957, and ethnicity (P = 0.526 of patients were not significant impact factors for the high heterogeneity. The results were stable according to the sensitivity analysis and no publication bias existed in this meta-analysis.Serum TNF-α level in T1DM patients has significantly elevated among all age, disease duration and ethnicity groups.

  6. Evaluation of pretreatment serum interleukin-6 and tumour necrosis factor alpha as a potential biomarker for recurrence in patients with oral squamous cell carcinoma.

    Science.gov (United States)

    Skrinjar, Ivana; Brailo, Vlaho; Vidovic-Juras, Danica; Vucicevic-Boras, Vanja; Milenovic, Aleksandar

    2015-07-01

    Oral squamous cell carcinoma (OSCC) constitutes 3 percent of all cancers with predominant occurrence in middle aged and elderly males. Tumour recurrence worsens disease prognosis and decreases quality of life in patients with OSCC. Proinflammatory cytokines such as interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-α) have been suggested to play a certain role in variety of tumours. The aim of this study was to investigate the relationship of pretreatment serum IL-6 and TNF-α levels on tumour recurrence in patients with OSCC in order to identify potential biomarkers for the early detection of disease recurrence. The patients with newly diagnosed OSCC were treated and followed from the first visit from November 2006 until January 2008. Serum IL-6 and TNF-α concentrations were measured. The records of the patients were re-examined in July 2012 and data were recorded about cancer characteristics and tumour recurrence. Disease free survival was analyzed by Kaplan-Meier survival curves, log rank test and Cox proportional hazards regression. Serum IL-6 was shown as an independent risk factor for tumour recurrence. Pretreatment serum IL-6 concentration may be a useful biomarker for identification of OSCC patients with increased risk of the disease recurrence.

  7. In vitro infection of bovine monocytes with Mycoplasma bovis delays apoptosis and suppresses production of gamma interferon and tumor necrosis factor alpha but not interleukin-10.

    Science.gov (United States)

    Mulongo, Musa; Prysliak, Tracy; Scruten, Erin; Napper, Scott; Perez-Casal, Jose

    2014-01-01

    Mycoplasma bovis is one of the major causative pathogens of bovine respiratory complex disease (BRD), which is characterized by enzootic pneumonia, mastitis, pleuritis, and polyarthritis. M. bovis enters and colonizes bovine respiratory epithelial cells through inhalation of aerosol from contaminated air. The nature of the interaction between M. bovis and the bovine innate immune system is not well understood. We hypothesized that M. bovis invades blood monocytes and regulates cellular function to support its persistence and systemic dissemination. We used bovine-specific peptide kinome arrays to identify cellular signaling pathways that could be relevant to M. bovis-monocyte interactions in vitro. We validated these pathways using functional, protein, and gene expression assays. Here, we show that infection of bovine blood monocytes with M. bovis delays spontaneous or tumor necrosis factor alpha (TNF-α)/staurosporine-driven apoptosis, activates the NF-κB p65 subunit, and inhibits caspase-9 activity. We also report that M. bovis-infected bovine monocytes do not produce gamma interferon (IFN-γ) and TNF-α, although the level of production of interleukin-10 (IL-10) is elevated. Our findings suggest that M. bovis takes over the cellular machinery of bovine monocytes to prolong bacterial survival and to possibly facilitate subsequent systemic distribution.

  8. Plasma Tumor Necrosis Factor-alpha (TNF-α) Levels Correlate with Disease Severity in Spastic Diplegia, Triplegia, and Quadriplegia in Children with Cerebral Palsy.

    Science.gov (United States)

    Wu, Jianxian; Li, Xueming

    2015-12-11

    BACKGROUND Inflammatory responses in utero and in neonates have been involved in the development of white matter lesions. This study aimed to investigate the role of tumor necrosis factor-alpha (TNF-α) in spastic cerebral palsy. MATERIAL AND METHODS Plasma TNF-α was measured by ELISA in 54 children with spastic cerebral palsy and 28 aged-matched controls. Both groups were split into age subgroups (1-3 vs. 4-12). Gross motor function and activities of daily living were assessed on enrollment and after 6 months of rehabilitation. RESULTS TNF-α was higher in patients with cerebral palsy than in controls in young (P<0.001) and older subjects (P<0.001). TNF-α levels were comparable in both control subgroups (P=0.819). Younger patients with cerebral palsy had significantly higher TNF-α levels compared with older ones (P<0.001). Pre-rehabilitation TNF-α levels correlated with improvements in activities of daily living after rehabilitation (P<0.001). CONCLUSIONS Children with cerebral palsy showed higher plasma levels of TNF-α than controls. In addition, pre-treatment TNF-α levels were correlated with the improvements after rehabilitation therapy.

  9. Tumor Necrosis Factor-Alpha Gene Promoter −308G/A and −238G/A Polymorphisms in Mexican Patients with Type 2 Diabetes Mellitus

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    Juan Manuel Guzmán-Flores

    2011-01-01

    Full Text Available The association between some Tumor necrosis factor-alpha (TNF-α promoter polymorphisms and Type 2 diabetes mellitus (T2DM remains controversial. Ethnic differences may play a role in these conflicting results. The aim of this study was to investigate the association between −308G/A and −238G/A polymorphisms located in the promoter region of the TNF-α gene and T2DM in Mexican mestizo patients. Nine hundred four individuals (259 patients with T2DM and 645 controls were genotyped for the −308G/A and −238G/A polymorphisms by PCR—RFLP. We found that the −238A allele increased the risk of developing T2DM in Mexican patients (OR = 1.57, 95% CI: 1.07–2.29; p = 0.018. Moreover, we found that the frequency of the GA haplotype (created by the −308G and −238A alleles was significantly increased in patients with T2DM when compared with controls (OR = 1.56, 95% CI: 1.05–2.31; p = 0.026. Our results suggest that the −238G/A polymorphism and a specific haplotype (GA are genetic risk factors for the development of T2DM in Mexican population.

  10. Tumor necrosis factor alpha is a promising circulating biomarker for the development of obstructive sleep apnea syndrome: a meta-analysis.

    Science.gov (United States)

    Li, Qingsheng; Zheng, Xin

    2017-04-18

    Obstructive sleep apnea syndrome (OSAS) is a chronic inflammatory disorder. The relationship between tumor necrosis factor alpha (TNF-alpha) and OSAS has been widely evaluated, but the results thus far remain inconclusive. We thereby decided to quantify the changes of TNF-alpha between OSAS patients and controls by a meta-analysis. This study complies with the MOOSE guidelines. Two reviewers independently searched articles and abstracted relevant data. In total, 47 articles (59 studies) were analyzed, including 2857 OSAS patients and 2115 controls. Overall, OSAS patients had a significantly higher level of circulating TNF-alpha than controls (weighted mean difference [WMD]: 9.66 pg/mL, 95% confidence interval [CI]: 8.66 to 11.24, Pgrades of OSAS. In patients with mild, mild-to-moderate, moderate, moderate-to-severe and severe OSAS, circulating TNF-alpha was higher than respective controls by 0.99, 1.48. 7.79, 10.08 and 8.85 pg/mL, with significant heterogeneity (I2: 91.2%, 74.5%, 97.6%, 99.0% and 98.1%). In conclusion, our findings demonstrated that circulating TNF-alpha was significantly higher in OSAS patients than in controls, and this difference became more pronounced with the more severe grades of OSAS, indicating that TNF-alpha might be a promising circulating biomarker for the development of OSAS.

  11. Tumor necrosis factor-alpha activates signal transduction in hypothalamus and modulates the expression of pro-inflammatory proteins and orexigenic/anorexigenic neurotransmitters.

    Science.gov (United States)

    Amaral, Maria E; Barbuio, Raquel; Milanski, Marciane; Romanatto, Talita; Barbosa, Helena C; Nadruz, Wilson; Bertolo, Manoel B; Boschero, Antonio C; Saad, Mario J A; Franchini, Kleber G; Velloso, Licio A

    2006-07-01

    Tumor necrosis factor-alpha (TNF-alpha) is known to participate in the wastage syndrome that accompanies cancer and severe infectious diseases. More recently, a role for TNF-alpha in the pathogenesis of type 2 diabetes mellitus and obesity has been shown. Much of the regulatory action exerted by TNF-alpha upon the control of energy stores depends on its action on the hypothalamus. In this study, we show that TNF-alpha activates canonical pro-inflammatory signal transduction pathways in the hypothalamus of rats. These signaling events lead to the transcriptional activation of an early responsive gene and to the induction of expression of cytokines and a cytokine responsive protein such as interleukin-1beta, interleukin-6, interleukin-10 and suppressor of cytokine signalling-3, respectively. In addition, TNF-alpha induces the expression of neurotransmitters involved in the control of feeding and thermogenesis. Thus, TNF-alpha may act directly in the hypothalamus inducing a pro-inflammatory response and the modulation of expression of neurotransmitters involved in energy homeostasis.

  12. Lipid profile of rheumatoid arthritis patients treated with anti-tumor necrosis factor-alpha drugs changes according to disease activity and predicts clinical response.

    Science.gov (United States)

    Cacciapaglia, Fabio; Anelli, Maria Grazia; Rinaldi, Angela; Serafino, Lucia; Covelli, Michele; Scioscia, Crescenzio; Iannone, Florenzo; Lapadula, Giovanni

    2014-11-01

    Patients with active rheumatoid arthritis (RA) frequently show an atherogenic lipid profile, which has been linked with the inflammatory reaction. Inflammatory cytokines, and particularly tumor necrosis factor-alpha (TNF-α), are implicated in the pathogenesis of both atherosclerosis and RA, and also involved in the development of the impaired lipid profile detected in active RA. Although anti-TNF-α agents have been proven effective in controlling joint damage and systemic inflammation, controversy remains about the effect of these drugs on the lipid profile; therefore, the aim of our study was to investigate the effect of anti-TNF-α treatment, in combination with disease-modifying anti-rheumatic drugs (DMARDs) and corticosteroid therapy, on the lipid profile of patients with active RA. Our data suggest that the combination anti-TNF-α/DMARDs/steroids do not significantly interfere with the lipid profile of RA patients. However, analysis of clinical response data showed that patients achieving low disease activity or remission seem to have a protective lipid profile, suggesting that better control of inflammation and disease activity can affect lipid metabolism. The available evidence indicates that high inflammation interferes with lipid metabolism, whereas good control of the chronic inflammatory state may positively influence the lipid profile and cardiovascular risk. Low cholesterol levels at baseline could predict a favorable outcome with anti-TNF-α treatment, but these data need to be confirmed by large prospective studies with long-term follow-up. © 2014 Wiley Periodicals, Inc.

  13. Tumor necrosis factor alpha promotes the expression of immunosuppressive proteins and enhances the cell growth in a human bone marrow-derived stem cell culture

    Energy Technology Data Exchange (ETDEWEB)

    Miettinen, Johanna A., E-mail: johanna.miettinen@oulu.fi [Institute of Clinical Medicine, Department of Internal Medicine, University of Oulu, P.O. Box 5000, FIN-90014 Oulu (Finland); Pietilae, Mika [Institute of Biomedicine, Department of Anatomy and Cell Biology, University of Oulu, P.O. Box 5000, FIN-90014 Oulu (Finland); Salonen, Riikka J. [Institute of Clinical Medicine, Department of Internal Medicine, University of Oulu, P.O. Box 5000, FIN-90014 Oulu (Finland); Institute of Biomedicine, Department of Anatomy and Cell Biology, University of Oulu, P.O. Box 5000, FIN-90014 Oulu (Finland); Ohlmeier, Steffen [Proteomics Core Facility, Biocenter Oulu, Department of Biochemistry, University of Oulu, P.O. Box 3000, FIN-90014 Oulu (Finland); Ylitalo, Kari; Huikuri, Heikki V. [Institute of Clinical Medicine, Department of Internal Medicine, University of Oulu, P.O. Box 5000, FIN-90014 Oulu (Finland); Lehenkari, Petri [Institute of Biomedicine, Department of Anatomy and Cell Biology, University of Oulu, P.O. Box 5000, FIN-90014 Oulu (Finland)

    2011-04-01

    Mesenchymal stem cells (MSCs) are widely used in experimental treatments for various conditions that involve normal tissue regeneration via inflammatory repair. It is known that MSCs can secrete multiple soluble factors and suppress inflammation. Even though the effect of MSCs on inflammation has been extensively studied, the effect of inflammation on MSCs is poorly understood. One of the major cytokines released at the site of inflammation is tumor necrosis factor alpha (TNF-{alpha}) which is known to induce MSC invasion and proliferation. Therefore, we wanted to test the effects of TNF-{alpha} exposure on MSCs derived from human bone marrow. We found, as expected, that cell proliferation was significantly enhanced during TNF-{alpha} exposure. However, according to the cell surface marker analysis, the intensity of several antigens in the minimum criteria panel for MSCs proposed by International Society of Cellular Therapy (ISCT) was decreased dramatically, and in certain cases, the criteria for MSCs were not fulfilled. In addition, TNF-{alpha} exposure resulted in a significant but transient increase in human leukocyte antigen and CD54 expression. Additional proteomic analysis by two-dimensional difference gel electrophoresis and mass spectrometry revealed three proteins whose expression levels decreased and 8 proteins whose expression levels increased significantly during TNF-{alpha} exposure. The majority of these proteins could be linked to immunosuppressive and signalling pathways. These results strongly support reactive and immunosuppressive activation of MSCs during TNF-{alpha} exposure, which might influence MSC differentiation stage and capacity.

  14. Azithromycin reduces tumor necrosis factor-alpha production in lipopolysaccharide-stimulated THP-1 monocytic cells by modification of stress response and p38 MAPK pathway.

    Science.gov (United States)

    Ikegaya, S; Inai, K; Iwasaki, H; Naiki, H; Ueda, T

    2009-08-01

    Macrolide antibiotics are known to have a variety of immunomodulatory effects in addition to antimicrobial activity, but the mechanisms of immunomodulation are still unclear. We investigated in vitro the effect of azithromycin on tumor necrosis factor alpha (TNF-alpha) production in lipopolysaccharide (LPS)-stimulated THP-1 cells, a human monocytic cell line, and compared the results with those for other macrolides, minocycline and ofloxacin. In the presence of LPS, treatment with azithromycin (AZM) resulted in a significant decrease in LPS-induced TNF-alpha production compared to that with other antimicrobial agents. the results of phosphorylation of three MAPKs, ERK, JNK and p38, indicated that the phospho-p38 level was reduced by AZM. Ikappab-alpha, an inhibitor of NFkappab, was not disrupted by the antibiotics. LPS-induced TNF-alpha release from THP-1 cells was inhibited in the presence of KNK437, a potent 70-kDa heat shock protein (HSP-70) inhibitor. Interestingly, the induction of HSP-70 by LPS was attenuated with the concurrent addition of AZM in the cells. AZM was found to restrain TNF-alpha production by monocytes at least in part by modifying the HSp-70 and p38 related signaling pathways to LPS stimulation.

  15. Tumor necrosis factor alpha -238 G/A and -308 G/A polymorphisms and soluble TNF-α levels in chronic kidney disease: correlation with clinical variables

    Science.gov (United States)

    Vázquez-Huerta, Diana I; Alvarez-Rodríguez, Bertha A; Topete-Reyes, Jorge F; Muñoz-Valle, José F; Parra-Michel, Renato; Fuentes-Ramírez, Francisco; Salazar-López, María A; Valle, Yeminia; Reyes-Castillo, Zyanya; Cruz-González, A; Brennan-Bourdon, Lorena M; Torres-Carrillo, Norma

    2014-01-01

    Chronic kidney disease (CKD) is characterized by accumulation of proinflammatory cytokines, mainly tumor necrosis factor alpha (TNF-α). Single nucleotide polymorphisms (SNPs) of TNFA gene, including -238 G/A and -308 G/A, have been associated with alteration in the soluble TNF-α (sTNF-α) expression. The aim was to investigate the association of -238 y -308 TNFA gene SNPs with sTNF-α levels in CKD patients. We included 150 CKD patients and 192 control subjects (CS). Both SNPs were genotyped with polymerase chain reaction-restriction fragment length polymorphism technique and sTNF-α levels were measured by enzyme-linked immunosorbent assay. The genotypic distribution of -238 and -308 SNPs was not significantly different between CKD patients and CS (p > 0.001). However, the sTNF-α levels were higher in CKD, compared to CS (p < 0.001). Also, sTNF-α correlated with creatinine (r = 0.279, p = 0.004), urea (r = 0.325, p = 0.001), phosphorus (r = 0.479, p = 0.001), glomerular filtration rate (r = -0.236, p = 0.019) and monocyte count (r = 0.276, p = 0.010). In conclusion, elevated sTNF-α levels are associated with CKD. However, the -238 and -308 TNFA gene SNPs were not associated with susceptibility to CKD and sTNF-α levels in a Mexican population. PMID:25232395

  16. Comparison of interferon {gamma} release assays and conventional screening tests before tumour necrosis factor {alpha} blockade in patients with inflammatory arthritis.

    LENUS (Irish Health Repository)

    Martin, J

    2012-02-01

    OBJECTIVE: To compare the performance of two interferon gamma release assays (IGRAs) and conventional screening tests in patients with inflammatory arthritis undergoing screening for latent tuberculosis infection (LTBI) before treatment with anti-tumour necrosis factor alpha (anti-TNFalpha) compounds. METHODS: Successive patients were subjected to conventional LTBI screening, including a tuberculin skin test (TST). The T-SPOT.TB test was performed on all patients and the QuantiFERON-TB Gold test was performed on a large subset. The results of the IGRAs were compared with the results of conventional screening tests. RESULTS: A total 150 patients were evaluated. The majority (57.9%) had rheumatoid arthritis. Previous vaccination with Bacille Calmette-Guerin was confirmed in 82% of patients. No patient had received prior anti-TB treatment. A total of 57 patients (38.0%) had at least one positive conventional risk factor. In contrast, an unequivocally positive T-SPOT.TB test was seen in only 14\\/143 (9.8%). There was 98.2% agreement between the two IGRAs. Statistically significant associations were found between each of the IGRAs and both TST and risk history, but not chest x-ray (CXR). A positive IGRA result was significantly associated with increased age. TB was not reactivated in any patient during the follow-up period. Interpretation: This study suggests that IGRAs may be useful when screening for LTBI before anti-TNFalpha therapy in patients with immune-mediated inflammatory diseases. The observations reported here also highlight the inadequate performance of CXR as a marker of LTBI.

  17. Effects of aqueous extracts of Taraxacum Officinale on expression of tumor necrosis factor-alpha and intracellular adhesion molecule 1 in LPS-stimulated RMMVECs.

    Science.gov (United States)

    Hu, Ge; Wang, Junjie; Hong, Dong; Zhang, Tao; Duan, Huiqin; Mu, Xiang; Yang, Zuojun

    2017-01-11

    Mastitis gives rise to big financial burden to farm industry (mainly dairy production) and public health. Its incidence is currently high and therefore, highly effective treatments for therapy, especially with natural products are required. Taraxacum officinale has been reported to use for anti-inflammation. However, its effect on endothelium during mastitis has not been reported. We firstly established inflammation experimental model of rat mammary microvascular endothelial cells (RMMVECs). We evaluated the effects of dandelion leaf aqueous extracts (DAE) on LPS-induced production of inflammatory mediators in RMMVECs by enzyme-linked immunosorbent assay and Western blot. We treated RMMVECs with 1 μg/ml LPS for 4 h and then incubated with 10, 100 and 200 μg/mL DAE for 4, 8, 12 and 24 h. The expression (mRNA and protein level) of targets (tumor necrosis factor-alpha (TNF- α) and Intracellular Adhesion Molecule 1 (ICAM1) was analyzed by employing real-time PCR and Western blots. The in vivo anti-inflammatory effect of DAE on mastitis within an Staphylococcus aureus-induced mouse model was also determined. The obtained results showed that dandelion extracts at the concentration of 100 and 200 μg/mL could significantly inhibit both TNF-α and ICAM-1 expression in all time points checked while 10 μg/mL of dandelion only suppress both expression at 8 and 12 h post-treatment. The in vivo tests showed that the DAE inhibited the expression of TNF-α and ICAM-1 in a time-dependent manner. All results suggest that the endothelium may use as as a possible target of dandelion for anti-inflammation.

  18. Blockade of Tumor Necrosis Factor-Alpha: A Role for Adalimumab in Neovascular Age-Related Macular Degeneration Refractory to Anti-Angiogenesis Therapy

    Directory of Open Access Journals (Sweden)

    Beatriz Fernández-Vega

    2016-03-01

    Full Text Available Aims: To report a case of wet age-related macular degeneration (wet-AMD refractory to intravitreal anti-vascular endothelial growth factor (anti-VEGF therapy in a patient who showed visual and anatomical improvement and stabilization after starting a subcutaneous treatment course with adalimumab, an anti-tumor necrosis factor-alpha (TNF-α drug, for concomitant Crohn's disease. Methods: Observational case report of a female patient. Ophthalmological evaluation was performed by slit lamp and ophthalmoscopy (posterior pole and anterior segment. Best-corrected visual acuity (BCVA was determined, and imaging was performed by fluorescein angiography, indocyanine green angiography, and optical coherence tomography (OCT. Intravitreal therapies used and treatment with anti-TNF-α were recorded. Results: A 64-year-old woman with wet-AMD was treated with fourteen intravitreal injections of ranibizumab (0.5 mg for a period of 40 months with intervals of 1-6 months. She initially showed a good visual and anatomical response to periodic anti-VEGF treatment but during check visits, anatomical and functional responses deteriorated. At the 40-month follow-up, the patient had developed Crohn's disease, and her rheumatologist started treatment with adalimumab (40 mg subcutaneously every 2 weeks. During the 25 months of treatment with adalimumab, the patient did not require any additional intravitreal anti-VEGF treatments because her BCVA, clinical, and OCT findings improved and remained stable. Conclusions: We described a case of a patient with wet-AMD refractory to anti-VEGF therapy, which clinically benefited from subcutaneous adalimumab therapy. Treatment with subcutaneous anti-TNF-α in combination with anti-VEGF therapy avoids the high cost and risks related to multiple intravitreal anti-VEGF injections with good functional and anatomic outcomes.

  19. Induction of Programmed Cell Death by Parvovirus H-1 in U937 Cells: Connection with the Tumor Necrosis Factor Alpha Signalling Pathway

    Science.gov (United States)

    Rayet, Béatrice; Lopez-Guerrero, José-Antonio; Rommelaere, Jean; Dinsart, Christiane

    1998-01-01

    The human promonocytic cell line U937 undergoes apoptosis upon treatment with tumor necrosis factor alpha (TNF-α). This cell line has previously been shown to be very sensitive to the lytic effect of the autonomous parvovirus H-1. Parvovirus infection leads to the activation of the CPP32 ICE-like cysteine protease which cleaves the enzyme poly(ADP-ribose)polymerase and induces morphologic changes that are characteristic of apoptosis in a way that is similar to TNF-α treatment. This effect is also observed when the U937 cells are infected with a recombinant H-1 virus which expresses the nonstructural (NS) proteins but in which the capsid genes are replaced by a reporter gene, indicating that the induction of apoptosis can be assigned to the cytotoxic nonstructural proteins in this cell system. The c-Myc protein, which is overexpressed in U937 cells, is rapidly downregulated during infection, in keeping with a possible role of this product in mediating the apoptotic cell death induced by H-1 virus infection. Interestingly, four clones (designated RU) derived from the U937 cell line and selected for their resistance to H-1 virus (J. A. Lopez-Guerrero et al., Blood 89:1642–1653, 1997) failed to decrease c-Myc expression upon treatment with differentiation agents and also resisted the induction of cell death after TNF-α treatment. Our data suggest that the RU clones have developed defense strategies against apoptosis, either by their failure to downregulate c-Myc and/or by activating antiapoptotic factors. PMID:9765434

  20. Neuronal injury and tumor necrosis factor-alpha immunoreactivity in the rat hippocampus in the early period of asphyxia-induced cardiac arrest under normothermia

    Directory of Open Access Journals (Sweden)

    Hyun-Jin Tae

    2017-01-01

    Full Text Available Low survival rate occurs in patients who initially experience a spontaneous return of circulation after cardiac arrest (CA. In this study, we induced asphyxial CA in adult male Sprague-Daley rats, maintained their body temperature at 37 ± 0.5°C, and then observed the survival rate during the post-resuscitation phase. We examined neuronal damage in the hippocampus using cresyl violet (CV and Fluore-Jade B (F-J B staining, and pro-inflammatory response using ionized calcium-binding adapter molecule 1 (Iba-1, glial fibrillary acidic protein (GFAP, and tumor necrosis factor-alpha (TNF-α immunohistochemistry in the hippocampus after asphyxial CA in rats under normothermia. Our results show that the survival rate decreased gradually post-CA (about 63% at 6 hours, 37% at 1 day, and 8% at 2 days post-CA. Rats were sacrificed at these points in time post-CA, and no neuronal damage was found in the hippocampus until 1 day post-CA. However, some neurons in the stratum pyramidale of the CA region in the hippocampus were dead 2 days post-CA. Iba-1 immunoreactive microglia in the CA1 region did not change until 1 day post-CA, and they were activated (enlarged cell bodies with short and thicken processes in all layers 2 days post-CA. Meanwhile, GFAP-immunoreactive astrocytes did not change significantly until 2 days post-CA. TNF-α immunoreactivity decreased significantly in neurons of the stratum pyramidale in the CA1 region 6 hours post-CA, decreased gradually until 1 day post-CA, and increased significantly again 2 days post-CA. These findings suggest that low survival rate of normothermic rats in the early period of asphyxia-induced CA is related to increased TNF-α immunoreactivity, but not to neuronal damage in the hippocampal CA1 region.

  1. Experimental study on inhibitory effect of niacinamide on tumor necrosis factor-alpha-induced matrix degradation of annulus fibrous tissue in vitro.

    Science.gov (United States)

    Xu, Runbing; Shao, Zengwu; Xiong, Liming

    2008-10-01

    The inhibitory effect of niacinamide on tumor necrosis factor-alpha (TNF-alpha) induced annulus fibrous (AF) degradation was assessed, and the mechanism of the inhibition was investigated. Chiba's intervertebral disc (IVD) culture model was established. Forty-eight IVDs from 12 adult Japanese white rabbits were randomly divided into 4 groups (12 IVDs in each group), and various concentrations of niacinamide and TNF-alpha were added to the medium for intervention: negative control group, niacinamide control group (0.5 mg/mL niacinamide), degeneration group (10 ng/mL TNF-alpha), and treatment group (0.5 mg/mL niacinamide and 10 ng/mL TNF-alpha). After one week's culture, AFs were collected for glycosaminoglycan (GS) content measurement, safranin O-fast green staining, and immunohistochemical staining for type I, II collagen and cysteine containing aspartate specific protease-3 (Caspase-3). It was found that the GS content in treatment group was increased by about 48% as compared with degeneration group (t=16.93, Pniacinamide control group (t=0.71, P=0.667). Safranine O-fast green staining exhibited higher staining density and better histological structure of AF in the treatment group as compared with the degeneration group. Immunohistochemical staining for both Type I and II collagen demonstrated that lamellar structure and continuity of collagen in treatment group were better reserved than in degeneration group. Positive staining rate of Caspase-3 in AFs of negative control group, niacinamide control group, degeneration group and treatment group was 3.4%, 4.3%, 17.9% and 10.3% respectively. The positive rate in treatment group was significantly lower than in degeneration group (Pniacinamide could effectively alleviate TNF-alpha induced destruction and synthesis inhibition of matrix ingredients in AFs. The inhibition may be related with reduction of expression of Caspase-3. Thus, niacinamide is of potential for IVD degeneration clinical treatment.

  2. Tumor necrosis factor-alpha during neonatal brain development affects anxiety- and depression-related behaviors in adult male and female mice.

    Science.gov (United States)

    Babri, Shirin; Doosti, Mohammad-Hossein; Salari, Ali-Akbar

    2014-03-15

    A nascent literature suggests that neonatal infection is a risk factor for the development of brain, behavior and hypothalamic-pituitary-adrenal axis which can affect anxiety- and depression-related behaviors in later life. It has been documented that neonatal infection raises the concentrations of tumor necrosis factor-alpha (TNF-α) in neonate rodents and such infections may result in neonatal brain injury, at least in part, through pro-inflammatory cytokines. In addition, previous studies have shown that TNF-α is involved in cellular differentiation, neurogenesis and programmed cell death during the development of the central nervous system. We investigated for the first time whether neonatal exposure to TNF-α can affect body weight, stress-induced corticosterone (COR), anxiety- and depression-related behaviors in adult mice. In the present study, neonatal mice were treated to recombinant mouse TNF-α (0.2, 0.4, 0.7 and 1 μg/kg) or saline on postnatal days 3 and 5, then adult male and female mice were exposed to different behavioral tests. The results indicated that neonatal TNF-α treatment reduced body weight in neonatal period in both sexes. In addition, this study presents findings indicating that high doses of TNF- increase stress-induced COR levels, anxiety- and depression-related behaviors in adult males, but increase levels of anxiety without significantly influencing depression in adult female mice [corrected]. Our findings suggest that TNF-α exposure during neonatal period can alter brain and behavior development in a dose and sex-dependent manner in mice. Copyright © 2014 Elsevier B.V. All rights reserved.

  3. Engineering N-terminal domain of tissue inhibitor of metalloproteinase (TIMP)-3 to be a better inhibitor against tumour necrosis factor-alpha-converting enzyme.

    Science.gov (United States)

    Lee, Meng-Huee; Verma, Vandana; Maskos, Klaus; Nath, Deepa; Knäuper, Vera; Dodds, Philippa; Amour, Augustin; Murphy, Gillian

    2002-01-01

    We previously reported that full-length tissue inhibitor of metalloproteinase-3 (TIMP-3) and its N-terminal domain form (N-TIMP-3) displayed equal binding affinity for tissue necrosis factor-alpha (TNF-alpha)-converting enzyme (TACE). Based on the computer graphic of TACE docked with a TIMP-3 model, we created a number of N-TIMP-3 mutants that showed significant improvement in TACE inhibition. Our strategy was to select those N-TIMP-3 residues that were believed to be in actual contact with the active-site pockets of TACE and mutate them to amino acids of a better-fitting nature. The activities of these mutants were examined by measuring their binding affinities (K(app)(i)) and association rates (k(on)) against TACE. Nearly all mutants at position Thr-2 exhibited slightly impaired affinity as well as association rate constants. On the other hand, some Ser-4 mutants displayed a remarkable increase in their binding tightness with TACE. In fact, the binding affinities of several mutants were less than 60 pM, beyond the sensitivity limits of fluorimetric assays. Further studies on cell-based processing of pro-TNF-alpha demonstrated that wild-type N-TIMP-3 and one of its tight-binding mutants, Ser-4Met, were capable of inhibiting the proteolytic shedding of TNF-alpha. Furthermore, the Ser-4Met mutant was also significantly more active (P<0.05) than the wild-type N-TIMP-3 in its cellular inhibition. Comparison of N-TIMP-3 and full-length TIMP-3 revealed that, despite their identical TACE-interaction kinetics, the latter was nearly 10 times more efficient in the inhibition of TNF-alpha shedding, with concomitant implications for the importance of the TIMP-3 C-terminal domain in vivo. PMID:11988096

  4. Tumour necrosis factor-alpha antagonists in the management of rheumatoid arthritis in the elderly: a review of their efficacy and safety.

    Science.gov (United States)

    Radovits, Beáta J; Kievit, Wietske; Laan, Roland F J M

    2009-01-01

    Rheumatoid arthritis (RA) is a chronic inflammatory disease that frequently affects people aged >or=65 years, causing significant impairment with pain and functional disability. Elderly RA patients have specific problems, including co-morbid diseases, numerous concomitant medications, greater number of damaged joints as a result of longer disease duration and often a more severe disease presentation in elderly-onset RA. These factors, together with an age-related decline in the immune defence mechanisms, make elderly patients more vulnerable. The new era of biologic medications has made intensive treatment of RA patients possible. Anti-tumour necrosis factor-alpha (anti-TNFalpha) agents can cause a dramatic improvement in disease activity and functional capacity, making complete remission of RA a possible target. TNFalpha has been shown to play an important role in both the healthy aging process and age-related diseases such as RA. Targeting this cytokine in elderly patients is therefore reasonable. However, it is not clear whether treatment effects can be reached to the same extent in both elderly and younger patients and whether anti-TNFalpha treatment specifically increases the risk of certain adverse events in elderly RA patients. This review discusses the currently available evidence relating to the efficacy and safety of anti-TNFalpha medication in RA patients aged >or=65 years treated in clinical trials and observational studies. Despite a slightly less robust effect in elderly patients, anti-TNFalpha treatment has a similar long-term efficacy in patients aged >or=65 years and patients aged relatively safe in the treatment of elderly RA patients, treatment with corticosteroids significantly elevated the risk of serious infections. Corticosteroids are frequently used in elderly patients, but the evidence suggests that preference should increasingly be given to anti-TNFalpha agents, for which the expected benefits will mostly outweigh the modestly increased

  5. Differential Gamma Interferon- and Tumor Necrosis Factor Alpha-Driven Cytokine Response Distinguishes Acute Infection of a Metatherian Host with Toxoplasma gondii and Neospora caninum

    Science.gov (United States)

    Donahoe, Shannon L.; Phalen, David N.; McAllan, Bronwyn M.; O'Meally, Denis; McAllister, Milton M.; Ellis, John

    2017-01-01

    ABSTRACT Toxoplasma gondii and Neospora caninum (both Apicomplexa) are closely related cyst-forming coccidian parasites that differ significantly in their host ranges and ability to cause disease. Unlike eutherian mammals, Australian marsupials (metatherian mammals) have long been thought to be highly susceptible to toxoplasmosis and neosporosis because of their historical isolation from the parasites. In this study, the carnivorous fat-tailed dunnart (Sminthopsis crassicaudata) was used as a disease model to investigate the immune response and susceptibility to infection of an Australian marsupial to T. gondii and N. caninum. The disease outcome was more severe in N. caninum-infected dunnarts than in T. gondii-infected dunnarts, as shown by the severity of clinical and histopathological features of disease and higher tissue parasite burdens in the tissues evaluated. Transcriptome sequencing (RNA-seq) of spleens from infected dunnarts and mitogen-stimulated dunnart splenocytes was used to define the cytokine repertoires. Changes in mRNA expression during the time course of infection were measured using quantitative reverse transcription-PCR (qRT-PCR) for key Th1 (gamma interferon [IFN-γ] and tumor necrosis factor alpha [TNF-α]), Th2 (interleukin 4 [IL-4] and IL-6), and Th17 (IL-17A) cytokines. The results show qualitative differences in cytokine responses by the fat-tailed dunnart to infection with N. caninum and T. gondii. Dunnarts infected with T. gondii were capable of mounting a more effective Th1 immune response than those infected with N. caninum, indicating the role of the immune response in the outcome scenarios of parasite infection in this marsupial mammal. PMID:28348050

  6. A comprehensive study of tumor necrosis factor-alpha genetic polymorphisms, its expression in skin and relation to histopathological features in psoriasis

    Directory of Open Access Journals (Sweden)

    Nikhil N Moorchung

    2015-01-01

    Full Text Available Background: Tumor necrosis factor-alpha (TNFα is an important inflammatory mediator in psoriasis and several genetic polymorphisms of this cytokine have been reported. Majority of studies have focused on the increased G- A polymorphism at the -308 position in psoriasis. There has been no comprehensive study evaluating the genetic polymorphisms, TNFα expression in the skin and histopathology. We are undertaking this study to outline TNFα genetic polymorphisms, its skin expression and histopathological correlation to help determine its role at the genetic and protein level. Materials and Methods : 112 patients of psoriasis and 243 healthy controls were included in this prospective study. 5 ml of peripheral blood was collected to study the TNFα genetic polymorphisms by polymerase chain reaction and restriction fragment length polymorphism analysis. Histopathological analysis of biopsies from the 112 patients were done using visual analogue scale and correlated with the findings. 61 of these cases were analyzed for TNFα expression by immunohistochemistry. The results of study were statistically analyzed using SPSS 13.0 statistical package program. Results: A strong association of TNFα -308 G/A polymorphism in psoriasis cases was detected. The A allele of the TNFα -308 G/A polymorphism occurs rarely in the Indian population, however there is an over representation of this allele in psoriatic patients. There was no association seen between TNFα genotype and histopathological severity of psoriasis. Conclusion: The study emphasized the central role of TNFα in the pathogenesis of psoriasis. TNFα genotyping may be helpful in identifying subjects in whom anti-TNFα therapeutic strategies may be tried.

  7. HBV Reactivation in Patients Treated with Antitumor Necrosis Factor-Alpha (TNF-α Agents for Rheumatic and Dermatologic Conditions: A Systematic Review and Meta-Analysis

    Directory of Open Access Journals (Sweden)

    Fabrizio Cantini

    2014-01-01

    Full Text Available Introduction. Antitumor necrosis factor-alpha (TNF-α agents are widely used for treatment of rheumatic and dermatological diseases. We conducted the systematic review and meta-analysis to assess the prevalence of HBV reactivation among patients treated with anti-TNF-α. Methods and Findings. A comprehensive literature search of MEDLINE, Scopus, and ISI Web of Knowledge databases was conducted. From 21 studies included in the systematic review, 9 included patients with occult chronic HBV infection and 6 included patients with overt infection while 6 addressed both groups. Based on 10 studies eligible for meta-analysis we report pooled estimate of HBV reactivation of 4.2% (95% CI: 1.4–8.2%, I2: 74.7%. The pooled prevalence of reactivation was 3.0% (95% CI: 0.6–7.2, I2: 77.1% for patients with occult infection, and 15.4% (95% CI: 1.2–41.2%, I2: 79.9% for overt infection. The prevalence of reactivation was 3.9% (95% CI: 1.1–8.4%, I2: 51.1% for treatment with etanercept and 4.6% (95% CI: 0.5–12.5%, I2: 28.7% for adalimumab. For subgroup of patients without any antiviral prophylaxis the pooled reactivation was 4.0% (95% CI: 1.2–8.3%, I2: 75.6%. Conclusion. Although HBV reactivation rate is relatively low in patients treated with anti-TNF-α for rheumatic and dermatological conditions, the antiviral prophylaxis would be recommended in patients with overt chronic HBV infection.

  8. B-lymfocytdepletring og andre biologiske behandlingsmuligheder ved Graves' oftalmopatiTumor necrosis factor-alpha binding capacity and anti-infliximab antibodies measured by fluid-phase radioimmunoassays as predictors of clinical efficacy of infliximab in Crohn's disease

    DEFF Research Database (Denmark)

    El, Fassi D.; Hegedus, L.; Nielsen, Claus Henrik

    2008-01-01

    The current medical treatment options for Graves' ophthalmopathy (GO) are unsatisfactory. Recent treatment of GO patients with the B-lymphocyte depleting monoclonal antibody rituximab or with the anti-tumor necrosis factor-alpha agents etanercept and infliximab has shown promising results. We...... discuss the use of these and other biological agents targeting B lymphocytes, T-lymphocyte interaction with antigen-presenting cells, or cytokines in the future treatment of GO Udgivelsesdato: 2008/6/9...

  9. Upregulation of heat shock protein 70 and the differential protein expression induced by tumor necrosis factor-alpha enhances migration and inhibits apoptosis of hepatocellular carcinoma cell HepG2

    OpenAIRE

    Huang, Bee-Piao; Lin, Chun-Shiang; Wang, Chau-Jong; Kao, Shao-Hsuan

    2017-01-01

    Tumor necrosis factor alpha (TNF?) plays diverse roles in liver damage and hepatocarcinogenesis with its multipotent bioactivity. However, the influence of TNF? on protein expression of hepatocellular carcinoma (HCC) is incompletely understood. Therefore, we aimed to investigate the differential protein expression of HCC in response to TNF? stimulus. We observed that HepG2 cell revealed a higher resistance to TNF?-induced apoptosis as compared to the non-tumorigenic hepatocyte THLE-2. By usin...

  10. Lipopolysaccharide and Tumor Necrosis Factor Alpha Inhibit Interferon Signaling in Hepatocytes by Increasing Ubiquitin-Like Protease 18 (USP18) Expression.

    Science.gov (United States)

    MacParland, Sonya A; Ma, Xue-Zhong; Chen, Limin; Khattar, Ramzi; Cherepanov, Vera; Selzner, Markus; Feld, Jordan J; Selzner, Nazia; McGilvray, Ian D

    2016-06-15

    Inflammation may be maladaptive to the control of viral infection when it impairs interferon (IFN) responses, enhancing viral replication and spread. Dysregulated immunity as a result of inappropriate innate inflammatory responses is a hallmark of chronic viral infections such as, hepatitis B virus and hepatitis C virus (HCV). Previous studies from our laboratory have shown that expression of an IFN-stimulated gene (ISG), ubiquitin-like protease (USP)18 is upregulated in chronic HCV infection, leading to impaired hepatocyte responses to IFN-α. We examined the ability of inflammatory stimuli, including tumor necrosis factor alpha (TNF-α), lipopolysaccharide (LPS), interleukin-6 (IL-6) and IL-10 to upregulate hepatocyte USP18 expression and blunt the IFN-α response. Human hepatoma cells and primary murine hepatocytes were treated with TNF-α/LPS/IL-6/IL-10 and USP18, phosphorylated (p)-STAT1 and myxovirus (influenza virus) resistance 1 (Mx1) expression was determined. Treatment of Huh7.5 cells and primary murine hepatocytes with LPS and TNF-α, but not IL-6 or IL-10, led to upregulated USP18 expression and induced an IFN-α refractory state, which was reversed by USP18 knockdown. Liver inflammation was induced in vivo using a murine model of hepatic ischemia/reperfusion injury. Hepatic ischemia/reperfusion injury led to an induction of USP18 expression in liver tissue and promotion of lymphocytic choriomeningitis replication. These data demonstrate that certain inflammatory stimuli (TNF-α and LPS) but not others (IL-6 and IL-10) target USP18 expression and thus inhibit IFN signaling. These findings represent a new paradigm for how inflammation alters hepatic innate immune responses, with USP18 representing a potential target for intervention in various inflammatory states. Inflammation may prevent the control of viral infection when it impairs the innate immune response, enhancing viral replication and spread. Blunted immunity as a result of inappropriate innate

  11. Serum biomarker profiles of interleukin-6, tumor necrosis factor alpha, matrix-metalloproteinase-2, and vascular endothelial growth factor in endometriosis staging

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    Wachyu Hadisaputra

    2013-05-01

    Full Text Available Background: The focus of this study was to compare serum biomarkers: interleukin-6 (IL-6, tumor necrosis factor-alpha (TNF-α, matrix-metalloproteinase-2 (MMP-2 and vascular endothelial growth factor (VEGF in endometriosis stage I-II and stage III-IV. Methods: This is a cross-sectional study. Forty endometriosis patients were diagnosed using laparoscopy procedure. Serum sample was taken before the surgery. The serum biomarkers (IL-6, TNF-α, MMP-2, and VEGF were analyzed with ELISA method at the end of research. Mean of serum biomarkers in endometrosis stage I-II and stage III-IV were compared using unpaired t-test. Variables that show significant mean difference were tested using ROC measurement and the optimal cut-off point was determined. Results: There was no significant difference in mean serum biomarkers level of IL-6, TNF-α, and MMP-2 between endometriosis stage I-II and stage III-IV (1.58 ± 0.78 vs 1.55 ± 0.98 pg/mL, 1.5 ± 0.47 vs 1.49 ± 0.29 pg/mL, and 152.04 ± 27.32 vs 140.98 ± 28.08 ng/mL, respectively. On the other hand, the comparison of VEGF level in endometriosis stage I-II and stage III-IV demonstrated significant difference (289.76 ± 188.13 vs 581.29 ± 512.85 pg/mL (p < 0.05. Mean difference of VEGF had AUC of 74.5%. Optimal cut-off point for VEGF was ≥ 314.75 pg/mL with sensitivity 78.6% and specificity 69.2%. Conclusion: This study showed that serum biomarkers of VEGF level (but not IL-6, TNF-α, and MMP-2 can be used to measure the degree of severity in endometriosis. VEGF level of 314.75 pg/mL represents the cut-off point between lower and higher stage of severity. (Med J Indones. 2013;22:76-82Keywords: Endometriosis, interleukin-6, matrix-metalloproteinase-2, TNF-α, vascular endhothelial growth factor

  12. HIV-1 transgene expression in rats induces differential expression of tumor necrosis factor alpha and zinc transporters in the liver and the lung

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    Guidot David M

    2011-10-01

    Full Text Available Abstract Background Highly effective antiviral treatment can suppress HIV-1 infection, but the chronic effects of HIV-1-related viral proteins, including gp120 and Tat, on organs such as the lungs can be damaging. HIV-1 transgenic rodent models are useful for studying the systemic effects of these proteins independently of viral infection. We have previously shown that HIV-1 transgene expression (and therefore, HIV-1-related protein expression in rats decreases alveolar macrophage zinc levels and phagocytic capacity by unknown mechanisms. We hypothesized that HIV-1 transgene expression induces chronic inflammation and zinc sequestration within the liver and thereby decreases zinc bioavailability in the lung. We examined the expression of the pro-inflammatory cytokine, tumor necrosis factor alpha (TNFα, the zinc storage protein, metallothionein (MT1, and the zinc exporter, ZNT1 in the livers and the lungs of wild type and HIV-1 transgenic rats ± dietary zinc supplementation. In addition, we measured zinc levels, the zinc importing protein ZIP1, and the phagocytic capacity in the alveolar macrophages. Results HIV-1 transgene expression increased the liver-specific expression of TNFα, suggesting a chronic inflammatory response within the liver in response to HIV-1-related protein expression. In parallel, HIV-1 transgene expression significantly increased MT1 and ZNT1 expression in the liver as compared to the lung, a pattern that is consistent with zinc sequestration in the liver as occurs during systemic inflammation. Further, HIV-1 transgene expression decreased intracellular zinc levels and increased expression of ZIP1 in the alveolar macrophages, a pattern consistent with zinc deficiency, and decreased their bacterial phagocytic capacity. Interestingly, dietary zinc supplementation in HIV-1 transgenic rats decreased gene expression of TNFα, MT1, and ZNT1 in the liver while simultaneously increasing their expression in the lung. In parallel

  13. Nuclear factor-kappa B family member RelB inhibits human immunodeficiency virus-1 Tat-induced tumor necrosis factor-alpha production.

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    Michelle Kiebala

    2010-07-01

    Full Text Available Human Immunodeficiency Virus-1 (HIV-1-associated neurocognitive disorder (HAND is likely neuroinflammatory in origin, believed to be triggered by inflammatory and oxidative stress responses to cytokines and HIV protein gene products such as the HIV transactivator of transcription (Tat. Here we demonstrate increased messenger RNA for nuclear factor-kappa B (NF-kappaB family member, transcription factor RelB, in the brain of doxycycline-induced Tat transgenic mice, and increased RelB synthesis in Tat-exposed microglial cells. Since genetic ablation of RelB in mice leads to multi-organ inflammation, we hypothesized that Tat-induced, newly synthesized RelB inhibits cytokine production by microglial cells, possibly through the formation of transcriptionally inactive RelB/RelA complexes. Indeed, tumor necrosis factor-alpha (TNFalpha production in monocytes isolated from RelB deficient mice was significantly higher than in monocytes isolated from RelB expressing controls. Moreover, RelB overexpression in microglial cells inhibited Tat-induced TNFalpha synthesis in a manner that involved transcriptional repression of the TNFalpha promoter, and increased phosphorylation of RelA at serine 276, a prerequisite for increased RelB/RelA protein interactions. The Rel-homology-domain within RelB was necessary for this interaction. Overexpression of RelA itself, in turn, significantly increased TNFalpha promoter activity, an effect that was completely blocked by RelB overexpression. We conclude that RelB regulates TNFalpha cytokine synthesis by competitive interference binding with RelA, which leads to downregulation of TNFalpha production. Moreover, because Tat activates both RelB and TNFalpha in microglia, and because Tat induces inflammatory TNFalpha synthesis via NF-kappaB, we posit that RelB serves as a cryoprotective, anti-inflammatory, counter-regulatory mechanism for pathogenic NF-kappaB activation. These findings identify a novel regulatory pathway for

  14. The allelic distribution of -308 Tumor Necrosis Factor-alpha gene polymorphism in South African women with cervical cancer and control women

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    Williamson Anna-Lise

    2006-01-01

    Full Text Available Abstract Background Cervical cancer is due to infection with specific high-risk types of human papillomavirus (HPV. Although the incidence of genital HPV infection in various population groups is high, most of these regress without intervention. Investigating genetic host factors and cellular immune responses, particularly cytokines, could help to understand the association between genital HPV infection and carcinogenesis. The tumor necrosis factor alpha (TNF-α cytokine plays an important role in all stages of cervical cancer and has the ability to induce the regression of human tumors. Therefore the aim of the study was to investigate the allelic distribution of -308 TNF-α gene polymorphism in South African women with cervical cancer compared to control women. Methods Included in our study were women with histologically proven cancer of the cervix (n = 244 and hospital-based controls (n = 228. All patients and controls were from mixed race and black population groups in South Africa. The detection of a bi-allelic -308 (A/G polymorphism in the promoter region of TNF-α was investigated using the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR technique. The distributions of the allelic frequencies were stratified in both patients and controls into two South African ethnic population groups. Results In this study we observed no association between the distribution of -308 TNF-α polymorphism and the risk of developing cervical cancer even after combining the data from the two ethnic populations (X2 = 2.26. In addition, using the chi-squared test we found no significant association between the known risk factors for cervical cancer and the allele distribution of -308 TNF-α. However, the frequency of the rare high-producing allele -308A of TNF-α was significantly lower in the South African population when compared to Caucasians and Chinese population groups. Conclusion We demonstrated no association between -308 TNF

  15. The VEGF and BMP-2 levels in patients with ankylosing spondylitis and the relationship to treatment with tumour necrosis factor alpha inhibitors.

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    Tošovský, Marian; Bradna, Petr; Andrýs, Ctirad; Andrýsová, Kateřina; Cermáková, Eva; Soukup, Tomáš

    2014-01-01

    Ankylosing spondylitis (AS) is an inflammatory rheumatic disease characterized by the development of osteoproductive changes in the spine which could possibly result in ankylosis. Treatment with tumour necrosis factor alpha (TNFα) inhibitors has proved to be an important step forward in the treatment of this disease, but for the time being it is not clear whether it favourably influences radiographic progression of the disease. Vascular endothelial growth factor most probably plays a role in the development of osteoproductive changes and recently its predictive influence on radiographic progression has been demonstrated. Bone morphogenic protein 2 (BMP-2) participates in the regulation of bone proliferation and its increased serum level has been demonstrated in patients with advanced AS and correlated with the degree of radiographic changes. The study aims to evaluate the VEGF and BMP-2 levels in patients with ankylosing spondylitis and how these levels relate to the concurrent treatment with TNFα inhibitors. Sera were evaluated from patients at the Rheumatologic Clinic of the Hradec Králové Faculty Hospital who fulfilled the modified New York Criteria for AS (n = 55). In these patients, the parameters of the activity of the disease (BASDAI = Bath Ankylosing Spondylitis Disease Activity Index, CRP = C-reactive protein) and the concurrent therapy (TNFα inhibitors, n = 21, vs. non-anti TNFα, n = 34) were recorded. The levels of VEGF and BMP-2 were analyzed using the ELISA method. In patients treated with TNFα inhibitors, a significantly lower VEGF level was found when compared to untreated patients (140.3 (109.4; 262.2) vs. 261 (172.4; 396.6) pg/ml; p = 0.02). No difference was found between BMP-2 levels in both groups (treated vs. untreated patients) (254.8 (2301; 267.3) vs. 261.1 (248.6; 273.5) pg/ml; p = 0.24). A correlation analysis did not reveal any relationship between VEG F and BMP-2 (r = 0.057; p = 0.68). Serum levels of VEGF correlated with serum

  16. Perbedaan Kadar Vitamin E dan Tumor Necrosis Factor Alpha (TNF-α berdasar atas Status Massa Lemak Pasien dalam Hemodialisis Kronik

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    Rudi Supriadi

    2017-10-01

    Difference between Vitamin E and Tumor Necrosis Factor Alpha (TNF-α Levels based on Fat Mass Status in Chronic Hemodialysis Patients Malnutrition-inflammation syndrome is a problem frequently found in patients who undergo chronic hemodialysis (HD. Increased level of inflammation has a higher risk for malnutrition. Fat mass shows better nutritional status changes in HD patients. TNF-α will cause increased ROS production and will be scavenged by vitamin E that are both saved in fat mass. This study aimed to determine the difference between vitamin E  and TNF-α levels in two fat mass groups of chronic HD patients. This study was a cross-sectional observational-analytic study on 42 male chronic HD patients at Dr. Hasan Sadikin General Hospital Bandung in the period of September–October 2016. Fat mass was measured by BIA and divided in two fat mass groups, higher and normal/lower mass groups. Vit E and TNF-α levels were measured by chromatography and ELISA. Non-paired groups difference test was used as the statistical analysis. The results showed a higher level of vitamin E in higher fat mass group than normal/lower group (p=0.042. TNF-α level tended to be lower in higher fat mass group than in the normal/lower group;  however, the difference was not significant statistically (p=0.443. Subjects who were  >55 years showed a higher level of vitamin E in hifher fat mass group than in normal/lower (p=0.029. The higher fat mass group with HD duration  >24 months showed lower vitamin E level than those with the HD duration ≤24 months (p=0.005. Normal/lower fat mass group with a HD duration of  >24 months showed a higher TNF-α level than≤24 months(p=0.031. In conclusion, in chronic HD patients the vitamin E level is higher in the higher fat mass group than in the normal/lower group. The vitamin E level in the higher fat mass with HD duration of  >24 months is lower than in the HD duration of  ≤24 months. There is no significant difference in TNF-α level

  17. Lung toxicity of hard metal particles and production of interleukin-1, tumor necrosis factor-alpha, fibronectin, and cystatin-c by lung phagocytes.

    Science.gov (United States)

    Huaux, F; Lasfargues, G; Lauwerys, R; Lison, D

    1995-05-01

    Hard metal alloys (WC-Co) are made of a mixture of cobalt (Co; 6%) and tungsten carbide (WC; 94%) particles. Chronic inhalation of hard metal dust can lead to the development of a fibrosing alveolitis, the pathogenesis of which is still undefined. The present investigation was undertaken to assess the effect of Co, WC, and WC-Co particles on the release by lung phagocytes of interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), fibronectin, and cystatin-c. The responses were compared with those induced by two other lung toxicants, i.e., crystalline silica (DQ12) and arsenic trioxide (As2O3). IL-1 and TNF-alpha activities produced in the presence and absence of LPS stimulation were measured with the aid of bioassays while fibronectin and cystatin-c were determined by latex immunoassays. In vitro, maximal noncytotoxic doses of As2O3, Co, WC, or WC-Co did not significantly affect the production of these mediators by rat alveolar macrophages. In contrast, DQ12 enhanced the production of TNF-alpha (with and without LPS stimulation) and IL-1 (after LPS stimulation) and decreased cystatin-c release (in the absence of LPS). Following a single intratracheal instillation of the different test preparations in the rat, the response of the lung phagocytes obtained by bronchoalveolar lavage (BAL) 24 hr later was examined. We were unable to detect any consistent effect of Co (0.06 mg/100 g body wt), WC (1 mg/100 g body wt), or WC-Co treatment (1 mg/100 g body wt) on the production of the above mediators. In contrast, after LPS stimulation, As2O3 (0.5 mg/100 g body wt) and DQ12 (1 mg/100 g body wt) stimulated the production of TNF-alpha and IL-1. In the absence of LPS, As2O3 stimulated fibronectin and cystatin-c production and DQ12 stimulated cystatin-c release. Since the dose of WC-Co used in vivo (1 mg/100 g body wt) caused pronounced lung inflammation (increased LDH, protein, and albumin levels in BAL fluid), we conclude that the acute lung toxicity of WC-Co particles

  18. The allelic distribution of -308 Tumor Necrosis Factor-alpha gene polymorphism in South African women with cervical cancer and control women

    International Nuclear Information System (INIS)

    Govan, Vandana A; Constant, Debbie; Hoffman, Margaret; Williamson, Anna-Lise

    2006-01-01

    Cervical cancer is due to infection with specific high-risk types of human papillomavirus (HPV). Although the incidence of genital HPV infection in various population groups is high, most of these regress without intervention. Investigating genetic host factors and cellular immune responses, particularly cytokines, could help to understand the association between genital HPV infection and carcinogenesis. The tumor necrosis factor alpha (TNF-α) cytokine plays an important role in all stages of cervical cancer and has the ability to induce the regression of human tumors. Therefore the aim of the study was to investigate the allelic distribution of -308 TNF-α gene polymorphism in South African women with cervical cancer compared to control women. Included in our study were women with histologically proven cancer of the cervix (n = 244) and hospital-based controls (n = 228). All patients and controls were from mixed race and black population groups in South Africa. The detection of a bi-allelic -308 (A/G) polymorphism in the promoter region of TNF-α was investigated using the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) technique. The distributions of the allelic frequencies were stratified in both patients and controls into two South African ethnic population groups. In this study we observed no association between the distribution of -308 TNF-α polymorphism and the risk of developing cervical cancer even after combining the data from the two ethnic populations (X 2 = 2.26). In addition, using the chi-squared test we found no significant association between the known risk factors for cervical cancer and the allele distribution of -308 TNF-α. However, the frequency of the rare high-producing allele -308A of TNF-α was significantly lower in the South African population when compared to Caucasians and Chinese population groups. We demonstrated no association between -308 TNF-α polymorphism and the risk of cervical cancer among two

  19. Dynorphin 1-17 and Its N-Terminal Biotransformation Fragments Modulate Lipopolysaccharide-Stimulated Nuclear Factor-kappa B Nuclear Translocation, Interleukin-1beta and Tumor Necrosis Factor-alpha in Differentiated THP-1 Cells.

    Directory of Open Access Journals (Sweden)

    Siti Sarah Fazalul Rahiman

    Full Text Available Dynorphin 1-17, (DYN 1-17 opioid peptide produces antinociception following binding to the kappa-opioid peptide (KOP receptor. Upon synthesis and release in inflamed tissues by immune cells, DYN 1-17 undergoes rapid biotransformation and yields a unique set of opioid and non-opioid fragments. Some of these major fragments possess a role in immunomodulation, suggesting that opioid-targeted therapeutics may be effective in diminishing the severity of inflammatory disorders. This study aimed to examine the immunomodulatory effects of DYN 1-17 and major N-terminal fragments found in the inflammatory environment on nuclear factor-kappaB/p65 (NF-κB/p65 nuclear translocation and the release of interleukin-1beta (IL-1β and tumor necrosis factor-alpha (TNF-α from lipopolysaccharide (LPS-stimulated, differentiated THP-1 cells. The results demonstrate that NF-κB/p65 nuclear translocation was significantly attenuated following treatment with DYN 1-17 and a specific range of fragments, with the greatest reduction observed with DYN 1-7 at a low concentration (10 nM. Antagonism with a selective KOP receptor antagonist, ML-190, significantly reversed the inhibitory effects of DYN 1-17, DYN 1-6, DYN 1-7 and DYN 1-9, but not other DYN 1-17 N-terminal fragments (DYN 1-10 and 1-11 on NF-κB/p65 nuclear translocation. DYN 1-17 and selected fragments demonstrated differential modulation on the release of IL-1β and TNF-α with significant inhibition observed with DYN 1-7 at low concentrations (1 nM and 10 pM. These effects were blocked by ML-190, suggesting a KOP receptor-mediated pathway. The results demonstrate that DYN 1-17 and certain N-terminal fragments, produced in an inflamed environment, play an anti-inflammatory role by inhibiting NF-κB/p65 translocation and the subsequent cytokine release through KOP receptor-dependent and independent pathways.

  20. Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord.

    Science.gov (United States)

    Kawasaki, Yasuhiko; Zhang, Ling; Cheng, Jen-Kun; Ji, Ru-Rong

    2008-05-14

    Central sensitization, increased sensitivity in spinal cord dorsal horn neurons after injuries, plays an essential role in the induction and maintenance of chronic pain. However, synaptic mechanisms underlying central sensitization are incompletely known. Growing evidence suggests that proinflammatory cytokines (PICs), such as interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNFalpha), are induced in the spinal cord under various injury conditions and contribute to pain hypersensitivity. Using patch-clamp recordings in lamina II neurons of isolated spinal cord slices, we compared the effects of IL-1beta, IL-6, and TNFalpha on excitatory and inhibitory synaptic transmission. Whereas TNFalpha enhanced the frequency of spontaneous EPSCs (sEPSCs), IL-6 reduced the frequency of spontaneous IPSCs (sIPSCs). Notably, IL-1beta both enhanced the frequency and amplitude of sEPSCs and reduced the frequency and amplitude of sIPSCs. Consistently, TNFalpha and IL-1beta enhanced AMPA- or NMDA-induced currents, and IL-1beta and IL-6 suppressed GABA- and glycine-induced currents. Furthermore, all the PICs increased cAMP response element-binding protein (CREB) phosphorylation in superficial dorsal horn neurons and produced heat hyperalgesia after spinal injection. Surprisingly, soluble IL-6 receptor (sIL-6R) produced initial decrease of sEPSCs, followed by increase of sEPSCs and CREB phosphorylation. Spinal injection of sIL-6R also induced heat hyperalgesia that was potentiated by coadministration with IL-6. Together, our data have demonstrated that PICs induce central sensitization and hyperalgesia via distinct and overlapping synaptic mechanisms in superficial dorsal horn neurons either by increasing excitatory synaptic transmission or by decreasing inhibitory synaptic transmission. PICs may further induce long-term synaptic plasticity through CREB-mediated gene transcription. Blockade of PIC signaling could be an effective way to suppress

  1. Cleft lip with or without cleft palate: Associations with transforming growth factor alpha and retinoic acid receptor loci

    Energy Technology Data Exchange (ETDEWEB)

    Chenevix-Trench, G.; Jones, K. (Queensland Inst. of Medical Research (Australia) Univ. of Queensland (Australia)); Green, A.C.; Duffy, D.L.; Martin, N.G. (Queensland Inst. of Medical Research (Australia))

    1992-12-01

    The first association study of cleft lip with or without cleft palate (CL/P), with candidate genes, found an association with the transforming growth-factor alpha (TGFA) locus. This finding has since been replicated, in whole or in part, in three independent studies. Here the authors extend their original analysis of the TGFA TaqI RFLP to two other TGFA RFLPs and seven other RFLPs at five candidate genes in 117 nonsyndromic cases of CL/P and 113 controls. The other candidate genes were the retinoic acid receptor (RARA), the bcl-2 oncogene, and the homeobox genes 2F, 2G, and EN2. Significant associations with the TGFA TaqI and BamHI RFLPs were confirmed, although associations of clefting with previously reported haplotypes did not reach significance. Of particular interest, in view of the known teratogenic role of retinoic acid, was a significant association with the RARA PstI RFLP (P = .016; not corrected for multiple testing). The effect on risk of the A2 allele appears to be additive, and although the A2A2 homozygote only has an odds ratio of about 2 and recurrence risk to first-degree relatives ([lambda][sub 1]) of 1.06, because it is so common it may account for as much as a third of the attributable risk of clefting. There is no evidence of interaction between the TGFA and RARA polymorphisms on risk, and jointly they appear to account for almost half the attributable risk of clefting. 43 refs., 1 fig., 4 tabs.

  2. miR-29a suppresses MCF-7 cell growth by downregulating tumor necrosis factor receptor 1.

    Science.gov (United States)

    Zhao, Yiling; Yang, Fenghua; Li, Wenyuan; Xu, Chunyan; Li, Li; Chen, Lifei; Liu, Yancui; Sun, Ping

    2017-02-01

    Tumor necrosis factor receptor 1 is the main receptor mediating many tumor necrosis factor-alpha-induced cellular events. Some studies have shown that tumor necrosis factor receptor 1 promotes tumorigenesis by activating nuclear factor-kappa B signaling pathway, while other studies have confirmed that tumor necrosis factor receptor 1 plays an inhibitory role in tumors growth by inducing apoptosis in breast cancer. Therefore, the function of tumor necrosis factor receptor 1 in breast cancer requires clarification. In this study, we first found that tumor necrosis factor receptor 1 was significantly increased in human breast cancer tissues and cell lines, and knockdown of tumor necrosis factor receptor 1 by small interfering RNA inhibited cell proliferation by arresting the cell cycle and inducing apoptosis. In addition, miR-29a was predicted as a regulator of tumor necrosis factor receptor 1 by TargetScan and was shown to be inversely correlated with tumor necrosis factor receptor 1 expression in human breast cancer tissues and cell lines. Luciferase reporter assay further confirmed that miR-29a negatively regulated tumor necrosis factor receptor 1 expression by binding to the 3' untranslated region. In our functional study, miR-29a overexpression remarkably suppressed cell proliferation and colony formation, arrested the cell cycle, and induced apoptosis in MCF-7 cell. Furthermore, in combination with tumor necrosis factor receptor 1 transfection, miR-29a significantly reversed the oncogenic role caused by tumor necrosis factor receptor 1 in MCF-7 cell. In addition, we demonstrated that miR-29a suppressed MCF-7 cell growth by inactivating the nuclear factor-kappa B signaling pathway and by decreasing cyclinD1 and Bcl-2/Bax protein levels. Taken together, our results suggest that miR-29a is an important regulator of tumor necrosis factor receptor 1 expression in breast cancer and functions as a tumor suppressor by targeting tumor necrosis factor receptor 1 to

  3. Comparison of CCL28, interleukin-8, interleukin-1β and tumor necrosis factor-alpha in subjects with gingivitis, chronic periodontitis and generalized aggressive periodontitis.

    Science.gov (United States)

    Ertugrul, A S; Sahin, H; Dikilitas, A; Alpaslan, N; Bozoglan, A

    2013-02-01

    Cytokines produced by various cells are strong local mediators of inflammation. Mucosa-associated epithelial chemokine (CCL28), interleukin-8 (IL-8), interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) are major cytokines that play important roles in the periodontal inflammatory process. In this study we aimed to compare the levels of CCL28, IL-8, IL-1β and TNF-α in the gingival crevicular fluid of both periodontally healthy subjects and in subjects diagnosed with gingivitis, chronic periodontitis and generalized aggressive periodontitis. A total of 84 subjects participated in the study: 21 subjects had gingivitis, 21 subjects had chronic periodontitis, 21 subjects had generalized aggressive periodontitis and 21 were periodontally healthy. The levels of CCL28, IL-8, IL-1β and TNF-α were analyzed using enzyme-linked immune sorbent assay (ELISA). The total levels of CCL28 and IL-8 in the gingival crevicular fluid of the generalized aggressive periodontitis group (324.74 ± 42.62 pg/30 s, 487.62 ± 49.21 pg/30 s) were significantly higher than those of the chronic periodontitis group (268.81 ± 28.64 pg/30 s, 423.65 ± 35.24 pg/30 s), the gingivitis group (146.35 ± 17.46 pg/30 s, 310.24 ± 48.20 pg/30 s) and the periodontally healthy group (92.46 ± 22.04 pg/30 s, 148.41 ± 24.64 pg/30 s). Similarly, the total levels of IL-1β and TNF-α in the generalized aggressive periodontitis group (110.23 ± 9.20 pg/30 s, 1284.46 ± 86.32 pg/30 s) were significantly higher than those in the chronic periodontitis group (423.65 ± 35.24 pg/30 s, 82.64 ± 9.12 pg/30 s), the gingivitis group (52.10 ± 7.15 pg/30 s, 824.24 ± 44.68 pg/30 s) and the periodontally healthy group (36.44 ± 8.86 pg/30 s, 628.26 ± 34.61 pg/30 s). CCL28, IL-8, IL-1β and TNF-α may play key roles in the host response to inflammation in periodontal diseases. As the severity of periodontal diseases increases, destruction of periodontal tissues also increases. Inflammation is one among

  4. [Association of occupational chronic psychological stress with heat shock protein 70 in serum and tumor necrosis factor-alpha expression levels].

    Science.gov (United States)

    Qiu, F Y; Tian, R L; Qiang, Y; He, K P; Liu, H R; Zhang, W; Song, H

    2016-05-01

    To investigate the relationship between occupational chronic psychological stress with heat shock protein 70 (HSP70) and tumor necrosis factor-alpha (TNF-α). Using case-control study design, we selected 622 cases in 20 to 60 years old and unrelated patients with metabolic syndrome as the case group between October 2011 and October 2012 at two hospitals of Ningxia hui autonomous region. At the same time, we selected 600 healthy people from health check-up crowd in the above two hospitals as control group. The the research objects were sex, age, nation, height, weight, smoking, drinking, exercise, and so on. After informed consent, all the research objects were collected fasting venous blood samples 10 ml in order to proceed laboratory testing of biochemical indicators. The expression of HSP70 and TNF-α in serum was determined by ELISA. Using the revised occupational stress inventory (OSI) to survey the occupational chronic psychological stress factors and stress level of research object. The correlation of occupational chronic psychological stress scores with HSP70 and TNF-α was investigated by partial correlation analysis. We built a multivariate linear regression equation With HSP70 and TNF alpha as the independent variable and occupational chronic psychological stress scores as the dependent variable, using equation of the determination coefficient R(2) to judge the degree of fitting equation. The total points of chronic stress factors in all respondents was (136.65±16.19). Among them, the mild stress level group was 313, moderate was 588, severe was 321, chronic heart stress factors scores were (119.96±13.30), (135.33±3.23), (155.33±13.55) points, respectively. In the case group subjects, the expression of HSP70 in mild, moderate and severe occupational chronic psychological stress levels were (29.88±30.08), (36.38±30.08), (27.16±23.77) ng/ml (F=6.85, P=0.001). The control group were (27.64±9.89), (39.78±29.77), (3.94±3.09) ng/ml (F=125

  5. The MC160 Protein Expressed by the Dermatotropic Poxvirus Molluscum Contagiosum Virus Prevents Tumor Necrosis Factor Alpha-Induced NF-κB Activation via Inhibition of I Kappa Kinase Complex Formation

    Science.gov (United States)

    Nichols, Daniel Brian; Shisler, Joanna L.

    2006-01-01

    The pluripotent cytokine tumor necrosis factor alpha (TNF-α) binds to its cognate TNF receptor I (TNF-RI) to stimulate inflammation via activation of the NF-κB transcription factor. To prevent the detrimental effects of TNF-α in keratinocytes infected with the molluscum contagiosum virus (MCV), this poxvirus is expected to produce proteins that block at least one step of the TNF-RI signal transduction pathway. One such product, the MC160 protein, is predicted to interfere with this cellular response because of its homology to other proteins that regulate TNF-RI-mediated signaling. We report here that expression of MC160 molecules did significantly reduce TNF-α-mediated NF-κB activation in 293T cells, as measured by gene reporter and gel mobility shift assays. Since we observed that MC160 decreased other NF-κB activation pathways, namely those activated by receptor-interacting protein, TNF receptor-associated factor 2, NF-κB-inducing kinase, or MyD88, we hypothesized that the MC160 product interfered with I kappa kinase (IKK) activation, an event common to multiple signal transduction pathways. Indeed, MC160 protein expression was associated with a reduction in in vitro IKK kinase activity and IKK subunit phosphorylation. Further, IKK1-IKK2 interactions were not detected in MC160-expressing cells, under conditions demonstrated to induce IKK complex formation, but interactions between the MC160 protein and the major IKK subunits were undetectable. Surprisingly, MC160 expression correlated with a decrease in IKK1, but not IKK2 levels, suggesting a mechanism for MC160 disruption of IKK1-IKK2 interactions. MCV has probably retained its MC160 gene to inhibit NF-κB activation by interfering with signaling via multiple biological mediators. In the context of an MCV infection in vivo, MC160 protein expression may dampen the cellular production of proinflammatory molecules and enhance persistent infections in host keratinocytes. PMID:16378960

  6. Association between HLA-DR2 and production of tumour necrosis factor alpha and interleukin 1 by mononuclear cells activated by lipopolysaccharide

    DEFF Research Database (Denmark)

    Bendtzen, K; Morling, N; Fomsgaard, A

    1988-01-01

    The production of tumour necrosis factor (TNF) and interleukin 1 (IL-1) by lipopolysaccharide-activated mononuclear cells from 39 healthy donors was studied in vitro by bioassay and ELISA. The donors were typed for HLA-A, -B, -C, -DR, and -DP antigens. There was no detectable production of TNF beta...

  7. Role of nitric oxide in recombinant tumor necrosis factor-alpha-induced circulatory shock : A study in patients treated for cancer with isolated limb perfusion

    NARCIS (Netherlands)

    Zwaveling, JH; Maring, JK; Moshage, H; vanGinkel, RJ; Hoekstra, HJ; Donse, IF; Girbes, ARJ; Schraffordt Koops, H.

    1996-01-01

    Objectives: To analyze the mechanism of vasodilation and circulatory shock occurring in patients who are treated with isolated limb perfusion with melphalan and recombinant tumor necrosis factor (TNF)-alpha for locally advanced malignant tumors, To determine the role of nitric oxide, if any, by

  8. Association between HLA-DR2 and production of tumour necrosis factor alpha and interleukin 1 by mononuclear cells activated by lipopolysaccharide

    DEFF Research Database (Denmark)

    Bendtzen, K; Morling, N; Fomsgaard, A

    1988-01-01

    The production of tumour necrosis factor (TNF) and interleukin 1 (IL-1) by lipopolysaccharide-activated mononuclear cells from 39 healthy donors was studied in vitro by bioassay and ELISA. The donors were typed for HLA-A, -B, -C, -DR, and -DP antigens. There was no detectable production of TNF be...

  9. Suspected de novo Hepatitis B in a Patient Receiving Anti-Tumor Necrosis Factor Alpha Therapy for the Treatment of Crohn's Disease

    Directory of Open Access Journals (Sweden)

    Tetsuya Ishida

    2014-01-01

    Full Text Available We report a 45-year-old female patient who developed acute hepatic disorder during anti-tumor necrosis factor α therapy for the treatment of Crohn's disease (CD. She was diagnosed as colonic CD and placed on infliximab (IFX. She was negative for hepatitis B surface antigen at the initiation of IFX therapy, but developed acute hepatitis after the 30th administration of IFX 4 years and 1 month after the first administration. She was suspected to have had occult hepatitis B virus infection before IFX therapy, and de novo hepatitis B was considered the most likely diagnosis. Hepatitis subsided after discontinuation of anti-tumor necrosis factor α therapy and initiation of treatment with entecavir. She started to receive adalimumab to prevent relapse of CD. She has continued maintenance therapy with entecavir and adalimumab and has since been asymptomatic. As de novo hepatitis B may be fatal, virological testing for hepatitis B is essential for patients who are being considered for treatment that may weaken the immune system.

  10. Effects of concurrent training on interleukin-6, tumour necrosis factor-alpha and C-reactive protein in middle-aged men.

    Science.gov (United States)

    Libardi, Cleiton Augusto; Souza, Giovana Verginia; Gáspari, Arthur Fernandes; Dos Santos, Claudinei Ferreira; Leite, Sabrina Toffoli; Dias, Rodrigo; Frollini, Anelena B; Brunelli, Diego Trevisan; Cavaglieri, Claudia Regina; Madruga, Vera Aparecida; Chacon-Mikahil, Mara P T

    2011-11-01

    The purpose of this study was to evaluate the effects of moderate- to high-intensity resistance and concurrent training on inflammatory biomarkers and functional capacity in sedentary middle-aged healthy men. Participants were selected on a random basis for resistance training (n = 12), concurrent training (n = 11) and a control group (n = 13). They performed three weekly sessions for 16 weeks (resistance training: 10 exercises with 3 × 8-10 repetition maximum; concurrent training: 6 exercises with 3 × 8-10 repetition maximum, followed by 30 minutes of walking or running at 55-85% [Vdot]O(2peak)). Maximal strength was tested in bench press and leg press. The peak oxygen uptake ([Vdot]O(2peak)) was measured by an incremental exercise test. Tumour necrosis factor-α, interleukin-6 and C-reactive protein were determined. The upper- and lower-body maximal strength increase for both resistance (+42.52%; +20.9%, respectively) and concurrent training (+28.35%; +21.5%, respectively) groups (P = 0.0001).[Vdot]O(2peak) increased in concurrent training when comparing pre- and post-training (P = 0.0001; +15.6%). No differences were found in tumour necrosis factor-α and interleukin-6 for both groups after the exercise. C-reactive protein increased in resistance training (P = 0.004). These findings demonstrated that 16 weeks of moderate- to high-intensity training could improve functional capacity, but did not decrease inflammatory biomarkers in middle-aged men.

  11. Analysis of polymorphisms of tumor necrosis factor-alpha and polymorphic xenobiotic metabolizing enzymes in inflammatory bowel disease: study from northern India.

    Science.gov (United States)

    Mittal, Rama D; Manchanda, Parmeet K; Bid, Hemant K; Ghoshal, Uday C

    2007-06-01

    Tumor necrosis factor (TNF)-alpha is a proinflammatory cytokine associated with inflammatory diseases, while GSTM1 and T1 enzymes catalyze detoxification of products of oxidative stress and hence reduce inflammation. Thus, both may play important roles in the pathogenesis of inflammatory bowel disease (IBD). The present study aimed to evaluate the effect of polymorphism of the TNF-alpha promoter at the -308 site, GSTM1 and GSTT1 in patients with IBD and healthy controls from northern India. Genotyping was performed in 114 patients with IBD (22 Crohn's disease [CD] and 92 ulcerative colitis [UC]) in TNF-alpha and 105 (20 CD and 85 UC) in GSTM1 and T1 and 164 healthy controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and multiplex PCR methods. Patients with IBD were comparable to healthy controls in relation to age and gender. Genotypic and allelic frequencies of TNF-alpha were comparable among patients with IBD and healthy controls. GSTM1 null genotype was more frequent in UC than in healthy controls (52/85 vs 49/164; P GST genotypes further increases the risk, possibly due to gene-gene interaction. TNF-alpha is unlikely to be an important determinant of susceptibility to IBD in the Indian population.

  12. Tumor necrosis factor-alpha and angiostatin are mediators of endothelial cytotoxicity in bronchoalveolar lavages of patients with acute respiratory distress syndrome.

    Science.gov (United States)

    Hamacher, Jürg; Lucas, Rudolf; Lijnen, H Roger; Buschke, Susanne; Dunant, Yves; Wendel, Albrecht; Grau, Georges E; Suter, Peter M; Ricou, Bara

    2002-09-01

    Acute respiratory distress syndrome (ARDS) is characterized by an extensive alveolar capillary leak, permitting contact between intra-alveolar factors and the endothelium. To investigate whether factors contained in the alveolar milieu induce cell death in human lung microvascular endothelial cells, we exposed these cells in vitro to bronchoalveolar lavage fluid (BALF) supernatants from control patients, patients at risk of developing ARDS, and patients with early- and late-phase ARDS. In contrast to BALF from control patients, a significant cytotoxicity was found in BALF from patients at risk of developing ARDS, with late-phase ARDS, and especially from patients with early-phase ARDS. Subsequently, we determined the levels of factors known to exert cytotoxicity in endothelial cells, i.e., tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1, and angiostatin. BALF from patients at risk of developing ARDS, with early-phase ARDS, and with late-phase ARDS, contained increased levels of TNF-alpha and angiostatin, but not of TGF-beta1, as compared with BALF from control patients. Whereas inhibition of TGF-beta1 had no effect in this setting, neutralization of TNF-alpha or angiostatin inhibited the cytotoxic activity on endothelial cells of part of the early-phase ARDS BALF. These results indicate that TNF-alpha and angiostatin may contribute to ARDS-related endothelial injury.

  13. Relapse rates of inflammatory bowel disease patients in deep and clinical remission after discontinuing anti-tumor necrosis factor alpha therapy.

    Science.gov (United States)

    Hlavaty, T; Krajcovicova, A; Letkovsky, J; Sturdik, I; Koller, T; Toth, J; Huorka, M

    2016-01-01

    Relapse rates after discontinuing anti-tumor necrosis factor-α (TNFα) therapy of inflammatory bowel disease (IBD) patients in deep remission are poorly understood. This prospective single-center open-label study evaluated the relapse rates of IBD patients after stopping anti-TNFα therapy. All IBD patients who were in clinical remission and stopped anti-TNFα therapy in 2011-2013 and were followed up for at least 12 months were enrolled. The "Ultradeep" patients were in calprotectin-negative (risk factors identified. One year after stopping, 27 % and 27 % of the Ultradeep (n = 11) and Clinical (n = 11) patients relapsed, respectively. Two years after stopping, 57 % and 62 % relapsed, respectively (p = 0.89). All relapsed patients who underwent retreatment with anti-TNFα therapy re-entered remission. Male sex was a significant risk factor for relapse (p = 0.03). Our study showed that even highly selected IBD patients who lack clinical, endoscopic or laboratory signs of disease activity have a relatively high relapse rate in the follow-up period after ceasing anti-TNFα therapy (Tab. 2, Fig. 3, Ref. 24).

  14. The Effect of Aerobic Training and Arbotin on Cardiac Nitric Oxide, Tumor Necrosis Factor alpha, and Vascular Endothelial Growth Factor in Male Diabetic Rats

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    Rahemeh Jahangiri Jahangiri

    2017-07-01

    Full Text Available Background and Objectives: Diabetes is one of the most important metabolic diseases, which its incidence rate has increased in recent years. In this disease, the insulin function is impaired, leading to several complications. Physical exercise and medicinal plants are considered as a way to control diabetes along with nutrition and medicine. The present study was conducted with the purpose of determining the effect of aerobic training and use of arbutin on cardiac nitric oxide, tumor necrosis factor-α and vessel endothelial growth factor in male diabetic rats. Methods: In this experimental study, 42 male adult Wistar rats (age, 8 weeks; weight, 190-220g, were randomly divided into 6 groups of 7 each (control, arbutin, diabetic, diabetic+training, diabetic+arbutin, and diabetic+training+arbutin. Training programs included 5 days of swimming per week for 6 weeks. Sampling from the heart was performed 72 hours after the last training session and arbutin consumption to analyze NO, TNF-α and VEGF. Data were analyzed using one-way ANOVA at the significance level p≤0.05. Results: Aerobic training along with use of arbutin led to increased levels of NO and VEGF and decreased level of TNF-α in cardiac tissue of diabetic rats (p<0.001. Conclusion: The results indicated that a period of regular aerobic training and use of arbutin can be considered as an appropriate non-medicinal method to control diabetes mellitus type 2 through decrease in inflammatory factors.

  15. Heritable major histocompatibility complex class II-associated differences in production of tumor necrosis factor. alpha. : Relevance to genetic predisposition to systemic lupus erythematosus

    Energy Technology Data Exchange (ETDEWEB)

    Jacob, C.O.; Fronek, Z.; Koo, M.; McDevitt, H.O. (Stanford Univ. School of Medicine, CA (USA)); Lewis, G.C. (Genentech Inc., San Francisco, CA (USA)); Hansen, J.A. (Fred Hutchinson Cancer Research Center, Seattle, WA (USA))

    1990-02-01

    The authors report on the production of tumor necrosis factor (TNF)-{alpha} and TNF-{beta} by mitogen-activated peripheral blood lymphocytes or enriched monocyte subpopulations from human leukocyte antigen (HLA)-typed healthy subjects. The results indicate that HLA-DR2- and DQw1-positive donors frequently exhibit low production of TNF-{alpha}, whereas DR3- and DR4-positive subjects show high levels of TNF-{alpha} production. No correlation between TNF-{alpha} levels and HLA-A, -B, and -C genotype was found. The relevance of this quantitative polymorphism to the genetic predisposition to lupus nephritis in systemic lupus erythematosus (SLE) patients was investigated. DR2, DQw1-positive SLE patients show low levels of TNF-{alpha} inducibility; this genotype is also associated with an increased incidence of lupus nephritis. DR3-positive SLE patients, on the other hand, are not predisposed to nephritis, and these patients have high TNF-{alpha} production. DR4 haplotype is associated with high TNF-{alpha} inducibility and is negatively correlated with lupus nephritis. These data may help explain the strong association between HLA-DR2, DQw1 in SLE patients and their susceptibility to nephritis.

  16. In vitro inhibition of enterobacteria-reactive CD4+Tumor necrosis factor-alpha binding capacity and anti-infliximab antibodies measured by fluid-phase radioimmunoassays as predictors of clinical efficacy of infliximab in Crohn's disease

    DEFF Research Database (Denmark)

    Mangano, K.; Sardesai, N.; D'Alcamo, M.

    2008-01-01

    VGX-1027 is an isozaxoline compound that has recently been found to primarily target the function of murine macrophages but not of T cells, inhibiting secretion of tumor necrosis factor (TNF)-alpha in response to different Toll-like receptor agonists in vitro and in vivo. The well-defined role of...

  17. Tributyltin (TBT) and Dibutyltin (DBT) Alter Secretion of Tumor Necrosis Factor Alpha (TNFα) from Human Natural Killer (NK) Cells and a Mixture of T cells and NK Cells

    Science.gov (United States)

    Hurt, Kelsi; Hurd-Brown, Tasia; Whalen, Margaret

    2012-01-01

    Butyltins (BTs) have been in widespread use. Tributyltin (TBT) has been used as a biocide in a variety of applications and is found in human blood samples. Dibutyltin (DBT) has been used as a stabilizer in polyvinyl chloride plastics and as a de-worming agent in poultry. DBT, like TBT, is found in human blood. Human natural killer (NK) cells are the earliest defense against tumors and viral infections and secrete the cytokine tumor necrosis factor (TNF) alpha (α). TNFα is an important regulator of adaptive and innate immune responses. TNFα promotes inflammation and an association between malignant transformation and inflammation has been established. Previously, we have shown that TBT and DBT were able to interfere with the ability of NK cells to lyse tumor target cells. Here we show that BTs alter cytokine secretion by NK cells as well as a mixture of T and NK lymphocytes (T/NK cells). We examined 24 h, 48 h, and 6 day exposures to TBT (200- 2.5 nM) and DBT (5- 0.05 µM) on TNFα secretion by highly enriched human NK cells and T/NK cells. The results indicate that TBT (200 - 2.5 nM) decreased TNFα secretion from NK cells. In the T/NK cells 200 nM TBT decreased secretion while 100-5 nM TBT increased secretion of TNFα. NK cells or T/NK cells exposed to higher concentrations of DBT showed decreased TNFα secretion while lower concentrations showed increased secretion. The effects of BTs on TNFα secretion are seen at concentrations present in human blood. PMID:23047847

  18. Prevotella intermedia lipopolysaccharide stimulates release of tumor necrosis factor-alpha through mitogen-activated protein kinase signaling pathways in monocyte-derived macrophages.

    Science.gov (United States)

    Kim, Sung-Jo; Choi, Eun-Young; Kim, Eun Gyung; Shin, Su-Hwa; Lee, Ju-Youn; Choi, Jeom-Il; Choi, In-Soon

    2007-11-01

    The purpose of this study was to investigate the effects of lipopolysaccharide from Prevotella intermedia, a major cause of inflammatory periodontal disease, on the production of tumor necrosis factor (TNF)-alpha and the expression of TNF-alpha mRNA in differentiated THP-1 cells, a human monocytic cell line. The potential involvement of the three main mitogen-activated protein kinase (MAPK) signaling pathways in the induction of TNF-alpha production was also investigated. Lipopolysaccharide from P. intermedia ATCC 25611 was prepared by the standard hot phenol-water method. THP-1 cells were incubated in the medium supplemented with phorbol myristate acetate to induce differentiation into macrophage-like cells. It was found that P. intermedia lipopolysaccharide can induce TNF-alpha mRNA expression and stimulate the release of TNF-alpha in differentiated THP-1 cells without additional stimuli. Treatment of the cells with P. intermedia lipopolysaccharide resulted in a simultaneous activation of three MAPKs [extracellular signal-related kinase 1/2 (ERK1/2), c-Jun N-terminal kinase 1/2 (JNK1/2) and p38]. Pretreatment of the cells with MAPK inhibitors effectively suppressed P. intermedia lipopolysaccharide-induced TNF-alpha production without affecting the expression of TNF-alpha mRNA. These data thus provided good evidence that the MAPK signaling pathways are required for the regulation of P. intermedia lipopolysaccharide-induced TNF-alpha synthesis at the level of translation more than at the transcriptional level.

  19. Anti-tumor Necrosis Factor Alpha (Infliximab) Attenuates Apoptosis, Oxidative Stress, and Calcium Ion Entry Through Modulation of Cation Channels in Neutrophils of Patients with Ankylosing Spondylitis.

    Science.gov (United States)

    Ugan, Yunus; Nazıroğlu, Mustafa; Şahin, Mehmet; Aykur, Mehmet

    2016-08-01

    Ankylosing Spondylitis (AS) is known to be associated with increased neutrophil activation and oxidative stress, however, the mechanism of neutrophil activation is still unclear. We have hypothesized that the antioxidant and anti-tumor necrosis factor properties of infliximab may affect intracellular Ca(2+) concentration in the neutrophils of AS patients. The objective of this study was to investigate the effects of infliximab on calcium signaling, oxidative stress, and apoptosis in neutrophils of AS patients. Neutrophils collected from ten patients with AS and ten healthy controls were used in the study. In a cell viability test, the ideal non-toxic dose and incubation time of infliximab were found as 100 μM and 1 h, respectively. In some experiments, the neutrophils were incubated with the voltage-gated calcium channel (VGCC) blockers verapamil + diltiazem (V + D) and the TRPM2 channel blocker 2-aminoethyl diphenylborinate (2-APB). Intracellular Ca(2+) concentration, lipid peroxidation, apoptosis, caspase 3, and caspase 9 values were high in neutrophils of AS patients and were reduced with infliximab treatment. Reduced glutathione level and glutathione peroxidase activity were low in the patients and increased with infliximab treatment. The intracellular Ca(2+) concentrations were low in 2-APB and V + D groups. In conclusion, the current study suggests that infliximab is useful against apoptotic cell death and oxidative stress in neutrophils of patients with AS, which seem to be dependent on increased levels of intracellular Ca(2+) through activation of TRPM2 and VGCC.

  20. DEVELOPMENT OF ALOPECIA DURING TREATMENT WITH A TUMOR NECROSIS FACTOR-ALPHA INHIBITOR IN A FEMALE PATIENT WITH PSORIATIC ARTHRITS: A CLINICAL CASE

    Directory of Open Access Journals (Sweden)

    R. G. Mukhina

    2016-01-01

    Full Text Available Objective: to describe a case of the total development of alopecia in a female patient with psoriatic arthritis during treatment with a tumor necrosis factor-αlpha (TNF-α inhibitor. Materials and methods. Patient I., aged 36 years has been followed up at the Kazan’ Center of Rheumatic Diseases and Osteoporosis since 1998. At approximately the same time, the patient noted the appearance of skin eruptions behind the ears, on the skin of the scalp. She was examined by a dermatologist who diagnosed psoriasis. In 2005, she was admitted to Kazan’ Rheumatology Center, City Clinical Hospital Seven, for the development of obvious synovitis of the knee joint and for the inefficiency of therapy with nonsteroidal anti-inflammatory drugs and diagnosed with psoriatic arthritis. During the prescribed therapy with methotrexate 10 mg/week, evident menstrual irregularities were observed in the patient who stopped using the drug herself. The second pregnancy occurred in 2008. Articular syndrome progression and eruptive psoriasis were recorded in the lactation period. After lactation cessation in 2009, she was hospitalized again. Her examination revealed high laboratory activity (erythrocyte sedimentation rate, as high as 40 mm/hr; magnetic resonance imaging of the knee joints showed the signs of bilateral synovitis; lumbar spine radiography exhibited grade II sacroiliitis. Leflunomide 20 mg/day was recommended as a basic drug. In 2012, the patient used leflunomide, her condition worsened; joint pain progressed; new joints were involved into the process, and cutaneous manifestations were aggravated. To verify a diagnosis and to choose therapy, the patient was referred to a consultation at the Moscow Research Institute of Rheumatology. Results. In connection with the high activity of the disease and with no response to the performed therapy, it was recommended to initiate therapy with biologics, such as infliximab, the drug of choice. Seven infliximab

  1. Contrasting effects of an ultraviolet B and an ultraviolet A tanning lamp on interleukin-6, tumour necrosis factor-alpha and intercellular adhesion molecule-1 expression.

    Science.gov (United States)

    Clingen, P H; Berneburg, M; Petit-Frère, C; Woollons, A; Lowe, J E; Arlett, C F; Green, M H

    2001-07-01

    Recent studies have demonstrated that a tanning lamp emitting predominantly ultraviolet (UV) A induces significant yields of the type of potentially mutagenic DNA damage that are associated with the onset of skin cancer (i.e. cyclobutane pyrimidine dimers). UV-induced immunosuppression is also an important event leading to skin cancer. To the modulation of key immunological molecules following exposure to a broad-spectrum UVB lamp and a predominantly UVA-emitting tanning lamp using model in vitro systems. We compared secretion and mRNA expression of interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha in normal human epidermal keratinocytes, and interferon (IFN)-gamma-induced intracellular adhesion molecule (ICAM)-1 in normal human fibroblasts irradiated in vitro with a broad-spectrum UVB lamp or with a Philips 'Performance' tanning lamp. With broad-spectrum UVB irradiation, upregulation of IL-6 and TNF-alpha mRNA was detected 6 h after irradiation, and a dose-dependent increase of cytokines in the supernatants of irradiated cells was found 24 h after irradiation. In contrast, there was no cytokine secretion and little evidence for mRNA upregulation following exposure to a tanning lamp. When cells were exposed first to broad-spectrum UVB, then the tanning lamp, UVB-induced cytokine secretion was inhibited, although mRNA levels were upregulated to a level close to that observed with UVB alone. By using a Schott WG 320 nm filter to attenuate the level of UVB relative to UVA emitted by the tanning lamp, the inhibition of cytokine secretion was shown to be associated with UVA exposure. Both UV sources inhibited IFN-gamma-induced ICAM-1 mRNA expression in a dose-dependent fashion. By using a Schott WG 335 nm filter, inhibition of ICAM-1 mRNA expression by the tanning lamp was shown to be associated with UVB exposure. These results suggest that UV sources emitting different levels of UVA and UVB have differential effects on the modulation of different

  2. Interleukin-1, tumor necrosis factor-alpha, and transforming growth factor-beta 1 and integrative meniscal repair: influences on meniscal cell proliferation and migration

    Science.gov (United States)

    2011-01-01

    Introduction Interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) are up-regulated in injured and osteoarthritic knee joints. IL-1 and TNF-α inhibit integrative meniscal repair; however, the mechanisms by which this inhibition occurs are not fully understood. Transforming growth factor-β1 (TGF-β1) increases meniscal cell proliferation and accumulation, and enhances integrative meniscal repair. An improved understanding of the mechanisms modulating meniscal cell proliferation and migration will help to improve approaches for enhancing intrinsic or tissue-engineered repair of the meniscus. The goal of this study was to examine the hypothesis that IL-1 and TNF-α suppress, while TGF-β1 enhances, cellular proliferation and migration in cell and tissue models of meniscal repair. Methods A micro-wound assay was used to assess meniscal cell migration and proliferation in response to the following treatments for 0, 24, or 48 hours: 0 to 10 ng/mL IL-1, TNF-α, or TGF-β1, in the presence or absence of 10% serum. Proliferated and total cells were fluorescently labeled and imaged using confocal laser scanning microscopy and the number of proliferated, migrated, and total cells was determined in the micro-wound and edges of each image. Meniscal cell proliferation was also assessed throughout meniscal repair model explants treated with 0 or 10 ng/mL IL-1, TNF-α, or TGF-β1 for 14 days. At the end of the culture period, biomechanical testing and histological analyses were also performed. Statistical differences were assessed using an ANOVA and Newman-Keuls post hoc test. Results IL-1 and TNF-α decreased cell proliferation in both cell and tissue models of meniscal repair. In the presence of serum, TGF-β1 increased outer zone cell proliferation in the micro-wound and in the cross section of meniscal repair model explants. Both IL-1 and TNF-α decreased the integrative shear strength of repair and extracellular matrix deposition in the meniscal repair model system

  3. Investigating the Impacts of Preoperative Steroid Treatment on Tumor Necrosis Factor-Alpha and Duration of Extubation Time underwent Ventricular Septal Defect Surgery

    Directory of Open Access Journals (Sweden)

    H. Hakan Poyrazoğlu

    2016-04-01

    Full Text Available Background: Cardiopulmonary bypass is known to cause inflammatory events. Inflammation occurs due to many known important biological processes. Numerous mechanisms are known to be responsible for the development of inflammatory processes. Currently, there are many defined mediators as a tumor necrosis factor-α (TNF-α playing an active role in this process. Aims: This research was to investigate the effects of preoperative steroid use on inflammatory mediator TNF-α and on time to extubation postoperatively in ventricular septal defect patients undergoing cardiopulmonary bypass surgery. Study Design: Controlled clinical study. Methods: This study included 30 patients. These patients were assigned into two groups, each containing 15 patients. 5 micrograms/kg methylprednisolone was injected intravenously 2 hours before the surgery to Group I, whereas there was no application to the patients in Group II. TNF-α (pg/mL level was measured in arterial blood samples obtained at four periods including: the preoperative period (Pre TNF; at the 5th minute of cross-clamping (Per TNF; 2 hours after termination of cardiopulmonary bypass (Post TNF; and at the postoperative 24th hours in cardiovascular surgery intensive care unit (Post 24 h TNF. Results: The mean cross-clamp time was 66±40 and 55±27 minutes in Group I and Group II respectively. No significant difference was found between the groups in terms of cross-clamp time (p>0.05. The mean time to extubation was 6.1±2.3 hours in Group I and 10.6±3.4 hours in Group II. Group I extubation time was significantly shorter than Group II. Group I TNF-α levels at Post TNF and Post24h TNF was lower than Group II. These differences are also statistically significant (p<0.05. Conclusion: There is a strong indication that preoperative steroid treatment reduced the TNF-α level together with shortens duration of postoperative intubation and positively contributes to extubation in ventricular septal defect

  4. Polymorphism of tumor necrosis factor alpha (TNF-alpha gene promoter, circulating TNF-alpha level, and cardiovascular risk factor for ischemic stroke

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    Cui Guanglin

    2012-10-01

    Full Text Available Abstract Background Tumor necrosis factor-α (TNF-α is one of the most typical pro-inflammatory cytokines with both beneficial and destructive properties for the central nervous system. Increasing evidences have demonstrated the important role of TNF-α in the development of ischemic stroke, but studies examining the possible association with stroke or direct functional effects of polymorphisms in TNF-α have been contradictory. Findings In this study, a 2-kb length of the proximal promoter of the TNF-α was screened and four polymorphisms were investigated in the case–control study. Our data confirmed the association between -308G/A variant with stroke in 1,388 stroke patients and 1,027 controls and replicated in an independent population of 961 stroke patients and 821 controls (odds ratio (OR = 1.34, 95% confidence interval (CI =1.02 to 1.77 and OR = 1.56, 95% CI = 1.09 to 2.23, respectively. To reconcile the association between polymorphisms and stroke and to give a comprehensive picture of the genetic architecture of this important gene, we performed a meta-analysis of 15 published studies in an Asian population. Our results demonstrated an association between rs1800629 and ischemic stroke (OR = 1.43, 95% CI = 1.21 to 1.69. Another meta-analysis results of 14 studies demonstrated that ischemic stroke patients have higher serum TNF-α level than the control subjects (standardized mean difference (SMD = 2.33, 95% CI = 1.85 to 2.81. In vitro evaluation of potential interaction between variants of the TNF-α gene (−308G/A, -857C/T, and -1031T/C demonstrated that these three polymorphisms could interact together to determine the overall activity of the TNF-α gene. Conclusions These findings strongly implicate the involvement of TNF-α in the pathogenesis of stroke.

  5. Possible reactivation of potential hepatitis B virus occult infection by tumor necrosis factor-alpha blocker in the treatment of rheumatic diseases.

    Science.gov (United States)

    Kim, Yun Jung; Bae, Sang-Cheol; Sung, Yoon-Kyoung; Kim, Tae-Hwan; Jun, Jae-Bum; Yoo, Dae-Hyun; Kim, Tae Yeob; Sohn, Joo Hyun; Lee, Hye-Soon

    2010-02-01

    To assess the safety of anti-tumor necrosis factor (TNF-alpha) therapy in patients with rheumatic diseases in terms of the reactivation of potential hepatitis B virus (HBV) occult infection. Patients who had taken anti-TNF-alpha for the treatment of rheumatic diseases from January 2002 to May 2008 were included in the study. In this patient group, we retrospectively investigated a series of serum aminotransferase levels, HBV serologic status, the type of anti-TNF-alpha therapy, duration of the anti-TNF-alpha treatment, and concurrent use of hepatotoxic drugs. A total of 266 cases were documented using 3 serologic markers for HBV infection: HBV surface antigen (HBsAg), HBV surface antibody (HBsAb), and HBV core IgG Ab (HBcAb). Of these, 8 cases had chronic hepatitis B (HBsAg+), 170 cases were HBcAb-negative, and 88 cases were identified as having potential HBV occult infections represented by HBsAg-negative and HBcAb-positive, irrespective of the status of the HBsAb. The frequency of clinically significant (> 2 times normal value) and persistent increase (> 2 consecutive tests) of aminotransferase levels was significantly higher in the group with a potential HBV occult infection compared to the HBcAb-negative group. In the multiple logistic regression analysis controlling for various potential confounding factors such as prophylactic anti-tuberculosis medication, methotrexate, nonsteroidal antiinflammatory drugs, and the type of anti-TNF-alpha therapy, only potential HBV occult infection was a significant risk factor for abnormal liver function test (LFT). All rheumatic patients who plan to take anti-TNF-alpha treatment should undergo a test for HBV serology, including HBcAb, and have a close followup with an LFT test during therapy. Further prospective studies for hepatitis B viral load using HBV-polymerase chain reaction in patients who are HbcAb positive are needed to identify whether the abnormal LFT comes from the reactivation of occult HBV infection.

  6. A Role for Protein Phosphatase 2A in Regulating p38 Mitogen Activated Protein Kinase Activation and Tumor Necrosis Factor-Alpha Expression during Influenza Virus Infection

    Directory of Open Access Journals (Sweden)

    Anna H. Y. Law

    2013-04-01

    Full Text Available Influenza viruses of avian origin continue to pose pandemic threats to human health. Some of the H5N1 and H9N2 virus subtypes induce markedly elevated cytokine levels when compared with the seasonal H1N1 virus. We previously showed that H5N1/97 hyperinduces tumor necrosis factor (TNF-alpha through p38 mitogen activated protein kinase (MAPK. However, the detailed mechanisms of p38MAPK activation and TNF-alpha hyperinduction following influenza virus infections are not known. Negative feedback regulations of cytokine expression play important roles in avoiding overwhelming production of proinflammatory cytokines. Here we hypothesize that protein phosphatases are involved in the regulation of cytokine expressions during influenza virus infection. We investigated the roles of protein phosphatases including MAPK phosphatase-1 (MKP-1 and protein phosphatase type 2A (PP2A in modulating p38MAPK activation and downstream TNF-alpha expressions in primary human monocyte-derived macrophages (PBMac infected with H9N2/G1 or H1N1 influenza virus. We demonstrate that H9N2/G1 virus activated p38MAPK and hyperinduced TNF-alpha production in PBMac when compared with H1N1 virus. H9N2/G1 induced PP2A activity in PBMac and, with the treatment of a PP2A inhibitor, p38MAPK phosphorylation and TNF-alpha production were further increased in the virus-infected macrophages. However, H9N2/G1 did not induce the expression of PP2A indicating that the activation of PP2A is not mediated by p38MAPK in virus-infected PBMac. On the other hand, PP2A may not be the targets of H9N2/G1 in the upstream of p38MAPK signaling pathways since H1N1 also induced PP2A activation in primary macrophages. Our results may provide new insights into the control of cytokine dysregulation.

  7. Effect of one night of sleep loss on changes in tumor necrosis factor alpha (TNF-α) levels in healthy men.

    Science.gov (United States)

    Chennaoui, M; Sauvet, F; Drogou, C; Van Beers, P; Langrume, C; Guillard, M; Gourby, B; Bourrilhon, C; Florence, G; Gomez-Merino, D

    2011-11-01

    Total sleep deprivation in humans is associated with increased daytime sleepiness, decreased performance, elevations in inflammatory cytokines, and hormonal/metabolic disturbances. To assess the effects of 40 h of total sleep deprivation (TSD) under constant and well controlled conditions, on plasma levels of TNF-α and its receptor (TNFR1), interleukin-6 (IL-6), cortisol and C-reactive protein (CRP), sleepiness and performance, 12 healthy men (29±3 years) participated in a 5-days sleep deprivation experiment (two control nights followed by a night of sleep loss and one recovery night). Between 0800 and 2300 (i.e. between 25 and 40 h of sleep deprivation), a serial of blood sampling, multiple sleep latency, subjective levels of sleepiness and reaction time tests were completed before (day 2: D2) and after (day 4: D4) one night of sleep loss. We showed that an acute sleep deprivation (i.e. after 34 and 37 h of sleep deprivation) induced a significant increase in TNF-α (Pstressors, an acute total sleep deprivation (from 34 h) was sufficient to induce secretion of pro-inflammatory cytokine such as TNF-α, a marker more described in chronic sleep restriction or deprivation and as mediators of excessive sleepiness in humans in pathological conditions. Copyright © 2011 Elsevier Ltd. All rights reserved.

  8. [Leptin and activity of tumor necrosis factor alpha relations with parameters of the trophologic status and digestion in patients with chronic obstructive pulmonary disease].

    Science.gov (United States)

    2011-01-01

    To study effects of leptin regulation of energy and activity of TNF-alpha on the trophologic status and digestion of main nutrients in patients with stable chronic obstructive pulmonary disease (COPD). Somatometric methods were used to examine trophologic status in 93 patients with stable COPD. Of them, 22 had stage I, 36 - stage II, 35 patients - stage III. Serum leptin was measured with enzyme immunoassay (EIA) using DSL kit (USA), TNF-alpha and receptors sTNF-R55 and -R75 with EIA (kits BioSource, Belgium). The absorption was assessed biochemically and with radionuclide investigation. Body fat was estimated by bioelectric impedance (OmRon BF-302, Japan). The level of circulating leptin decreased with progression of COPD and correlated with body fat depletion (r = 0.88 +/- 0.12). Activation of the TNF-alpha system was detected in the presence and progression of trophologic insufficiency (TI) in patients with COPD stage II and III. A correlation was found between an elevated level of circulating TNF-alpha and enhanced fat and 131-I-albumin excretion, subnormal excretion of D-xylose. Low blood serum leptin concentration in patients with moderate and severe stable COPD correlates with fat tissue depletion reflecting reduced energetic potential of adipocytes. High TNF-alpha concentration in the serum was seen only in TI and its progression. This evidences for cytokine involvement in induction of metabolic disorders in COPD patients. Elevated concentration of circulating TNF-alpha closely correlated with excretion of higher quantities of fats, protein, low excretion of D-xylose and proves its involvement in TI development in COPD patients. Activation of TNF-alpha system in COPD does not influence leptin concentration in blood serum as it functions as an independent physiological system.

  9. Cervical squamous carcinoma cells are resistant to the combined action of tumor necrosis factor-alpha and histamine whereas normal keratinocytes undergo cytolysis.

    Science.gov (United States)

    Diaconu, Nicolae-Costin; Rummukainen, Jaana; Mättö, Mikko; Naukkarinen, Anita; Harvima, Rauno J; Pelkonen, Jukka; Harvima, Ilkka T

    2008-02-07

    Previous reports showed that mast cells can typically be found in the peritumoral stroma of cervix carcinomas as well as in many other cancers. Both histamine and TNF-alpha are potent preformed mast cell mediators and they can act simultaneously after release from mast cells. Thus, the effect of TNF-alpha and histamine on cervical carcinoma cell lines was studied. TNF-alpha alone induced slight growth inhibition and cell cycle arrest at G0/G1 phase in SiHa cells, but increased their migration. Histamine alone had no effect on cells. In addition, TNF-alpha and histamine in combination showed no additional effect over that by TNF-alpha alone, although SiHa cells were even pretreated with a protein synthesis inhibitor. Furthermore, TNF-alpha-sensitive ME-180 carcinoma cells were also resistant to the combination effect of TNF-alpha and histamine. In comparison, TNF-alpha or histamine alone induced growth inhibition in a non-cytolytic manner in normal keratinocytes, an effect that was further enhanced to cell cytolysis when both mediators acted in combination. Keratinocytes displayed strong TNF receptor (TNFR) I and II immunoreactivity, whereas SiHa and ME-180 cells did not. Furthermore, cervix carcinoma specimens revealed TNF-alpha immunoreactivity in peritumoral cells and carcinoma cells. However, the immunoreactivity of both TNFRs was less intense in carcinoma cells than that in epithelial cells in cervical specimens with non-specific inflammatory changes. SiHa and ME-180 cells are resistant to the cytolytic effect of TNF-alpha and histamine whereas normal keratinocytes undergo cytolysis, possibly due to the smaller amount of TNFRs in SiHa and ME-180 cells. In the cervix carcinoma, the malignant cells may resist this endogenous cytolytic action and TNF-alpha could even enhance carcinoma cell migration.

  10. The tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20) imposes a brake on antitumor activity of CD8 T cells.

    Science.gov (United States)

    Giordano, Marilyn; Roncagalli, Romain; Bourdely, Pierre; Chasson, Lionel; Buferne, Michel; Yamasaki, Sho; Beyaert, Rudi; van Loo, Geert; Auphan-Anezin, Nathalie; Schmitt-Verhulst, Anne-Marie; Verdeil, Grégory

    2014-07-29

    The transcription factor NF-κB is central to inflammatory signaling and activation of innate and adaptive immune responses. Activation of the NF-κB pathway is tightly controlled by several negative feedback mechanisms, including A20, an ubiquitin-modifying enzyme encoded by the tnfaip3 gene. Mice with selective deletion of A20 in myeloid, dendritic, or B cells recapitulate some human inflammatory pathology. As we observed high expression of A20 transcripts in dysfunctional CD8 T cells in an autochthonous melanoma, we analyzed the role of A20 in regulation of CD8 T-cell functions, using mice in which A20 was selectively deleted in mature conventional T cells. These mice developed lymphadenopathy and some organ infiltration by T cells but no splenomegaly and no detectable pathology. A20-deleted CD8 T cells had increased sensitivity to antigen stimulation with production of large amounts of IL-2 and IFNγ, correlated with sustained nuclear expression of NF-κB components reticuloendotheliosis oncogene c-Rel and p65. Overexpression of A20 by retroviral transduction of CD8 T cells dampened their intratumor accumulation and antitumor activity. In contrast, relief from the A20 brake in NF-κB activation in adoptively transferred antitumor CD8 T cells led to improved control of melanoma growth. Tumor-infiltrating A20-deleted CD8 T cells had enhanced production of IFNγ and TNFα and reduced expression of the inhibitory receptor programmed cell death 1. As manipulation of A20 expression in CD8 T cells did not result in pathologic manifestations in the mice, we propose it as a candidate to be targeted to increase antitumor efficiency of adoptive T-cell immunotherapy.

  11. Upregulation of heat shock protein 70 and the differential protein expression induced by tumor necrosis factor-alpha enhances migration and inhibits apoptosis of hepatocellular carcinoma cell HepG2.

    Science.gov (United States)

    Huang, Bee-Piao; Lin, Chun-Shiang; Wang, Chau-Jong; Kao, Shao-Hsuan

    2017-01-01

    Tumor necrosis factor alpha (TNFα) plays diverse roles in liver damage and hepatocarcinogenesis with its multipotent bioactivity. However, the influence of TNFα on protein expression of hepatocellular carcinoma (HCC) is incompletely understood. Therefore, we aimed to investigate the differential protein expression of HCC in response to TNFα stimulus. We observed that HepG2 cell revealed a higher resistance to TNFα-induced apoptosis as compared to the non-tumorigenic hepatocyte THLE-2. By using a label-free quantitative proteomic analysis, we found that 520 proteins were differentially expressed in the HepG2 cells exposed to TNFα, including 211 up-regulated and 309 down-regulated proteins. We further confirmed several proteins with significant expression change (TNFα/control ratio>2.0 or expressed proteins using Gene ontology and KEGG annotations, and the results implicated that TNFα might regulate ribosome, spliceosome, antigen processing and presentation, and energy metabolism in HepG2 cells. Moreover, we demonstrated that upregulation of heat shock protein 70 (HSP70) was involved in both the promoted migration and the inhibited apoptosis of HepG2 cells in response to TNFα. Collectively, these findings indicate that TNFα alters protein expression such as HSP70, which triggering specific molecular processes and signaling cascades that promote migration and inhibit apoptosis of HepG2 cells.

  12. Differential role of tumor necrosis factor receptors in mouse brain inflammatory responses in cryolesion brain injury

    DEFF Research Database (Denmark)

    Quintana, Albert; Giralt, Mercedes; Rojas, Santiago

    2005-01-01

    Tumor necrosis factor-alpha (TNF-alpha) is one of the mediators dramatically increased after traumatic brain injury that leads to the activation, proliferation, and hypertrophy of mononuclear, phagocytic cells and gliosis. Eventually, TNF-alpha can induce both apoptosis and necrosis via...... by TNFR1 deficiency. Overall, these results suggest that TNFR1 is involved in the early establishment of the inflammatory response and that its deficiency causes a decreased inflammatory response and tissue damage following brain injury....

  13. The role of tumor necrosis factor-alpha -308 G/A and transforming growth factor-beta 1 -915 G/C polymorphisms in childhood idiopathic thrombocytopenic purpura

    Directory of Open Access Journals (Sweden)

    Emel Okulu

    2011-09-01

    Full Text Available Objective: To increase our understanding of the etiology of idiopathic thrombocytopenic purpura (ITP some cytokine gene polymorphisms were analyzed for susceptibility to the disease. The aim of this study was to investigate the role of tumor necrosis factor-alpha (TNF-α -308 G/A and transforming growth factor-beta 1 (TGF-β1 –915 G/C polymorphisms in the development and clinical progression of childhood ITP.Materials and Methods: In all, 50 pediatric patients with ITP (25 with acute ITP and 25 with chronic ITP and 48 healthy controls were investigated via LightCycler® PCR analysis for TNF-α -308 G/A and TGF-β1 -915 G/C polymorphisms.Results: The frequency of TNF-α -308 G/A polymorphism was 20%, 16%, and 22.9% in the acute ITP patients, chronic ITP patients, and controls, respectively (p>0.05. The frequency of TGF-β1 -915 G/C polymorphism was 16%, 8%, and 8.3% in the acute ITP patients, chronic ITP patients, and controls, respectively (p>0.05. The risk of developing ITP and clinical progression were not associated with TNF-α -308 G/A (OR: 0.738, 95% CI: 0.275-1.981, and OR: 0.762, 95% CI: 0.179-3.249 or TGF-β1 -915 G/C (OR: 1.5, 95% CI: 0.396-5.685, and OR: 0.457, 95% CI: 0.076-2.755 polymorphisms. Conclusion: The frequency of TNF-α -308 G/A and TGF-β1 -915 G/C polymorphisms did not differ between pediatric ITP patients and healthy controls, and these polymorphisms were not associated with susceptibility to the development and clinical progression of the disease.

  14. Normal Ranges for Acute Phase Reactants (Interleukin-6, Tumour Necrosis Factor-alpha and C-reactive Protein) in Umbilical Cord Blood of Healthy Term Neonates at the Mount Hope Women's Hospital, Trinidad.

    Science.gov (United States)

    Khan, A; Ali, Z

    2014-09-01

    To determine normal ranges for interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α) and C-reactive protein (CRP) in umbilical cord blood from healthy term neonates at the Mount Hope Women's Hospital (MHWH), Trinidad. A prospective cohort study was conducted on healthy pregnant women admitted to the MHWH during the period October 1 to December 31, 2010. Women who were term with no signs of or risk factors for sepsis were recruited into the study after informed consent was obtained. Data were collected including maternal age, antenatal and perinatal history. Umbilical cord blood samples were collected and analysed for IL-6, TNF-α and CRP. Ethical approval was obtained from the Ethics Committee, Faculty of Medical Sciences, The University of the West Indies, Trinidad and Tobago. One hundred and sixty-two samples from healthy term neonates were analysed for IL-6 and TNF-α. One hundred and thirty-one samples were analysed for CRP due to one faulty kit. There were almost equal numbers of males (55%) and females (45%). Ninety per cent were > 2500 g at birth and 10% had low birthweight. Reference ranges of 0-16.4 pg/ml, 0-29.4 pg/ml and 0-12.4 mg/L were found for IL-6, TNF-α and CRP, respectively with 95% confidence intervals (11.6, 21.5 pg/ml; 24.0, 33.1 and 8.4, 15.1, respectively). The normal ranges for IL-6, TNF-α and CRP in umbilical cord blood for healthy term Trinidadian neonates were 0-16.4 pg/ml, 0-29.4 pg/ml and 0-12.4 mg/L, respectively.

  15. Expression of tumor necrosis factor-alpha converting enzyme and matrix metalloproteinase-3 in proliferated synovium in a patient with synovitis-acne-pustulosis-hyperostosis-osteitis syndrome: a case report

    Directory of Open Access Journals (Sweden)

    Komiya Koichiro

    2009-09-01

    Full Text Available Abstract Introduction Synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO syndrome is a rare disorder. The etiology remains unknown and the treatment is still empirical. Synovitis is one of the major manifestations, but information on histopathological features is still lacking. In this case, we investigated the histopathological features of SAPHO syndrome synovitis. Case presentation We present the case of a 53-year-old Japanese woman with SAPHO syndrome accompanied by marked knee synovitis and palmoplantar pustulosis. We found abundant sterile joint fluid in the right knee, and a blood test showed abnormally high values of C-reactive protein (17.26 mg/dl and matrix metalloproteinase-3 (800 ng/ml. Arthroscopic surgery revealed marked proliferation of villous synovial tissues similar to rheumatoid arthritis and standard microscopic findings were also similar to rheumatoid arthritis. Furthermore, for the first time, we demonstrated by immunohistochemistry the expression of tumor necrosis factor-alpha (TNF-α converting enzyme, TNF-α and matrix metalloproteinase-3 in the proliferated synovial lining cells. After arthroscopic synovectomy, her knee symptoms immediately diminished and laboratory data (matrix metalloproteinase-3 and C-reactive protein normalized within 2 weeks of surgery. Conclusion We demonstrate the expression of TNF-α converting enzyme, TNF-α and matrix metalloproteinase-3 in SAPHO syndrome synovitis for the first time and also show, both macro- and microscopically, the similarity between SAPHO syndrome and rheumatoid arthritis synovitis. These new findings support the recently reported successful treatment of SAPHO syndrome with antirheumatic drugs, especially with anti-TNF-α agents.

  16. A Meta-analysis on the Effect of Ulinastatin on Serum Levels of C-Reactive Protein, Interleukin 6, and Tumor Necrosis Factor Alpha in Asian Patients with Acute Pancreatitis.

    Science.gov (United States)

    Zhang, Chunze; Wang, Yijia; Fu, Wenzheng; Zhang, Weihua; Wang, Tao; Qin, Hai

    2016-03-01

    We aimed to investigate the influence of ulinastatin (UTI) on the serum levels of C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α) in Asian patients with acute pancreatitis (AP) by performance of a meta-analysis. Two investigators independently searched 11 databases, including PUBMED, EBSCO, Ovid, SpringerLink, Wiley, Web of Science, Cochrane Library, Wanfang database, China National Knowledge Infrastructure (CNKI), Chinese Journal Full-text Database, and China Biomedicine Database. The full-text articles were screened and the data were extracted using a standardized data extraction form. All statistical analyses were conducted with Stata software, version 12.0 (Stata Corporation, College Station, TX). A total of 94 studies were initially retrieved, and 10 studies containing 424 Asian patients with AP were ultimately enrolled in this meta-analysis. The results revealed that the serum levels of CRP, IL-6, and TNF-α in Asian AP patients significantly decreased after UTI therapy (CRP: standardized mean difference [SMD] = 3.26, 95% confidence interval [CI] = 1.69-4.83, p < 0.001; IL-6: SMD = 5.92, 95% CI = 2.09-9.75, p = 0.002; TNF-α: SMD = 4.07, 95% CI = 0.79-7.35, p = 0.015). The results of this meta-analysis suggest that UTI can effectively depress the serum levels of CRP, IL-6, and TNF-α in Asian patients with AP, and thereby inhibit inflammation.

  17. Three-Dimensional Conformal Radiotherapy in Prostate Cancer Patients: Rise in Interleukin 6 (IL-6) but not IL-2, IL-4, IL-5, Tumor Necrosis Factor-{alpha}, MIP-1-{alpha}, and LIF Levels

    Energy Technology Data Exchange (ETDEWEB)

    Oliveira Lopes, Carlos [Universidade do Vale do Paraiba, Centro de Oncologia Radioterapica do Vale do Paraiba, Universidade do Vale do Paraiba Instituto de Pesquisa e Desenvolvimento, Universidade do Vale do Paraiba, Sao Jose dos Campos, Sao Paulo (Brazil); Callera, Fernando, E-mail: fcallera@gmail.com [Centro de Hematologia Onco-hematologia e Transplantes de Medula Ossea do Vale do Paraiba, Sao Paulo (Brazil)

    2012-03-15

    Purpose: To investigate the effect of radiotherapy (RT) on serum levels of interleukin-2 (IL-2), IL-4, IL-5, IL-6, tumor necrosis factor alpha (TNF-{alpha}), macrophage inflammatory protein-1-alpha (MIP-1-{alpha}) and leukemia inhibitory factor (LIF) in patients with prostate cancer. Methods and Materials: Forty eight patients with prostate cancer received three-dimensional conformal blocking radiation therapy with a linear accelerator. IL-2, IL-4, IL-5, IL-6, TNF-{alpha}, MIP-1-{alpha}, and LIF levels were measured by the related immunoassay kit 1 day before the beginning of RT and during RT at days 15 and 30. Results: The mean IL-2 values were elevated before and during the RT in contrast with those of IL-4, IL-5, IL-6, TNF-{alpha}, MIP-1-{alpha}, and LIF, which were within the normal range under the same conditions. Regarding markers IL-2, IL-4, IL-5, TNF-{alpha}, MIP-1-{alpha}, and LIF, comparisons among the three groups (before treatment and 15 and 30 days during RT) did not show significant differences. Although values were within the normal range, there was a significant rise in IL-6 levels at day 15 of RT (p = 0.0049) and a decline at day 30 to levels that were similar to those observed before RT. Conclusions: IL-6 appeared to peak after 15 days of RT before returning to pre-RT levels. In contrast, IL-2, IL-4, IL-5, TNF-{alpha}, MIP-1-{alpha}, and LIF levels were not sensitive to irradiation. The increased levels of IL-6 following RT without the concurrent elevation of other cytokines involved in the acute phase reaction did not suggest a classical inflammatory response to radiation exposure. Further studies should be designed to elucidate the role of IL-6 levels in patients with prostate cancer treated with RT.

  18. Anti-inflammatory effects of the butanolic fraction of Byrsonima verbascifolia leaves: Mechanisms involving inhibition of tumor necrosis factor alpha, prostaglandin E(2) production and migration of polymorphonuclear leucocyte in vivo experimentation.

    Science.gov (United States)

    Saldanha, Aline Aparecida; de Siqueira, João Máximo; Castro, Ana Hortência Fonsêca; de Azambuja Ribeiro, Rosy Iara Maciel; de Oliveira, Flávio Martins; de Oliveira Lopes, Débora; Pinto, Flávia Carmo Horta; Silva, Denise Brentan; Soares, Adriana Cristina

    2016-02-01

    The leaves of Byrsonima verbascifolia (Malpighiaceae) are traditionally used to treat various diseases including inflammatory conditions. The main goal of this study was to evaluate the in vivo anti-inflammatory activity of the polar constituents from the butanolic fraction of B. verbascifolia leaves (BvBF), as well as to investigate the mechanisms involved in the anti-inflammatory activity. The polar constituents were identified by liquid chromatography coupled to diode array detector and mass spectrometry (LC-DAD–MS) and matrix-assisted laser desorption/ionization – time-of-flight mass spectrometry (MALDI-TOF MS) to obtain a complete chemical profile of the fraction. Forty-five compounds were detected in the BvBF by LC-DAD–MS/MS, including condensed tannins, phenolic acids, flavonoids (flavones and flavonols) and other compounds. In addition, several condensed tannins were identified by MALDI-MS/MS, which are composed predominantly by procyanidin units (PCY) and up to six flavan-3-ol units. The BvBF exhibited significant antioxidant and anti-inflammatory activities. The BvBF inhibited paw edema and polymorphonuclear (PMN) leukocyte migration to the footpad and pleural cavity induced by carrageenan. Furthermore, a minor dose (12.50 mg/kg) of BvBF effectively decreased tumor necrosis factor alpha (TNF-α) and prostaglandin E2 (PGE2) levels in the footpad. These findings suggest that the mechanism of the anti-inflammatory action in the BvBF is linked to the inhibition of the production of inflammatory mediators such as TNF-α and PGE2 and the PMN cell migration.

  19. Analysis of the local kinetics and localization of interleukin-1 alpha, tumour necrosis factor-alpha and transforming growth factor-beta, during the course of experimental pulmonary tuberculosis.

    Science.gov (United States)

    Hernandez-Pando, R; Orozco, H; Arriaga, K; Sampieri, A; Larriva-Sahd, J; Madrid-Marina, V

    1997-01-01

    A mouse model of pulmonary tuberculosis induced by the intratracheal instillation of live and virulent mycobacteria strain H37-Rv was used to examine the relationship of the histopathological findings with the local kinetics production and cellular distribution of tumour necrosis factor-alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha) and transforming growth factor-beta (TGF-beta). The histopathological and immunological studies showed two phases of the disease: acute or early and chronic or advanced. The acute phase was characterized by inflammatory infiltrate in the alveolar-capillary interstitium, blood vessels and bronchial wall with formation of granulomas. During this acute phase, which lasted from 1 to 28 days, high percentages of TNF-alpha and IL-1 alpha immunostained activated macrophages were observed principally in the interstium-intralveolar inflammatory infiltrate and in granulomas. Electron microscopy studies of these cells, showed extensive rough endoplasmic reticulum, numerous lysosomes and occasional mycobacteria. Double labelling with colloid gold showed that TNF-alpha and IL-1 alpha were present in the same cells, but were confined to separate vacuoles near the Golgi area, and mixed in larger vacuoles near to cell membrane. The concentration of TNF-alpha and IL-1 alpha as well as their respective mRNAs were elevated in the early phase, particularly at day 3 when the bacillary count decreased. A second peak was seen at days 14 and 21-28 when granulomas appeared and evolved to full maturation. In contrast, TGF-beta production and numbers of immunoreactive cells were low in comparison with the advanced phase of the disease. The chronic phase was characterized by histopathological changes indicative of more severity (i.e. pneumonia, focal necrosis and extensive interstitial fibrosis) with a decrease in the TNF-alpha and IL-1 alpha production that coincided with the highest level of TGF-beta. The bacillary counts were highest as the macrophages

  20. Interleukin-10 does not mediate the inhibitory effect of PDE-4 inhibitors and other cAMP-elevating drugs on lipopolysaccharide-induced tumors necrosis factor-alpha generation from human peripheral blood monocytes.

    Science.gov (United States)

    Seldon, P M; Barnes, P J; Giembycz, M A

    1998-01-01

    Lipopolysaccharide (LPS)-induced liver injury in mice and LPS-induced tumor necrosis factor-alpha (TNF-alpha) generation by murine macrophages and hepatocytes are suppressed markedly by agents that elevate intracellular cAMP. Phosphodiesterase (PDE)-4 inhibitors, beta 2-adrenoceptor agonists, and E-series prostaglandins also attenuate the induction of the TNF-alpha gene in human monocytes in response to bacterial LPS. The mechanism of action of cAMP is unclear, but in the mouse, is believed to involve the generation of this anti-inflammatory cytokine, interleukin-10 (IL-10). In this article, we describe the results of studies designed to determine the extent to which IL-10 contributes to the suppression of TNF-alpha generation from LPS-stimulated human monocytes evoked by 8-bromo cyclic AMP (8-Br-cAMP), rolipram, salbutamol, and prostaglandin E2 (PGE2). LPS evoked a time- and concentration-dependent generation of TNF-alpha (t1/2 = 4.5 h; EC50 = 273 pg/mL), which was inhibited by exogenous human recombinant (h) IL-10 (IC50 = 124 pg/mL), and by rolipram (EC50 = 420 nM), 8-Br-cAMP (EC50 = 77 (microM), PGE2 (EC50 = 15 nM) and salbutamol (EC50 = 20 nM). In addition, 8-Br-cAMP, PGE2; and salbutamol (but not rolipram) augmented significantly LPS-induced IL-10 production (two-to-fivefold) under identical experimental conditions. Pretreatment of monocytes with an anti-IL-10 monoclonal antibody (MAb) that abolished the inhibitory action of a maximally effective concentration of exogenous hrIL-10, failed to attenuate the inhibitory effect of rolipram, PGE2, salbutamol, and 8-Br-cAMP. Anti-IL-10 was similarly inactive when the number of monocytes seeded was increased from 0.5 to 4 x 10(6)/mL or when measurements were made at 42 h post-LPS, a time when the concentration of IL-10 released was maximal. Collectively, these data suggest that in contrast to murine hepatocytes and macrophages, IL-10 does not mediate the inhibitory effect of cAMP-elevating drugs on TNF

  1. Expressão local do fator de necrose tumoral alfa na ruptura prematura de membranas Local expression of tumor necrosis factor-alpha on premature rupture of membranes

    Directory of Open Access Journals (Sweden)

    Valquíria Roveran

    2009-05-01

    Full Text Available OBJETIVO: comparar a expressão do fator de necrose tumoral alfa (TNF-α em membranas ovulares com ruptura prematura (RPM e com ruptura oportuna das mesmas; verificar a associação entre a expressão do TNF-α em membranas ovulares e o grau de corioamnionite das mesmas e correlacionar a expressão do TNF-α e o tempo de ruptura das membranas. MÉTODOS: foram analisadas as membranas ovulares de 31 parturientes com RPM, com idade gestacional acima de 34 semanas, e de 14 parturientes com ruptura oportuna das membranas, com idade gestacional igual ou maior de 37 semanas. A detecção da corioamnionite foi feita por meio de estudo histopatológico. A avaliação da expressão do TNF-α foi feita por meio de técnica imunoistoquímica, na qual foi empregado o método streptavidina-biotina-peroxidase (LSAB. RESULTADOS: o tempo médio de ruptura foi de 16,6 horas. A frequência da expressão de TNF-α, nos Grupos Controle e Estudo, não mostrou diferença significante (χ2=6,6; p=0,08. No Grupo Estudo, houve correlação entre o grau de corioamnionite e a intensidade da expressão de TNF-α (coeficiente de Spearman (Rs=0,4; p=0,02. CONCLUSÕES: não houve diferença significante entre as expressões do TNF-α em membranas ovulares com ruptura prematura e com ruptura oportuna das mesmas; no Grupo Estudo, constatou-se associação significante entre a expressão do TNF-α e o grau de corioamnionite e não houve associação entre o tempo de ruptura e a intensidade da expressão do TNF-α.PURPOSE: to compare the expression of tumor necrosis factor-alpha (TNF-α in ovular membranes with premature rupture (MPR and with opportune rupture; to verify the association between the expression of the TNF-α in ovular membranes and the degree of chorioamnionitis, correlating the expression of the TNF-α and the membranes' time of rupture. METHODS: ovular membranes from 31 parturients with MPR, with gestational ages over 34 weeks, and from parturients with opportune

  2. Retraction RETRACTION of "Tumor necrosis factor alpha gene -308G>A polymorphism association with the risk of esophageal cancer in a Han Chinese population" by H. Zhao, H.W. Zhang, T. Zhang and X.M. Gu - Genet. Mol. Res. 15 (2): gmr.15025866 DOI: http://dx.doi.org/10.4238/gmr.15025866.

    Science.gov (United States)

    Zhao, H; Zhang, H W; Zhang, T; Gu, X M

    2016-10-07

    The retracted article is: Zhao H, Zhang HW, Zhang T and Gu XM (2016). Tumor necrosis factor alpha gene -308G>A polymorphism association with the risk of esophageal cancer in a Han Chinese population. Genet. Mol. Res. 15: gmr.15025866. Two major concerns were found in this article. Firstly, it was found to be substantially equal to the article "Tumor necrosis factor-alpha gene -308G > A polymorphism alters the risk of hepatocellular carcinoma in a Han Chinese population" published in the Diagnostic Pathology Diagnostic Pathology (2014) 9: 199, by Feng et al.; licensee BioMed Central. 2014 - DOI: 10.1186/s13000-014-0199-3. Secondly, the authors do not discuss limitations of their approaches in the discussion. The discussion is largely an elaboration of the literature in the introduction part. However, even in that context, the discussion does not appropriately review the literature and there are frequent references to conclusions that are not supported by the cited literature. The GMR editorial staff was alerted and after a thorough investigation, there is strong reason to believe that the peer review process was failure. Also, after review and contacting the authors, the editors of Genetics and Molecular Research decided to retract this article in accordance with the recommendations of the Committee on Publication Ethics (COPE). The authors and their institutions were advised of this serious breach of ethics.

  3. Does the simultaneous tumor necrosis factor receptor 2, tumor necrosis factor promoter gene polymorphism represent a higher risk for alcoholic liver disease?

    Science.gov (United States)

    Machado, Mariana Verdelho; Martins, Alexandra; Almeida, Rosário; Marques-Vidal, Pedro; Gonçalves, Maria S; Camilo, Maria E; Cortez-Pinto, Helena

    2009-02-01

    Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine that seems to play a crucial role in the pathogenesis of alcoholic liver disease (ALD). TNF-alpha exerts its effects by binding to specific receptors (TNFR); the polymorphism of TNFRII T587G has been associated with increased TNF apoptotic response and its presence may increase the risk to develop liver disease. The aim of this study was to evaluate the prevalence of the TNF-alpha G238A promoter and TNFRII polymorphisms, individually or simultaneously, in ALD. TNF-alpha G238A and TNFRII T587G polymorphisms were studied in 103 unrelated patients with ALD (biopsy confirmed or clinical evidence) and in 76 heavy drinkers without liver disease (NLD). Single nucleotide polymorphism gene was detected by a polymerase chain reaction-restriction fragment length polymorphisms method. All patients had, at least, a 5 year history of alcohol consumption greater than 80 g/day. TNF-alpha G238A allele frequency was similar in both groups. TNFRII T587G allele frequency was slightly higher in the ALD group than in the NLD group (21 vs. 18%, P=NS). TNF-alpha G238A and TNFRII T587G were simultaneously present in six ALD patients and in none of NLD patients (P=0.04). Although individually there was no association between TNFRII T587G or TNF-alpha G238A polymorphisms and ALD, this study suggests that the presence of both polymorphisms may enhance the susceptibility for ALD. TNF-alpha G238A may increase TNF-alpha production, which when associated with TNFRII T587G, can further exacerbate TNF-alpha response leading to a greater risk of ALD.

  4. A matrix of cholesterol crystals, but not cholesterol alone, primes human monocytes/macrophages for excessive endotoxin-induced production of tumor necrosis factor-alpha. Role in atherosclerotic inflammation?

    DEFF Research Database (Denmark)

    Bendtzen, Klaus; Christensen, Ole; Nielsen, Claus Henrik

    2014-01-01

    When exposed to small amounts of bacterial endotoxin, matrices of cholesterol crystals, but not cholesterol itself, primed human monocytes/macrophages to a highly augmented (>10-fold) production of inflammatory tumor necrosis factor-α. Priming also sensitized the cells, as 10- to 100-fold lower...... suggest that cholesterol matrix formation may play a pathogenic role in atherosclerotic inflammation, and they indicate a mechanism by which bacteria and/or bacterial products may play a role in processes leading to arteriosclerosis....

  5. A matrix of cholesterol crystals, but not cholesterol alone, primes human monocytes/macrophages for excessive endotoxin-induced production of tumor necrosis factor-alpha. Role in atherosclerotic inflammation?

    DEFF Research Database (Denmark)

    Bendtzen, Klaus; Christensen, Ole; Nielsen, Claus Henrik

    2014-01-01

    When exposed to small amounts of bacterial endotoxin, matrices of cholesterol crystals, but not cholesterol itself, primed human monocytes/macrophages to a highly augmented (>10-fold) production of inflammatory tumor necrosis factor-α. Priming also sensitized the cells, as 10- to 100-fold lower l...... suggest that cholesterol matrix formation may play a pathogenic role in atherosclerotic inflammation, and they indicate a mechanism by which bacteria and/or bacterial products may play a role in processes leading to arteriosclerosis....

  6. O papel do Fator de Necrose Tumoral Alfa (TNF-alfa no processo de erosão óssea presente no colesteatoma adquirido da orelha média The role of Tumor Necrosis Factor -Alpha (TNF- alpha in bone resorption present in middle ear cholesteatoma

    Directory of Open Access Journals (Sweden)

    Rodrigo Faller Vitale

    2007-02-01

    Full Text Available O colesteatoma adquirido da orelha média causa erosão óssea, com altas taxas de morbidade e mortalidade. O TNF-alfa (TNF-alfa lambda uma das principais citocinas envolvidas neste processo. OBJETIVO: Avaliar o papel do TNF-alfa na reabsorsão óssea e a ação dele no colesteatoma. MATERIAL E MÉTODOS: Foi realizado um levantamento e uma revisão crítica da literatura. RESULTADOS: Todos os autores estudados concordam com a importância do TNF-alfa no processo de reabsorção óssea presente no colesteatoma e com o grau de destruição observado. Diferentes trabalhos demonstraram que o TNF-alfa é capaz de provocar erosão óssea, através de diferentes vias de ação. Ele pode estimular a diferenciação e a maturação dos osteoclastos ou, ainda, agir na matriz óssea expondo-a à ação dos osteoclastos. Existe a possibilidade de inibir a ação do TNF-alfa, diminuindo seus efeitos e prevenindo a perda óssea em doenças como a artrite reumatóide. Não existe, entretanto, trabalhos específicos em colesteatoma. Não existe consenso sobre a sua localização. Estas diferenças, provavelmente, ocorrem devido à distribuição dos receptores. CONCLUSÃO: O TNF-alfa, presente no colesteatoma promove a reabsorsão óssea, juntamente com outras citocinas (RANKL e IL-1, estando relacionado com a presença de complicações.Cholesteatoma may cause bone erosion, with high morbidity and mortality rates. Tumor Necrosis Factor -Alpha (TNF-a is one of the main cytokines involved in this process. Our goal was to evaluate the role of TNF-a in Bone Resorption and its effect on cholesteatoma. MATERIAL AND METHODS: analysis and critical literature review. RESULTS: Different studies have demonstrated that TNF-a is capable of causing bone erosion. It may stimulate the differentiation and maturation of osteoclasts or it may act on the bone matrix, exposing it to the action of the osteoclasts. It is possible to inhibit TNF-a, reducing its effects and prevent

  7. Infections and treatment of patients with rheumatic diseasesTumor necrosis factor-alpha binding capacity and anti-infliximab antibodies measured by fluid-phase radioimmunoassays as predictors of clinical efficacy of infliximab in Crohn's disease

    DEFF Research Database (Denmark)

    Atzeni, F.; Bendtzen, K.; Bobbio-Pallavicini, F.

    2008-01-01

    , and for the shortest possible time should therefore greatly reduce the risk of infections. Infection is a major co-morbidity in rheumatoid arthritis (RA), and conventional disease-modifying anti-rheumatic drugs (DMARDs) can increase the risk of their occurrence, including tuberculosis. TNF-alpha plays a key role....../inflammatory conditions, and current therapies have the aim of providing adequate (low) compensatory doses, the timing of GC administration, such as during the nocturnal turning-on phase of tumour necrosis factor (TNF) secretion, can be extremely important. The use of the lowest possible GC dose, at night...

  8. Epidermal growth factor, transforming growth factor-alpha, and epidermal growth factor receptor expression and localization in the canine endometrium during the estrous cycle and in bitches with pyometra.

    Science.gov (United States)

    Kida, K; Maezono, Y; Kawate, N; Inaba, T; Hatoya, S; Tamada, H

    2010-01-01

    Gene expression and immunohistochemical localization of epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), and epidermal growth factor receptor (EGF-R) were compared between the endometrium of bitches (Canis familiaris) with pyometra accompanied by cystic endometrial hyperplasia (CEH) and that of healthy bitches at similar stages of the estrous cycle. In normal bitches, endometrial TGF-alpha mRNA levels were highest at proestrus and gradually decreased as the cycle progressed to anestrus. Epidermal growth factor receptor mRNA levels were not significantly affected by the stage of the estrous cycle. Epidermal growth factor mRNA levels were higher at Day 35 of diestrus than at other stages of the estrous cycle (Ppyometra, endometrial TGF-alpha and EGF-R mRNA levels did not differ significantly from those at diestrus in normal bitches, but EGF mRNA levels were lower than those at Day 35 of diestrus in normal bitches (Ppyometra, immunoreactivity for EGF was clearly present in endometrial stromal cells. Inflammatory cells that had infiltrated the endometrial stroma stained strongly for TGF-alpha and EGF-R. Luminal and glandular epithelial cells also stained positive for EGF-R. In conclusion, expression of TGF-alpha by inflammatory cells and a low level of expression and differential localization of EGF may be involved in aberrant growth of endometrial glands and development of CEH.

  9. CD4+ T cells of schistosomiasis naturally resistant individuals living in an endemic area produce interferon-gamma and tumour necrosis factor-alpha in response to the recombinant 14KDA Schistosoma mansoni fatty acid-binding protein.

    Science.gov (United States)

    Brito, C F; Caldas, I R; Coura Filho, P; Correa-Oliveira, R; Oliveira, S C

    2000-06-01

    Cellular immune responses to recombinant (r) Sm14 were examined in chronic, treated patients and uninfected individuals living in an endemic area for schistosomiasis. The lymphocyte proliferative responses and cytokine profile to this antigen were evaluated. Peripheral blood mononuclear cells (PBMC) of all groups studied proliferated to rSm14. However, the highest proliferation index to rSm14 was detected in uninfected endemic normal (EN) individuals who are naturally resistant to schistosomiasis. Regarding the cytokines produced, the levels of interleukin (IL)-5 and IL-10, known as Th2 cytokines, were not statistically different among all groups studied. In contrast, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha were produced in significantly higher amounts by PBMC of EN individuals following rSm14 stimulation. Additionally, we have determined by flow cytometry that CD4+ T cells from these individuals are the main lymphocyte subpopulation producing IFN-gamma and TNF-alpha. Moreover, we have used rIL-10 or rIFN-gamma, or monoclonal antibodies (MoAb) against these two cytokines to determine their role on cellular reactivity to rSm14. Exogenous IL-10 suppressed T-cell proliferation and neutralization of endogenous IL-10 restored lymphocyte activation and enhanced IFN-gamma and TNF-alpha production in chronically infected patients. In contrast, the addition of anti-IFN-gamma totally abrogated the PBMC proliferation within the EN group. This study demonstrated that IL-10 is an important cytokine down-regulating T-cell responses in chronic schistosomiasis, whereas lymphocyte proliferation in the uninfected resistant group is dependent on IFN-gamma. Taken together these results suggest that Th1 type of immune response induced in EN individuals to a specific schistosome antigen might be associated with resistance to infection and also highlighted the importance of Sm14 as a potential vaccine candidate.

  10. Tumor necrosis factor-alpha and apoptosis signal-regulating kinase 1 control reactive oxygen species release, mitochondrial autophagy, and c-Jun N-terminal kinase/p38 phosphorylation during necrotizing enterocolitis.

    Science.gov (United States)

    Baregamian, Naira; Song, Jun; Bailey, C Eric; Papaconstantinou, John; Evers, B Mark; Chung, Dai H

    2009-01-01

    Oxidative stress and inflammation may contribute to the disruption of the protective gut barrier through various mechanisms; mitochondrial dysfunction resulting from inflammatory and oxidative injury may potentially be a significant source of apoptosis during necrotizing enterocolitis (NEC). Tumor necrosis factor (TNF)-alpha is thought to generate reactive oxygen species (ROS) and activate the apoptosis signal-regulating kinase 1 (ASK1)-c-Jun N-terminal kinase (JNK)/p38 pathway. Hence, the focus of our study was to examine the effects of TNF-alpha/ROS on mitochondrial function, ASK1-JNK/p38 cascade activation in intestinal epithelial cells during NEC. We found (a) abundant tissue TNF-alpha and ASK1 expression throughout all layers of the intestine in neonates with NEC, suggesting that TNF-alpha/ASK1 may be a potential source (indicators) of intestinal injury in neonates with NEC; (b) TNF-alpha-induced rapid and transient activation of JNK/p38 apoptotic signaling in all cell lines suggests that this may be an important molecular characteristic of NEC; (c) TNF-alpha-induced rapid and transient ROS production in RIE-1 cells indicates that mitochondria are the predominant source of ROS, demonstrated by significantly attenuated response in mitochondrial DNA-depleted (RIE-1-rho) intestinal epithelial cells; (d) further studies with mitochondria-targeted antioxidant PBN supported our hypothesis that effective mitochondrial ROS trapping is protective against TNF-alpha/ROS-induced intestinal epithelial cell injury; (e) TNF-alpha induces significant mitochondrial dysfunction in intestinal epithelial cells, resulting in increased production of mtROS, drop in mitochondrial membrane potential (MMP) and decreased oxygen consumption; (f) although the significance of mitochondrial autophagy in NEC has not been unequivocally shown, our studies provide a strong preliminary indication that TNF-alpha/ROS-induced mitochondrial autophagy may play a role in NEC, and this process is a

  11. Soluble receptors for tumor necrosis factor as markers of disease activity in visceral leishmaniasis

    NARCIS (Netherlands)

    Zijlstra, E. E.; van der Poll, T.; Mevissen, M.

    1995-01-01

    Serum concentrations of soluble receptors for tumor necrosis factor (sTNFRs) were measured before and after antimony therapy in 25 Sudanese patients with active visceral leishmaniasis (VL). Both sTNFR types I and II were significantly elevated in patients with VL compared with healthy controls from

  12. [From gene to disease; tumor necrosis factor receptor and a syndrome of familial periodic fever

    NARCIS (Netherlands)

    Simon, A.; Drenth, J.P.H.; Meer, J.W.M. van der

    2001-01-01

    Familial Hibernian fever (FHF) is a rare hereditary syndrome that causes periodic attacks of fever and inflammation. It is an autosomal dominantly inherited disorder. The gene involved in FHF encodes for a receptor for tumour necrosis factor (TNFR1). These mutations are thought to result in impaired

  13. Efficacy of scaling and root planning with and without adjunct Nd:YAG laser therapy on clinical periodontal parameters and gingival crevicular fluid interleukin 1-beta and tumor necrosis factor-alpha levels among patients with periodontal disease: A prospective randomized split-mouth clinical study.

    Science.gov (United States)

    Abduljabbar, Tariq; Vohra, Fahim; Kellesarian, Sergio Varela; Javed, Fawad

    2017-04-01

    Limited evidence exists regarding the role of scaling and root planning (SRP) with adjunct neodymium yttrium aluminum garnet (Nd:YAG) laser therapy in reducing periodontal parameters (plaque index [PI], bleeding on probing [BOP] and probing pocket depth [PPD]) and levels of proinflammatory cytokines in the gingival crevicular fluid (GCF) among patients with periodontal disease (PD). The aim was to assess the effect of SRP with and without adjunct Nd:YAG laser therapy on clinical periodontal parameters and GCF interleukin 1-beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) levels among patients with PD. Demographic data was collected using a questionnaire. Mandibular right and left quadrants were randomly divided into test- (SRP+Nd:YAG laser) and control-sites (SRP alone). PI, BOP and PPD were assessed and GCF IL-1β and TNF-α levels were measured at baseline and at 3- and 6-month follow-up. Level of significance was set at Pperiodontal inflammatory parameters and GCF IL-1β and TNF-α levels compared with SRP alone. Copyright © 2017. Published by Elsevier B.V.

  14. Stabilization of the bioactivity of tumor necrosis factor by its soluble receptors

    OpenAIRE

    1992-01-01

    The receptors for tumor necrosis factor (TNF) exist in cell-associated as well as soluble forms, both binding specifically to TNF. Since the soluble forms of TNF receptors (sTNF-Rs) can compete with the cell- associated TNF receptors for TNF, it was suggested that they function as inhibitors of TNF activity; at high concentrations, the sTNF-Rs indeed inhibit TNF effects. However, we report here that in the presence of low concentrations of the sTNF-Rs, effects of TNF whose induction depend on...

  15. Implication of Tumor Necrosis Factor - Alpha in Preeclampsia

    Directory of Open Access Journals (Sweden)

    Dan MIHU

    2008-12-01

    Full Text Available Introduction: Preeclampsia is an exacerbation of a generalized inflammatory response, physiologically present in the third trimester of pregnancy.Aim: The aim of the study consists in the evaluation of proinflammatory cytokine TNF-α in the context of preeclampsia. Material and Method: A transversal study was performed in three groups of patients: non-pregnant patients, patients with normal pregnancies in the third trimester, patients with preeclampsia. Serum TNF-α levels were determined using the immunometric sandwich EIA method.Results: The results obtained confirm a significant increase (p<0.01 in circulating TNF-α levels in the last trimester of pregnancy, compared to the non-pregnant status. Significantly increased serum TNF-α concentrations (p<0.001 were also found in pregnant patients with preeclampsia, compared to normotensive pregnant women. Conclusion: This proinflammatory cytokine can be a potential marker of the severity of the preeclamptic syndrome, without being an indicator of the fetal status at birth.

  16. Tumour necrosis factor alpha (TNF-α) genetic polymorphisms and ...

    Indian Academy of Sciences (India)

    Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People's Republic of China; Department of Occupational Health and Environmental Health, School of Public Health at Guangxi Medical University, Nanning, Guangxi 530021, People's Republic of China ...

  17. Tumour necrosis factor alpha and interleukin 10 gene ...

    Indian Academy of Sciences (India)

    2011-08-19

    Aug 19, 2011 ... Hypertension was defined according to Joint National Committee VI–VII, as a systolic blood pressure >140 mm Hg and/or a diastolic blood pressure. >90 mm Hg based on the average of two blood pressure measurements. Diabetes was diagnosed if fasting plasma glucose was >126 mg/dL, in accordance ...

  18. Tumor necrosis factor-alpha modulates human in vivo lipolysis

    DEFF Research Database (Denmark)

    Plomgaard, Peter; Fischer, Christian P; Ibfelt, Tobias

    2008-01-01

    in lipolysis, increasing circulatory free fatty acid (FFA) levels. SUBJECTS AND METHODS: Using a randomized controlled, crossover design, healthy young male individuals (n = 10) received recombinant human (rh) TNF-alpha (700 ng/m(-2).h(-1)) for 4 h, and energy metabolism was evaluated using a combination...... of tracer dilution methodology and arterial-venous differences over the leg. RESULTS: Plasma TNF-alpha levels increased from 0.7 +/- 0.04 to 16.7 +/- 1.8 pg/ml, and plasma IL-6 increased from 1.0 +/- 0.2 to 9.2 +/- 1.0 pg/ml (P rhTNF-alpha infusion. Here, we demonstrate that 4-h rh......TNF-alpha infusion increases whole body lipolysis by 40% (P rhTNF-alpha infusion. CONCLUSION...

  19. Tumour necrosis factor alpha (TNF-α) genetic polymorphisms and ...

    Indian Academy of Sciences (India)

    Sensitivity analysis of the summary odds ratio coefficients on the association between TNF-α-308G/A polymorphism and AILD risk using a random effects model. (A allele vs G allele). Results were computed by omitting each study in turn. Error bars are 95% confidence interval. Journal of Genetics, Vol. 92, No. 3, December ...

  20. Tumour necrosis factor alpha and interleukin 10 gene ...

    Indian Academy of Sciences (India)

    2011-08-19

    Aug 19, 2011 ... TNF(-308) promoter polymorphism and stroke risk in children with sickle cell anemia. Stroke 38, 2241–2246. Karahan Z. C., Deda G., Sipahi T., Elhan A. H. and Akar N. 2005. TNF-alpha -308G/A and IL-6 -174 G/C polymorphisms in the. Turkish pediatric stroke patients. Thromb. Res. 115, 393–398. Koch W.

  1. Simultaneous Inhibition of Tumor Necrosis Factor Receptor 1 and Matrix Metalloproteinase 8 Completely Protects Against Acute Inflammation and Sepsis.

    Science.gov (United States)

    Steeland, Sophie; Van Ryckeghem, Sara; Vandewalle, Jolien; Ballegeer, Marlies; Van Wonterghem, Elien; Eggermont, Melanie; Decruyenaere, Johan; De Bus, Liesbet; Libert, Claude; Vandenbroucke, Roosmarijn E

    2018-01-01

    Sepsis causes very high mortality and morbidity rates and remains one of the biggest medical challenges. This study investigates whether plasma levels of both matrix metalloproteinase 8 and tumor necrosis factor receptor 1 are associated with sepsis severity and also investigates the therapeutic applicability of simultaneous inhibition of the two molecules in sepsis. Observational human pilot study-prospective controlled animal study. University hospital and research laboratory. Sepsis patients and C57BL/6 mice deficient for matrix metalloproteinase 8 and/or tumor necrosis factor receptor 1. Plasma and whole blood RNA were collected from 13 sepsis patients for 7 consecutive days and within 24 hours of admission to ICU. Matrix metalloproteinase 8 and tumor necrosis factor receptor 1 plasma and expression levels were determined in these patients. Mice deficient for both matrix metalloproteinase 8 and tumor necrosis factor receptor 1 were generated and subjected to endotoxemia and cecal ligation and puncture. Additionally, a bispecific Nanobody that simultaneously blocks matrix metalloproteinase 8 and tumor necrosis factor receptor 1 was created. Plasma levels of matrix metalloproteinase 8 and tumor necrosis factor receptor 1 were positively correlated with the Sequential Organ Failure Assessment score (r, 0.51 and 0.58) and interleukin 6 levels (r, 0.59 and 0.52) in 13 sepsis patients. Combined elimination of tumor necrosis factor receptor 1 and matrix metalloproteinase 8 in double knockout mice resulted in superior survival in endotoxemia and CLP compared with single knockouts and wild-type mice. Cotreatment with our bispecific Nanobody in CLP resulted in improved survival rates (28% vs 19%) compared with untreated mice. Inhibition of matrix metalloproteinase 8 and tumor necrosis factor receptor 1 might have therapeutic potential to treat sepsis and proof-of-principle was provided as therapeutics that inhibit both tumor necrosis factor receptor 1 and matrix

  2. Quantification of active infliximab in human serum with liquid chromatography-tandem mass spectrometry using a tumor necrosis factor alpha -based pre-analytical sample purification and a stable isotopic labeled infliximab bio-similar as internal standard: A target-based, sensitive and cost-effective method.

    Science.gov (United States)

    El Amrani, Mohsin; van den Broek, Marcel P H; Göbel, Camiel; van Maarseveen, Erik M

    2016-07-08

    The therapeutic monoclonal antibody Infliximab (IFX) is a widely used drug for the treatment of several inflammatory autoimmune diseases. However, approximately 10% of patients develop anti-infliximab antibodies (ATIs) rendering the treatment ineffective. Early detection of underexposure to unbound IFX would result in a timely switch of therapy which could aid in the treatment of this disease. Streptavidin coated 96 well plates were used to capture biotinylated-tumor necrosis factor -alpha (b-TNF-α), which in turn was used to selectively extract the active form of IFX in human serum. After elution, IFX was digested using trypsin and one signature peptide was selected for subsequent analysis on liquid chromatography-tandem mass spectrometry (LC-MS/MS). The internal standard used was a stable isotopic labeled IFX bio-similar. The assay was successfully validated according to European Medicines Agency (EMA) guidelines and was found to be linear in a range of 0.5-20μg/mL (r(2)=0.994). Lower limit of quantification for the assay (<20% CV) was 0.5μg/mL, requiring only 2μL of sample. Cross-validation against enzyme-linked immunosorbent assay (ELISA) resulted in a high correlation between methods (r(2)=0.95 with a ρc=0.83) and the accuracy was in line with previously published results. In conclusion, a sensitive, robust and cost-effective method was developed for the bio-analysis of IFX with LC-MS/MS by means of a target-based pre-analytical sample purification. Moreover, low volume and costs of consumables per sample promote its feasibility in (pre)clinical studies and in therapeutic drug monitoring. This method should be considered as first choice due to its accuracy and multiple degree of selectivity. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Retinol as a micronutrients related to cervical local immunity: The expression of tumor necrosis factor-alpha specifically stimulated with E6 epitope of human papillomavirus type-16 and ratio of CD4+/CD8+ T cell in natural history of cervical cancer

    Science.gov (United States)

    Utami, T. W.; Aziz, M. F.; Ibrahim, F.; Andrijono

    2017-08-01

    Retinol is one of the antioxidant micronutrients that plays essential roles in the immune system, by preventing the persistence of modulating CD4+ and CD8+ T cells and cytokines production. Tumor Necrosis Factor-Alpha (TNF-α) is an acute pro-inflammatory cytokine which has many crucial roles in controlling HPV. In contrast, when persistent infection occurs, TNF-α induces carcinogenesis. The ratio of CD4+ cells to CD8+ T cells and adequate TNF-α production in acute HPV infection are key points for clearance. The aim of this research is to analyze the sufficiency level of retinol deposit, the expression of TNF-α, and the ratio of CD4+: CD8+ T cells in a normal cervix, clearance and persistent HPV subclinical infection, and cervical cancer group. The sufficiency level of retinol deposit was analyzed from peripheral blood using the ELISA method. The cervico-vaginal secretions, which were incubated for 24 hours, were stimulated specifically by E6 epitope HPV type-16, measuring TNF-α expression semi-quantitatively by the ELISpot method and CD4+/CD8+ T cells quantitatively by flowcytometry method. The sufficient level of retinol deposit in a normal cervix, clearance HPV subclinical infection, persistent, and cervical cancer group was 85%, 75% (OR 1.89), 33.3% (OR 11.33), and 75% (OR 1.89), respectively. The expression of TNF-α in normal cervix group was 10%, while for cervical cancer it was 75% (OR 27.00; p < 0.001). There was no expression in clearance and persistent HPV subclinical infection groups. A high ratio of CD4+: CD8+ T cells in the normal cervix and cervical cancer group was 10% and 25% (OR 0.33). There was no high ratio of CD4+: CD8+ T cells in clearance (OR 1.22) and persistent (OR 0.95) HPV subclinical infection groups. This study was able to prove that the normal cervix group has the highest retinol deposit sufficiency level and the cervical cancer group has the highest TNF-α expression (OR 27; p < 0.001). The lowest of retinol deposit sufficiency

  4. Regulation of tumour necrosis factor (TNF) induced apoptosis by soluble TNF receptors in Helicobacter pylori infection

    OpenAIRE

    Shibata, J; Goto, H; Arisawa, T; Niwa, Y; Hayakawa, T; Nakayama, A; Mori, N

    1999-01-01

    BACKGROUND—Tumour necrosis factor (TNF) is a predominant cytokine produced in the gastric mucosa of patients with Helicobacter pylori infection. TNF induces apoptosis in a variety of cells. The soluble TNF receptors (sTNF-Rs) can be divided into sTNF-RI and sTNF-RII, both of which inhibit TNF activity. However, their precise mechanisms remain unclear.
AIM—To investigate the role of sTNF-Rs in H pylori infection.
METHODS—In 40 patients, production of TNF and sTNF-Rs in gastric mucosa was measu...

  5. Expressions of toll-like receptors 2 and 4, and relative cellular ...

    African Journals Online (AJOL)

    Purpose: To investigate the expressions of toll-like receptor 2 (TLR2), toll-like receptor 4 (TLR4), tumor necrosis factor alpha (TNF-α), IFN-γ (IFN- gamma), interleukin 2 (IL-2), interleukin 6 (IL-6) and interleukin 10 (IL-10) in human immunodeficiency virus (HIV) patients with tuberculosis (TB) infection. Methods: Two groups of ...

  6. Endothelin-receptor gene-expression in rat endotoxemia.

    Science.gov (United States)

    Bucher, Michael; Taeger, Kai

    2002-05-01

    The reduced vascular response to endothelin-1 has focused interest onto the regulation of the endothelin-receptor subtypes ET(A) and ET(B) during severe sepsis. Prospective animal trial followed by a controlled cell culture study in the laboratory of the Department of Anesthesiology. Male Sprague-Dawley rats weighing 200-250 g, aortic vascular smooth muscle cell line A7r5. Rats were injected with lipopolysaccharide to induce severe experimental endotoxemia. ET(A)/ET(B) receptor gene expression was investigated by specific RNase protection assay, and abundance of tumor necrosis factor alpha was determined in the lung and kidney. Aortic vascular smooth muscle cells were incubated with the proinflammatory cytokines interleukin-1beta, tumor necrosis factor alpha, and interferon gamma or with the nitric oxide donor S-nitroso- N-acetylpenicillamine to investigate the regulation of ET(A) receptor gene expression during severe inflammation. ET(A)/ET(B) receptor gene expression was markedly downregulated in the lung but was unchanged in the kidney during endotoxemia. ET(A) receptor gene expression was downregulated in aortic vascular smooth muscle cells by tumor necrosis factor alpha but not by interleukin 1beta, interferon gamma, or nitric oxide. In vivo there seems to be a correlation between the tissue concentration of tumor necrosis factor alpha and gene expression of ET(A) receptors in the lung and kidney. Our data show that sepsis causes downregulation of ET(A) receptors at the level of gene expression, and provide correlative evidence that this effect can be mediated by tumor necrosis factor alpha. This downregulation of ET(A) receptors possibly contributes to the attenuated vascular response to endothelin-1 in the pulmonary circulation.

  7. Familial clustering of recurrent pericarditis may disclose tumour necrosis factor receptor-associated periodic syndrome.

    Science.gov (United States)

    Cantarini, Luca; Lucherini, Orso Maria; Baldari, Cosima Tatiana; Laghi Pasini, Franco; Galeazzi, Mauro

    2010-01-01

    Although several causes of recurrent pericarditis have been identified, the etiology remains obscure in most cases. The tumour necrosis factor receptor-1 associated periodic syndrome (TRAPS) is the most common autosomal dominant autoinflammatory disorder and is caused by mutations in the TNFRSF1A gene encoding the 55-kD receptor for tumour necrosis factor-(TNF)-alpha. Serosal membrane inflammation is a common feature of TRAPS, usually in the form of polyserositis. In addition, patients affected with recurrent pericarditis as the only clinical manifestation of TRAPS have been recently described. Our aim was to investigate the possible involvement of mutations in the TNFRSF1A gene in a cohort of patients affected with idiopathic recurrent pericarditis. Twenty consecutive patients diagnosed with idiopathic recurrent pericarditis were enrolled. Each patient underwent detailed examinations in order to rule out underlying diseases such as infections, connective tissue disorders and malignancies, and mutations of the TNFRSF1A gene were searched for by amplifying, using polymerase chain reaction (PCR), genomic DNA, and direct sequencing. TNFRSF1A mutations were found in 2 of the 20 patients. They were siblings, and they both carried a heterozygous low-penetrance R92Q mutation in the TNFRSF1A gene. Familial clustering has been recently reported in up to 10% of patients with recurrent pericarditis, thus suggesting in some cases a possible genetic predisposition. Our study suggests that familial clustering may represent a clue for investigating mutations in the TNFRSF1A gene in these patients and eventually disclose TRAPS.

  8. Dual role of the p75 tumor necrosis factor (TNF) receptor in TNF cytotoxicity

    DEFF Research Database (Denmark)

    Bigda, J; Beletsky, I; Brakebusch, C

    1994-01-01

    Whereas there is ample evidence for involvement of the p55 tumor necrosis factor (TNF) receptor (p55-R) in the cytocidal effect of TNF, the role of the p75 TNF receptor (p75-R) in this effect is a matter of debate. In this study, we probed the function of p75-R in cells sensitive...... to the cytotoxicity of TNF using a wide panel of antibodies (Abs) against the receptor's extracellular domain. Two distinct Ab effects were observed. The Abs triggered signaling for cytotoxicity. This effect: (a) was correlated with the extent of p75-R expression by the cells; (b) was dependent on receptor cross...... against p55-R. Moreover, it seemed to reverse induced desensitization to the cytocidal effect of anti p55-R Abs, suggesting that it involves mechanisms different from those of the signaling by the p55 TNF-R. In addition, the Abs affected the response to TNF in a way that does not involve the signaling...

  9. Functionality of intrinsic disorder in tumor necrosis factor-α and its receptors.

    Science.gov (United States)

    Uversky, Vladimir N; El-Baky, Nawal Abd; El-Fakharany, Esmail M; Sabry, Amira; Mattar, Ehab H; Uversky, Alexey V; Redwan, Elrashdy M

    2017-11-01

    Tumor necrosis factor-α (TNF-α) is a pleiotropic inflammatory cytokine that exerts potent cytotoxic effects on solid tumor cells, while not affecting their normal counterparts. It is also known that TNF-α exerts many of its biological functions via interaction with specific receptors. To understand the potential roles of intrinsic disorder in the functioning of this important cytokine, we explored the peculiarities of intrinsic disorder distribution in human TNF-α and its homologs from various species, ranging from zebrafish to chimpanzee. We also studied the peculiarities of intrinsic disorder distribution in human TNF-α receptors, TNFR1 and TNFR2. Analysis revealed that cytoplasmic domains of TNF-α and its receptors are expected to be highly disordered. Furthermore, although the sequence identities of analyzed TNF-α homologs range from 99.57% (between human and chimpanzee proteins) to 22.33% (between frog and fish proteins), their intrinsic disorder profiles are characterized by a remarkable similarity. These observations indicate that the peculiarities of distribution of the intrinsic disorder propensity within the amino acid sequences are evolutionary conserved, and therefore could be of functional importance for this family of proteins. We also show that disordered and flexible regions of human TNF-α and its TNFR1 and TNFR2 receptors are crucial for some of their biological activities. © 2017 Federation of European Biochemical Societies.

  10. Clinical effectiveness and cost-effectiveness of use of therapeutic monitoring of tumour necrosis factor alpha (TNF-α) inhibitors [LISA-TRACKER® enzyme-linked immunosorbent assay (ELISA) kits, TNF-α-Blocker ELISA kits and Promonitor® ELISA kits] versus standard care in patients with Crohn's disease: systematic reviews and economic modelling.

    Science.gov (United States)

    Freeman, Karoline; Connock, Martin; Auguste, Peter; Taylor-Phillips, Sian; Mistry, Hema; Shyangdan, Deepson; Court, Rachel; Arasaradnam, Ramesh; Sutcliffe, Paul; Clarke, Aileen

    2016-11-01

    Systematic reviews and economic modelling of clinical effectiveness and cost-effectiveness of therapeutic monitoring of tumour necrosis factor alpha (TNF-α) inhibitors [using LISA-TRACKER ® enzyme-linked immunosorbent assay (ELISA) kits (Theradiag, Marne La Vallee, France, or Alpha Laboratories, Heriot, UK), TNF-α-Blocker ELISA kits (Immundiagnostik AG, Bensheim, Germany) and Promonitor ® ELISA kits (Proteomika, Progenika Biopharma, Bizkaia, Spain)] versus standard care for Crohn's disease (CD). Multiple electronic databases were searched from inception to December 2014 in order to identify primary studies and meta-analyses. Patients with moderate to severe active CD treated with infliximab (IFX) (Remicade ® , Merck Sharp & Dohme Ltd, Kenilworth, NJ, USA) or adalimumab (ADA) (Humira ® , AbbVie Inc., North Chicago, IL, USA). Monitoring of serum anti-TNF-α (IFX or ADA) and/or of anti-drug antibody levels using test assays with a test-treatment algorithm. Standard care. Any patient-related outcome, test agreement and cost-effectiveness estimates. The quality assessments used recognised checklists (Quality Assessment of Diagnostic Accuracy Studies-2, Cochrane, Philips and Consolidated Health Economic Evaluation Reporting Standards). Evidence was synthesised using narrative review and meta-analysis. A Markov model was built in TreeAge Pro 2013 (TreeAge Software, Inc., Williamstown, MA, USA). The model had a 4-week cycle and a 10-year time horizon, adopted a NHS and Personal Social Services perspective and used a linked evidence approach. Costs were adjusted to 2013/14 prices and discounted at 3.5%. We included 68 out of 2434 and 4 out of 2466 studies for the clinical effectiveness and cost-effectiveness reviews, respectively. Twenty-three studies comparing test methods were identified. Evidence on test concordance was sparse and contradictory, offering scant data for a linked evidence approach. Three studies [two randomised controlled trials (RCTs) and one

  11. Selective tumor necrosis factor receptor I blockade is antiinflammatory and reveals immunoregulatory role of tumor necrosis factor receptor II in collagen-induced arthritis.

    Science.gov (United States)

    McCann, Fiona E; Perocheau, Dany P; Ruspi, Gerhard; Blazek, Katrina; Davies, Marie L; Feldmann, Marc; Dean, Jonathan L E; Stoop, A Allart; Williams, Richard O

    2014-10-01

    Tumor necrosis factor (TNF) signals via 2 receptors, TNFR type I (TNFRI) and TNFRII, with distinct cellular distribution and signaling functions. In rheumatoid arthritis (RA), the net effect of TNFR signaling favors inflammatory responses while inhibiting the activity of regulatory T cells. TNFRII signaling has been shown to promote Treg cell function. To assess the relative contributions of TNFRI and TNFRII signaling to inflammatory and regulatory responses in vivo, we compared the effect of TNF blockade, hence TNFRI/II, versus TNFRI alone in collagen-induced arthritis (CIA) as a model of RA. Mice with established arthritis were treated for 10 days with anti-mouse TNFRI domain antibody (dAb; DMS5540), an isotype control dAb (DMS5538), or murine TNFRII genetically fused with mouse IgG1 Fc domain (mTNFRII-Fc) beginning on the day of arthritis onset, and disease progression was monitored. Systemic cytokine concentrations and numbers of T cell subsets in lymph nodes and spleens were measured, and intrinsic Treg cell function was determined by ex vivo suppression assays. Progression of CIA was suppressed similarly by TNFRI (DMS5540) and TNFRI/II (mTNFRII-Fc) blockade. However, blockade of TNFRI/II led to increased effector T cell activity, which was not observed after selective TNFRI blockade, suggesting an immunoregulatory role of TNFRII. In support of this, TNFRI blockade, but not TNFRI/II blockade, expanded and activated Treg cells. Furthermore, a dramatic increase in expression of the Treg cell signature genes FoxP3 and TNFRII was observed in joints undergoing remission, which supports the notion that these molecules have a physiologic role in the resolution of inflammation. We propose that a therapeutic strategy that targets TNFRI while sparing TNFRII has the potential to both inhibit inflammation and promote Treg cell activity, which might be superior to TNF blockade. Copyright © 2014 by the American College of Rheumatology.

  12. Genomic profiling of tumor necrosis factor alpha (TNF-alpha) receptor and interleukin-1 receptor knockout mice reveals a link between TNF-alpha signaling and increased severity of 1918 pandemic influenza virus infection

    Science.gov (United States)

    The influenza pandemic of 1918-1919 was one of the worst global pandemics in recent history. The highly pathogenic nature of the 1918 virus is thought to be mediated in part by a dysregulation of the host response, including an exacerbated pro-inflammatory cytokine response. In the present study, we...

  13. MATERNAL PLASMA CONCENTRATIONS OF THE SOLUBLE TUMOR NECROSIS FACTOR RECEPTOR 2 ARE INCREASED PRIOR TO THE DEVELOPMENT OF PREECLAMPSIA

    Science.gov (United States)

    Sibai, Baha; Romero, Roberto; Klebanoff, Mark A.; Rice, Madeline Murguia; Caritis, Steve; Hauth, John; Lindheimer, Marshall D.; Van Dorsten, Peter; Landon, Mark; Miodovnik, Menachem; Paul, Richard; Dombrowski, Mitchell; Meis, Paul; Thurnau, Gary

    2009-01-01

    OBJECTIVE Circulating tumor necrosis factor-alpha (TNF-α), a potent pro-inflammatory cytokine, capable of activating endothelial cells, as well as its soluble receptors (sTNF-R1 and sTNF-R2), is increased during overt preeclampsia, consistent with hypotheses that enhanced systemic inflammatory response and endothelial cell dysfunction are important in the pathophysiology of the preeclamptic syndrome. If so, such increases in levels should precede the onset of the disease. This study was designed to examine whether plasma concentrations of sTNF-R1 and sTNF-R2 are elevated prior to the onset of preeclampsia. METHODS This was a retrospective biomarker study of stored maternal plasma from an NICHD preeclampsia prevention trial conducted in patients with risk factors for developing preeclampsia to test the effectiveness of low dose aspirin compared with placebo. The first sample was collected at 13–26 weeks’ gestation and the second at 24–28 weeks’ gestation. Serial sTNF-R1 and sTNF-R2 concentrations were assessed using sensitive and specific immunoassays in 1,004 patients in whom both samples were collected. RESULTS The incidence of preeclampsia was 21.3% (214/1004). Median plasma levels of the sTNF-R2, but not sTNF-R1, were significantly higher at 13–26 weeks (sample 1) and at 24–28 weeks (sample 2) in patients who developed preeclampsia than in those who did not (sample 1: sTNF-R2: median 2,678 pg/ml, range 934–7,835 vs. median 2,535 pg/ml, range 1,022–13,000, p=0.02; sTNF-R1: median 936 pg/ml, range 449–3,239 vs. median 913 pg/ml, range 359–5,060, p=0.19). There was a significantly increased odds of preeclampsia for an increase in sTNF-R2 from sample 1 to sample 2 (OR=1.23 per 1,000 unit increase). Women in the fourth quartile of sTNF-R2 at 24–28 weeks, had a significantly increased adjusted odds of preeclampsia (OR=1.55, 95%CI=1.02–2.35, p=0.04), compared with women in the first quartile. This association, however, varied by treatment group

  14. Characterization in vitro of a human tumor necrosis factor-binding protein. A soluble form of a tumor necrosis factor receptor.

    OpenAIRE

    Lantz, M; Gullberg, U; Nilsson, E; Olsson, I

    1990-01-01

    Tumor necrosis factor (TNF) is a pleiotropic mediator of inflammatory responses. A cysteine-rich, highly glycosylated 30-kD TNF-binding protein (TNF-BP) purified from urine may have a role in regulation because it protects in vitro against the biological effects of TNF. The cytotoxic effect of TNF on the fibrosarcoma cell line WEHI 164 was inhibited by 50% at a 10-fold excess of TNF-BP. The binding of TNF to the receptor was partially reversed after the addition of TNF-BP. Results from biosyn...

  15. Suberoylanilide hydroxamic acid increases anti-cancer effect of tumor necrosis factor-α through up-regulation of TNF receptor 1 in lung cancer cells.

    Science.gov (United States)

    You, Bo Ra; Han, Bo Ram; Park, Woo Hyun

    2017-03-14

    Suberoylanilide hydroxamic acid (SAHA) as a histone deacetylase (HDAC) inhibitor has anti-cancer effect. Here, we evaluated the effect of SAHA on HDAC activity and cell growth in many normal lung and cancer cells. We observed that the HDAC activities of lung cancer cells were higher than that of normal lung cells. SAHA inhibited the growth of lung cancer cells regardless of the inhibitory effect on HDAC. This agent induced a G2/M phase arrest and apoptosis, which was accompanied by mitochondrial membrane potential (MMP: ΔΨm) loss in lung cancer cells. However, SAHA did not induce cell death in normal lung cells. All tested caspase inhibitors prevented apoptotic cell death in SAHA-treated A549 and Calu-6 lung cancer cells. Treatment with tumor necrosis factor-alpha (TNF-α) enhanced apoptosis in SAHA-treated lung cancer cells through caspase-8 and caspase-9 activations. Especially, SAHA increased the expression level of TNF-α receptor 1 (TNFR1), especially acetylation of the region of TNFR1 promoter -223/-29 in lung cancer cells. The down-regulation of TNFR1 suppressed apoptosis in TNF-α and SAHA-treated lung cancer cells. In conclusion, SAHA inhibited the growth of lung cancer cells via a G2/M phase arrest and caspase-dependent apoptosis. SAHA also enhanced apoptotic effect of TNF-α in human lung cancer cells through up-regulation of TNFR1. TNF-α may be a key to improve anti-cancer effect of HDAC inhibitors.

  16. Homogeneous expansion of human T-regulatory cells via tumor necrosis factor receptor 2.

    Science.gov (United States)

    Okubo, Yoshiaki; Mera, Toshiyuki; Wang, Limei; Faustman, Denise L

    2013-11-06

    T-regulatory cells (T(regs)) are a rare lymphocyte subtype that shows promise for treating infectious disease, allergy, graft-versus-host disease, autoimmunity, and asthma. Clinical applications of T(regs) have not been fully realized because standard methods of expansion ex vivo produce heterogeneous progeny consisting of mixed populations of CD4 + T cells. Heterogeneous progeny are risky for human clinical trials and face significant regulatory hurdles. With the goal of producing homogeneous T(regs), we developed a novel expansion protocol targeting tumor necrosis factor receptors (TNFR) on T(regs). In in vitro studies, a TNFR2 agonist was found superior to standard methods in proliferating human T(regs) into a phenotypically homogeneous population consisting of 14 cell surface markers. The TNFR2 agonist-expanded T(regs) also were functionally superior in suppressing a key T(reg) target cell, cytotoxic T-lymphocytes. Targeting the TNFR2 receptor during ex vivo expansion is a new means for producing homogeneous and potent human T(regs) for clinical opportunities.

  17. NF-κB Protects NKT Cells from Tumor Necrosis Factor Receptor 1-induced Death.

    Science.gov (United States)

    Kumar, Amrendra; Gordy, Laura E; Bezbradica, Jelena S; Stanic, Aleksandar K; Hill, Timothy M; Boothby, Mark R; Van Kaer, Luc; Joyce, Sebastian

    2017-11-15

    Semi-invariant natural killer T (NKT) cells are innate-like lymphocytes with immunoregulatory properties. NKT cell survival during development requires signal processing by activated RelA/NF-κB. Nonetheless, the upstream signal(s) integrated by NF-κB in developing NKT cells remains incompletely defined. We show that the introgression of Bcl-x L -coding Bcl2l1 transgene into NF-κB signalling-deficient IκBΔN transgenic mouse rescues NKT cell development and differentiation in this mouse model. We reasoned that NF-κB activation was protecting developing NKT cells from death signals emanating either from high affinity agonist recognition by the T cell receptor (TCR) or from a death receptor, such as tumor necrosis factor receptor 1 (TNFR1) or Fas. Surprisingly, the single and combined deficiency in PKC-θ or CARMA-1-the two signal transducers at the NKT TCR proximal signalling node-only partially recapitulated the NKT cell deficiency observed in IκBΔN tg mouse. Accordingly, introgression of the Bcl2l1 transgene into PKC-θ null mouse failed to rescue NKT cell development. Instead, TNFR1-deficiency, but not the Fas-deficiency, rescued NKT cell development in IκBΔN tg mice. Consistent with this finding, treatment of thymocytes with an antagonist of the inhibitor of κB kinase -which blocks downstream NF-κB activation- sensitized NKT cells to TNF-α-induced cell death in vitro. Hence, we conclude that signal integration by NF-κB protects developing NKT cells from death signals emanating from TNFR1, but not from the NKT TCR or Fas.

  18. Transforming growth factor alpha and epidermal growth factor in laryngeal carcinomas demonstrated by immunohistochemistry

    DEFF Research Database (Denmark)

    Christensen, M E; Therkildsen, M H; Poulsen, Steen Seier

    1993-01-01

    Fifteen laryngeal squamous cell carcinomas were investigated for the presence of transforming growth factor alpha (TGF-alpha) and epidermal growth factor (EGF) using immunohistochemical methods. In a recent study the same material was characterized for epidermal growth factor receptors (EGF recep...

  19. Increased concentrations of tumour necrosis factor (TNF) and soluble TNF receptors in biliary obstruction in mice; soluble TNF receptors as prognostic factors for mortality

    NARCIS (Netherlands)

    Bemelmans, M. H.; Greve, J. W.; Gouma, D. J.; Buurman, W. A.

    1996-01-01

    Systemic tumour necrosis factor (TNF) is present in jaundiced mice. Two soluble TNF receptors, sTNFr-P55 and sTNFr-P75 are reported to play a part in the natural defence against TNF. This study investigated the properties of circulating TNF and sTNFr in jaundiced mice. The data show that TNF in

  20. Neurodegenerative and neuroprotective effects of tumor necrosis factor (TNF) in retinal ischemia : Opposite roles of TNF receptor 1 and TNF receptor 2

    NARCIS (Netherlands)

    Fontaine, Sharon; Mohand-Said, S; Hanoteau, N; Fuchs, L; Pfizenmaier, K; Eisel, U

    2002-01-01

    Tumor necrosis factor (TNF) is an important factor in various acute and chronic neurodegenerative disorders. In retinal ischemia, we show early, transient upregulation of TNF, TNF receptor 1 (TNF-R1), and TNF-R2 6 hr after reperfusion preceding neuronal cell loss. To assess the specific role of TNF

  1. Critical role of tumor necrosis factor receptor 1 in the pathogenesis of pulmonary emphysema in mice

    Directory of Open Access Journals (Sweden)

    Fujita M

    2016-07-01

    Full Text Available Masaki Fujita,1 Hiroshi Ouchi,2 Satoshi Ikegame,2 Eiji Harada,2 Takemasa Matsumoto,1 Junji Uchino,1 Yoichi Nakanishi,2 Kentaro Watanabe1 1Department of Respiratory Medicine, Faculty of Medicine, Fukuoka University, 2Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan Abstract: COPD is a major cause of chronic morbidity and mortality throughout the world. Although tumor necrosis factor-α (TNF-α has a critical role in the development of COPD, the role of different TNF receptors (TNFRs in pulmonary emphysema has not been resolved. We aimed to clarify the role of TNFRs in the development of pulmonary emphysema. TNF-α transgenic mice, a murine model of COPD in which the mice spontaneously develop emphysema with a large increase in lung volume and pulmonary hypertension, were crossed with either TNFR1-deficient mice or TNFR2-deficient mice. After 6 months, the gross appearance of the lung, lung histology, and pulmonary and cardiac physiology were determined. In addition, the relationship between apoptosis and emphysema was investigated. Pulmonary emphysema-like changes disappeared with deletion of TNFR1. However, slight improvements were attained with deletion of TNFR2. Apoptotic cells in the interstitium of the lung were observed in TNF-α transgenic mice. The apoptotic signals through TNFR1 appear critical for the pathogenesis of pulmonary emphysema. In contrast, the inflammatory process has a less important role for the development of emphysema. Keywords: TNF-α, receptor, emphysema, apoptosis

  2. Molecular and functional characterization of pigeon (Columba livia) tumor necrosis factor receptor-associated factor 3.

    Science.gov (United States)

    Zhou, Yingying; Kang, Xilong; Xiong, Dan; Zhu, Shanshan; Zheng, Huijuan; Xu, Ying; Guo, Yaxin; Pan, Zhiming; Jiao, Xinan

    2017-04-01

    Tumor necrosis factor receptor-associated factor 3 (TRAF3) plays a key antiviral role by promoting type I interferon production. We cloned the pigeon TRAF3 gene (PiTRAF3) according to its predicted mRNA sequence to investigate its function. The 1704-bp full-length open reading frame encodes a 567-amino acid protein. One Ring finger, two TRAF-type Zinc fingers, one Coiled coil, and one MATH domain were inferred. RT-PCR showed that PiTRAF3 was expressed in all tissues, with relatively weak expression in the heart and liver. In HEK293T cells, over-expression of wild-type, △Ring, △Zinc finger, and △Coiled coil PiTRAF3, but not a △MATH form, significantly increased IFN-β promoter activity. Zinc finger and Coiled coil domains were essential for NF-κB activation. In chicken HD11 cells, PiTRAF3 increased IFN-β promoter activity and four domains were all contributing. R848 stimulation of pigeon peripheral blood mononuclear cells and splenocytes significantly increased expression of PiTRAF3 and the inflammatory cytokine genes CCL5, IL-8, and IL-10. These data demonstrate TRAF3's innate immune function and improve understanding of its involvement in poultry antiviral defense. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Critical role of tumor necrosis factor receptor 1 in the pathogenesis of pulmonary emphysema in mice.

    Science.gov (United States)

    Fujita, Masaki; Ouchi, Hiroshi; Ikegame, Satoshi; Harada, Eiji; Matsumoto, Takemasa; Uchino, Junji; Nakanishi, Yoichi; Watanabe, Kentaro

    2016-01-01

    COPD is a major cause of chronic morbidity and mortality throughout the world. Although tumor necrosis factor-α (TNF-α) has a critical role in the development of COPD, the role of different TNF receptors (TNFRs) in pulmonary emphysema has not been resolved. We aimed to clarify the role of TNFRs in the development of pulmonary emphysema. TNF-α transgenic mice, a murine model of COPD in which the mice spontaneously develop emphysema with a large increase in lung volume and pulmonary hypertension, were crossed with either TNFR1-deficient mice or TNFR2-deficient mice. After 6 months, the gross appearance of the lung, lung histology, and pulmonary and cardiac physiology were determined. In addition, the relationship between apoptosis and emphysema was investigated. Pulmonary emphysema-like changes disappeared with deletion of TNFR1. However, slight improvements were attained with deletion of TNFR2. Apoptotic cells in the interstitium of the lung were observed in TNF-α transgenic mice. The apoptotic signals through TNFR1 appear critical for the pathogenesis of pulmonary emphysema. In contrast, the inflammatory process has a less important role for the development of emphysema.

  4. Cytokines and soluble tumour necrosis factor I receptor levels during pretransplant conditioning in allogeneic stem-cell transplantation

    DEFF Research Database (Denmark)

    Andersen, Johnny; Heilmann, Carsten; Jacobsen, Niels

    2005-01-01

    a broad range of cytokines in plasma samples drawn daily immediately before start of pretransplant conditioning and during the conditioning. The presented data indicate that single-day measurements of inflammatory cytokines during conditioning may lead to unreliable conclusions concerning their prognostic...... significance. However, serial quantitation of soluble tumour necrosis factor receptor I (sTNFRI) is more likely to reflect the degree of inflammatory activation induced by pretransplant conditioning....

  5. Functional discrepancies between tumor necrosis factor and lymphotoxin alpha explained by trimer stability and distinct receptor interactions

    DEFF Research Database (Denmark)

    Schuchmann, M; Hess, S; Bufler, P

    1995-01-01

    interaction with the human p55TNFR. This was demonstrated in NIH 3T3 cells transfected with the human p55TNFR, where cytotoxicity is mediated exclusively by the transfected receptor. Although the p55ATNFR had virtually identical affinities for TNF and LT alpha, as defined by Scatchard analysis......Tumor necrosis factor (TNF) and lymphotoxin alpha (LT alpha) are closely related cytokines which bind with nearly identical affinities to the same pair of cell surface receptors, p55 and p75TNFR. Therefore it is assumed that TNF and LT alpha are redundant cytokines. This study, however...

  6. Glucocorticoid-induced tumor necrosis factor receptor expression in patients with cervical human papillomavirus infection

    Directory of Open Access Journals (Sweden)

    Cacilda Tezelli Junqueira Padovani

    2013-06-01

    Full Text Available Introduction The progression of human papillomavirus (HPV infection in the anogenital tract has been associated with the involvement of cells with regulatory properties. Evidence has shown that glucocorticoid-induced tumor necrosis factor receptor (GITR is an important surface molecule for the characterization of these cells and proposes that GITR ligand may constitute a rational treatment for many cancer types. We aimed to detect the presence of GITR and CD25 in cervical stroma cells with and without pathological changes or HPV infection to better understand the immune response in the infected tissue microenvironment. Methods We subjected 49 paraffin-embedded cervical tissue samples to HPV DNA detection and histopathological analysis, and subsequently immunohistochemistry to detect GITR and CD25 in lymphocytes. Results We observed that 76.9% of all samples with high GITR expression were HPV-positive regardless of histopathological findings. High GITR expression (77.8% was predominant in samples with ≥1,000 RLU/PCB. Of the HPV-positive samples negative for intraepithelial lesion and malignancy, 62.5% had high GITR expression. High GITR expression was observed in both carcinoma and high-grade squamous intraepithelial lesion (HSIL samples (p = 0.16. CD25 was present in great quantities in all samples. Conclusions The predominance of high GITR expression in samples with high viral load that were classified as HSIL and carcinoma suggests that GITR+ cells can exhibit regulatory properties and may contribute to the progression of HPV-induced cervical neoplasia, emphasizing the importance of GITR as a potential target for immune therapy of cervical cancer and as a disease evolution biomarker.

  7. Tumor necrosis factor-α levels correlate with postoperative pain severity in lumbar disc hernia patients: opposite clinical effects between tumor necrosis factor receptor 1 and 2.

    Science.gov (United States)

    Andrade, Pablo; Visser-Vandewalle, Veerle; Philippens, Marjan; Daemen, Marc A; Steinbusch, Harry W M; Buurman, Wim A; Hoogland, Govert

    2011-11-01

    Lumbar disc hernia (LDH) is a leading cause of chronic pain in adults. The underlying pathology of chronic pain after discectomy remains unclear. Chronic local inflammation is considered to underlie painful symptomatology. In this context, we investigated tumor necrosis factor (TNF)-α, TNF receptor 1 (TNFR1), and TNF receptor 2 (TNFR2) expression at the time of surgery in LDH patients and correlated it with the severity of postoperative pain. We analyzed protein and mRNA levels from muscle, ligamentum flavum (LF), annulus fibrosus (AF), and nucleus pulposus (NP) in LDH patients and scoliosis patients (SP), who served as controls. Pain assessment with the visual analogue scale (VAS) was performed 1 day before surgery and 6 weeks and 12 months postoperatively. TNF-α protein levels were detected in AF, LF, and NP in all LDH patients, but not in SP. TNF-α mRNA was significantly greater in LDH patients than in SP; ie, 5-fold in AF, 3-fold in NP, and 2-fold in LF. For NP, TNF-α protein levels correlated with VAS scores (r=0.54 at 6-week and r=0.65 at 12-month follow-up). Also, TNFR1 protein levels in NP positively correlated with VAS scores (r=0.75 at 6-week and r=0.80 at 12-month follow-up). However, TNFR2 protein levels in AF negatively correlated with VAS scores (r=-0.60 at 6 weeks and r=-0.60 at 12 months follow-up). These data indicate that TNF-α levels could determine the clinical outcome in LDH patients after discectomy. Moreover, the opposite correlation of TNF receptors with pain sensation suggests that an unbalanced expression plays a role in the generation of pain. Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  8. Antibodies to a soluble form of a tumor necrosis factor (TNF) receptor have TNF-like activity

    DEFF Research Database (Denmark)

    Engelmann, H; Holtmann, H; Brakebusch, C

    1990-01-01

    Immunological cross-reactivity between tumor necrosis factor (TNF) binding proteins which are present in human urine (designated TBPI and TBPII) and two molecular species of the cell surface receptors for TNF is demonstrated. The two TNF receptors are shown to be immunologically distinct, to differ...... in molecular weight (58,000 and 73,000), and to be expressed differentially in different cells. It is further shown that polyclonal antibodies against one of the TNF binding proteins (TBPI) display, by virtue of their ability to bind the TNF receptor, activities which are very similar to those of TNF....... These antibodies are cytotoxic to cells which are sensitive to TNF toxicity, induce resistance to TNF toxicity, enhance the incorporation of thymidine into normal fibroblasts, inhibit the growth of chlamydiae, and induce the synthesis of prostaglandin E2. Monovalent F(ab) fragments of the polyclonal antibodies...

  9. The Link Between Oxidative Stress Response and Tumor Necrosis ...

    African Journals Online (AJOL)

    Dr Olaleye Samuel

    Factor-Alpha (TNF-alpha) in Hepatic Tissue of Rats With Induced. Thyroid Dysfunction. 1Suzan Hazzaa ... Tumor necrosis factor-alpha (TNF-α) is a cytokine with numerous immunological and metabolic activities. Several studies ... However, when free radical generation exceeds the antioxidant capacity of cells, oxidative ...

  10. Tumor necrosis factor receptor- associated factor 6 (TRAF6) regulation of development, function, and homeostasis of the immune system.

    Science.gov (United States)

    Walsh, Matthew C; Lee, JangEun; Choi, Yongwon

    2015-07-01

    Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) is an adapter protein that mediates a wide array of protein-protein interactions via its TRAF domain and a RING finger domain that possesses non-conventional E3 ubiquitin ligase activity. First identified nearly two decades ago as a mediator of interleukin-1 receptor (IL-1R)-mediated activation of NFκB, TRAF6 has since been identified as an actor downstream of multiple receptor families with immunoregulatory functions, including members of the TNFR superfamily, the Toll-like receptor (TLR) family, tumor growth factor-β receptors (TGFβR), and T-cell receptor (TCR). In addition to NFκB, TRAF6 may also direct activation of mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), and interferon regulatory factor pathways. In the context of the immune system, TRAF6-mediated signals have proven critical for the development, homeostasis, and/or activation of B cells, T cells, and myeloid cells, including macrophages, dendritic cells, and osteoclasts, as well as for organogenesis of thymic and secondary lymphoid tissues. In multiple cellular contexts, TRAF6 function is essential not only for proper activation of the immune system but also for maintaining immune tolerance, and more recent work has begun to identify mechanisms of contextual specificity for TRAF6, involving both regulatory protein interactions, and messenger RNA regulation by microRNAs. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Tumor necrosis factor receptor associated factor 6 (TRAF6) regulation of development, function, and homeostasis of the immune system

    Science.gov (United States)

    Walsh, Matthew C.; Lee, JangEun; Choi, Yongwon

    2016-01-01

    Summary Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) is an adaptor protein that mediates a wide array of protein-protein interactions via its TRAF domain and a RING finger domain that possesses non-conventional E3 ubiquitin ligase activity. First identified nearly two decades ago as a mediator of IL-1 receptor (IL-1R)-mediated activation of NFκB, TRAF6 has since been identified as an actor downstream of multiple receptor families with immunoregulatory functions, including members of the TNFR superfamily, the toll-like receptor (TLR) family, tumor growth factor-β receptors (TGFβR), and T cell receptor (TCR). In addition to NFκB, TRAF6 may also direct activation of mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), and interferon regulatory factor (IRF) pathways. In the context of the immune system, TRAF6-mediated signals have proven critical for the development, homeostasis, and/or activation of B cells, T cells, and myeloid cells, including macrophages, dendritic cells, and osteoclasts, as well as for organogenesis of thymic and secondary lymphoid tissues. In multiple cellular contexts, TRAF6 function is essential not only for proper activation of the immune system, but also for maintaining immune tolerance, and more recent works have begun to identify mechanisms of contextual specificity for TRAF6, involving both regulatory protein interactions, and messenger RNA regulation by microRNAs. PMID:26085208

  12. Brefeldin A-Inhibited Guanine Nucleotide-Exchange Factor 1 (BIG1 Governs the Recruitment of Tumor Necrosis Factor Receptor-Associated Factor 2 (TRAF2 to Tumor Necrosis Factor Receptor 1 (TNFR1 Signaling Complexes

    Directory of Open Access Journals (Sweden)

    Takuya Noguchi

    2016-11-01

    Full Text Available Tumor necrosis factor receptor-associated factor 2 (TRAF2 is a critical mediator of tumor necrosis factor-α (TNF-α signaling. However, the regulatory mechanisms of TRAF2 are not fully understood. Here we show evidence that TRAF2 requires brefeldin A-inhibited guanine nucleotide-exchange factor 1 (BIG1 to be recruited into TNF receptor 1 (TNFR1 signaling complexes. In BIG1 knockdown cells, TNF-α-induced c-Jun N-terminal kinase (JNK activation was attenuated and the sensitivity to TNF-α-induced apoptosis was increased. Since these trends correlated well with those of TRAF2 deficient cells as previously demonstrated, we tested whether BIG1 functions as an upstream regulator of TRAF2 in TNFR1 signaling. As expected, we found that knockdown of BIG1 suppressed TNF-α-dependent ubiquitination of TRAF2 that is required for JNK activation, and impaired the recruitment of TRAF2 to the TNFR1 signaling complex (complex I. Moreover, we found that the recruitment of TRAF2 to the death-inducing signaling complex termed complex II was also impaired in BIG1 knockdown cells. These results suggest that BIG1 is a key component of the machinery that drives TRAF2 to the signaling complexes formed after TNFR1 activation. Thus, our data demonstrate a novel and unexpected function of BIG1 that regulates TNFR1 signaling by targeting TRAF2.

  13. Microparticles of Human Atherosclerotic Plaques Enhance the Shedding of the Tumor Necrosis Factor-α Converting Enzyme/ADAM17 Substrates, Tumor Necrosis Factor and Tumor Necrosis Factor Receptor-1

    Science.gov (United States)

    Canault, Matthias; Leroyer, Aurélie S.; Peiretti, Franck; Lesèche, Guy; Tedgui, Alain; Bonardo, Bernadette; Alessi, Marie-Christine; Boulanger, Chantal M.; Nalbone, Gilles

    2007-01-01

    Human atherosclerotic plaques express the metalloprotease tumor necrosis factor (TNF)-α converting enzyme (TACE/ADAM-17), which cleaves several transmembrane proteins including TNF and its receptors (TNFR-1 and TNFR-2). Plaques also harbor submicron vesicles (microparticles, MPs) released from plasma membranes after cell activation or apoptosis. We sought to examine whether TACE/ADAM17 is present on human plaque MPs and whether these MPs would affect TNF and TNFR-1 cellular shedding. Flow cytometry analysis detected 12,867 ± 2007 TACE/ADAM17+ MPs/mg of plaques isolated from 25 patients undergoing endarterectomy but none in healthy human internal mammary arteries. Plaque MPs harbored mainly mature active TACE/ADAM17 and dose dependently cleaved a pro-TNF mimetic peptide, whereas a preferential TACE/ADAM17 inhibitor (TMI-2) and recombinant TIMP-3 prevented this cleavage. Plaque MPs increased TNF shedding from the human cell line ECV-304 overexpressing TNF (ECV-304TNF), as well as TNFR-1 shedding from activated human umbilical vein endothelial cells or ECV-304TNF cells, without affecting TNF or TNFR-1 synthesis. MPs also activated the shedding of the endothelial protein C receptor from human umbilical vein endothelial cells. All these effects were inhibited by TMI-2. The present study shows that human plaque MPs carry catalytically active TACE/ADAM17 and significantly enhance the cell surface processing of the TACE/ADAM17 substrates TNF, TNFR-1, and endothelial protein C receptor, suggesting that TACE/ADAM17+ MPs could regulate the inflammatory balance in the culprit lesion. PMID:17872973

  14. MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis

    NARCIS (Netherlands)

    Cai, Bishuang; Thorp, Edward B.; Doran, Amanda C.; Sansbury, Brian E.; Daemen, Mat J. A. P.; Dorweiler, Bernhard; Spite, Matthew; Fredman, Gabrielle; Tabas, Ira

    2017-01-01

    Atherothrombotic vascular disease is often triggered by a distinct type of atherosclerotic lesion that displays features of impaired inflammation resolution, notably a necrotic core and thinning of a protective fibrous cap that overlies the core. A key cause of plaque necrosis is defective clearance

  15. Cloning of Human Tumor Necrosis Factor (TNF) Receptor cDNA and Expression of Recombinant Soluble TNF-Binding Protein

    Science.gov (United States)

    Gray, Patrick W.; Barrett, Kathy; Chantry, David; Turner, Martin; Feldmann, Marc

    1990-10-01

    The cDNA for one of the receptors for human tumor necrosis factor (TNF) has been isolated. This cDNA encodes a protein of 455 amino acids that is divided into an extracellular domain of 171 residues and a cytoplasmic domain of 221 residues. The extracellular domain has been engineered for expression in mammalian cells, and this recombinant derivative binds TNFα with high affinity and inhibits its cytotoxic activity in vitro. The TNF receptor exhibits similarity with a family of cell surface proteins that includes the nerve growth factor receptor, the human B-cell surface antigen CD40, and the rat T-cell surface antigen OX40. The TNF receptor contains four cysteine-rich subdomains in the extra-cellular portion. Mammalian cells transfected with the entire TNF receptor cDNA bind radiolabeled TNFα with an affinity of 2.5 x 10-9 M. This binding can be competitively inhibited with unlabeled TNFα or lymphotoxin (TNFβ).

  16. Antibodies against amino acids 1-15 of tumor necrosis factor block its binding to cell-surface receptor.

    OpenAIRE

    Socher, S H; Riemen, M W; Martinez, D; Friedman, A; Tai, J; Quintero, J C; Garsky, V; Oliff, A

    1987-01-01

    Human tumor necrosis factor (hTNF) mediates a variety of biologic activities, which are dependent on the attachment of hTNF to cell-surface receptors. To identify regions of the hTNF protein involved in binding hTNF to its receptor, we prepared five synthetic peptides [hTNF-(1-15), hTNF-(1-31), hTNF-(65-79), hTNF-(98-111), and hTNF-(124-141)] and two hydroxylamine cleavage fragments [hTNF-(1-39) and hTNF-(40-157)] of hTNF. The hTNF-synthetic peptides and hTNF fragments were tested in hTNF rec...

  17. Dual role of the p75 tumor necrosis factor (TNF) receptor in TNF cytotoxicity

    DEFF Research Database (Denmark)

    Bigda, J; Beletsky, I; Brakebusch, C

    1994-01-01

    to the cytotoxicity of TNF using a wide panel of antibodies (Abs) against the receptor's extracellular domain. Two distinct Ab effects were observed. The Abs triggered signaling for cytotoxicity. This effect: (a) was correlated with the extent of p75-R expression by the cells; (b) was dependent on receptor cross...

  18. Genetic variants in toll-like receptors are not associated with rheumatoid arthritis susceptibility or anti-tumour necrosis factor treatment outcome

    DEFF Research Database (Denmark)

    Coenen, Marieke J H; Enevold, Christian; Barrera, Pilar

    2010-01-01

    Several studies point to a role of Toll-like receptors (TLRs) in the development of rheumatoid arthritis (RA). We investigated if genetic variants in TLR genes are associated with RA and response to tumour necrosis factor blocking (anti-TNF) medication.......Several studies point to a role of Toll-like receptors (TLRs) in the development of rheumatoid arthritis (RA). We investigated if genetic variants in TLR genes are associated with RA and response to tumour necrosis factor blocking (anti-TNF) medication....

  19. Pretreatment with a 55-kDa tumor necrosis factor receptor-immunoglobulin fusion protein attenuates activation of coagulation, but not of fibrinolysis, during lethal bacteremia in baboons

    NARCIS (Netherlands)

    van der Poll, T.; Jansen, P. M.; van Zee, K. J.; Hack, C. E.; Oldenburg, H. A.; Loetscher, H.; Lesslauer, W.; Lowry, S. F.; Moldawer, L. L.

    1997-01-01

    Baboons (Papio anubis) receiving a lethal intravenous infusion with live Escherichia coli were pretreated with either a 55-kDa tumor necrosis factor (TNF) receptor-IgG fusion protein (TNFR55:IgG) (n = 4, 4.6 mg/kg) or placebo (n = 4). Neutralization of TNF activity in TNFR55:IgG-treated animals was

  20. Genetic variants in toll-like receptors are not associated with rheumatoid arthritis susceptibility or anti-tumour necrosis factor treatment outcome

    DEFF Research Database (Denmark)

    Coenen, Marieke J H; Enevold, Christian; Barrera, Pilar

    2010-01-01

    Several studies point to a role of Toll-like receptors (TLRs) in the development of rheumatoid arthritis (RA). We investigated if genetic variants in TLR genes are associated with RA and response to tumour necrosis factor blocking (anti-TNF) medication....

  1. Tumor necrosis factor and its receptors in the neuroretina and retinal vasculature after ischemia-reperfusion injury in the pig retina

    DEFF Research Database (Denmark)

    Gesslein, Bodil; Håkansson, Gisela; Gustafsson, Lotta

    2010-01-01

    Numerous studies have been performed aimed at limiting the extent of retinal injury after ischemia, but there is still no effective pharmacological treatment available. The aim of the present study was to examine the role of tumor necrosis factor (TNF)α and its receptors (TNF-R1 and TNF-R2), espe...

  2. Elevated interferon gamma expression in the central nervous system of tumour necrosis factor receptor 1-deficient mice with experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Wheeler, Rachel D; Zehntner, Simone P; Kelly, Lisa M

    2006-01-01

    Inflammation in the central nervous system (CNS) can be studied in experimental autoimmune encephalomyelitis (EAE). The proinflammatory cytokines interferon-gamma (IFN-gamma) and tumour necrosis factor (TNF) are implicated in EAE pathogenesis. Signals through the type 1 TNF receptor (TNFR1...

  3. Increased levels of soluble tumour necrosis factor receptor-I (P55) and decreased IgG1 reactivities in HIV-1 patients with cytomegalovirus disease

    DEFF Research Database (Denmark)

    Jakobsen, Palle Høy; Dodt, K K; Meyer, C N

    1998-01-01

    The purpose of the study was to investigate potential associations between tumour necrosis factor (TNF), soluble TNF receptors (sTNF-Rs), immunoglobulin (Ig)G subclasses and development of cytomegalovirus (CMV) disease amongst human immunodeficiency virus (HIV)-1 patients. We enrolled HIV-1...

  4. Evaluation of BCL-2 and transforming growth factor alpha ...

    African Journals Online (AJOL)

    Evaluation of BCL-2 and transforming growth factor alpha oncoproteins in patients with chronic hepatitis C infection: impact on hepatocellular carcinoma. Mahmoud I Hassan, Amal Abou El Fadle, Gamal M Kenawy, Fayda I Abdel Motaleb, Fatma M AbdelSalam ...

  5. Dynamic Arginine Methylation of Tumor Necrosis Factor (TNF) Receptor-associated Factor 6 Regulates Toll-like Receptor Signaling.

    Science.gov (United States)

    Tikhanovich, Irina; Kuravi, Sudhakiranmayi; Artigues, Antonio; Villar, Maria T; Dorko, Kenneth; Nawabi, Atta; Roberts, Benjamin; Weinman, Steven A

    2015-09-04

    Arginine methylation is a common post-translational modification, but its role in regulating protein function is poorly understood. This study demonstrates that, TNF receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase involved in innate immune signaling, is regulated by reversible arginine methylation in a range of primary and cultured cells. Under basal conditions, TRAF6 is methylated by the methyltransferase PRMT1, and this inhibits its ubiquitin ligase activity, reducing activation of toll-like receptor signaling. In response to toll-like receptor ligands, TRAF6 is demethylated by the Jumonji domain protein JMJD6. Demethylation is required for maximal activation of NF-κB. Loss of JMJD6 leads to reduced response, and loss of PRMT1 leads to basal pathway activation with subsequent desensitization to ligands. In human primary cells, variations in the PRMT1/JMJD6 ratio significantly correlate with TRAF6 methylation, basal activation of NF-κB, and magnitude of response to LPS. Reversible arginine methylation of TRAF6 by the opposing effects of PRMT1 and JMJD6 is, therefore, a novel mechanism for regulation of innate immune pathways. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  6. Transforming growth factor alpha and epidermal growth factor in laryngeal carcinomas demonstrated by immunohistochemistry

    DEFF Research Database (Denmark)

    Christensen, M E; Therkildsen, M H; Poulsen, Steen Seier

    1993-01-01

    the basal cell layer. The present investigation and our previous results confirm the existence of EGF receptors, TGF-alpha and EGF in laryngeal carcinomas. In addition, we conclude that the conditions do exist for growth factors to act through an autocrine system in poorly differentiated tumours and through......Fifteen laryngeal squamous cell carcinomas were investigated for the presence of transforming growth factor alpha (TGF-alpha) and epidermal growth factor (EGF) using immunohistochemical methods. In a recent study the same material was characterized for epidermal growth factor receptors (EGF...... receptors) which were confined predominantly to the undifferentiated cells. The expression of this growth factor system in malignant cells may play a role in carcinogenesis and/or tumour growth. All carcinomas were positive for TGF-alpha and 12 were positive for EGF. In moderately-to-well differentiated...

  7. First report of circulating microRNAs in tumour necrosis factor receptor-associated periodic syndrome (TRAPS.

    Directory of Open Access Journals (Sweden)

    Orso Maria Lucherini

    Full Text Available Tumor necrosis factor-receptor associated periodic syndrome (TRAPS is a rare autosomal dominant autoinflammatory disorder characterized by recurrent episodes of long-lasting fever and inflammation in different regions of the body, such as the musculo-skeletal system, skin, gastrointestinal tract, serosal membranes and eye. Our aims were to evaluate circulating microRNAs (miRNAs levels in patients with TRAPS, in comparison to controls without inflammatory diseases, and to correlate their levels with parameters of disease activity and/or disease severity. Expression levels of circulating miRNAs were measured by Agilent microarrays in 29 serum samples from 15 TRAPS patients carrying mutations known to be associated with high disease penetrance and from 8 controls without inflammatory diseases. Differentially expressed and clinically relevant miRNAs were detected using GeneSpring GX software. We identified a 6 miRNAs signature able to discriminate TRAPS from controls. Moreover, 4 miRNAs were differentially expressed between patients treated with the interleukin (IL-1 receptor antagonist, anakinra, and untreated patients. Of these, miR-92a-3p and miR-150-3p expression was found to be significantly reduced in untreated patients, while their expression levels were similar to controls in samples obtained during anakinra treatment. MiR-92b levels were inversely correlated with the number of fever attacks/year during the 1(st year from the index attack of TRAPS, while miR-377-5p levels were positively correlated with serum amyloid A (SAA circulating levels. Our data suggest that serum miRNA levels show a baseline pattern in TRAPS, and may serve as potential markers of response to therapeutic intervention.

  8. Expression of tumor necrosis factor receptor-associated protein 1 and its clinical significance in kidney cancer.

    Science.gov (United States)

    Si, Tong; Yang, Guosheng; Qiu, Xiaofu; Luo, Youhua; Liu, Baichuan; Wang, Bingwei

    2015-01-01

    To investigate the expression and clinical significance of TRAP1 (tumor necrosis factor receptor-associated protein 1) in kidney cancer. TRAP1 expression was detected in kidney cancer and normal kidney tissues by qRT-PCR and immunohistochemistry (IHC), respectively. Then, the correlation of TRAP1 expression with clinicopathological characters and patients' prognosis was evaluated in kidney cancer. IHC results revealed that the high-expression rates of TRAP1 in kidney cancer tissues and normal kidney tissues were 51.3% (41/80), 23.3% (7/30), and the difference was statistically significant (P=0.01). Also, TRAP1 mRNA level in kidney cancer was found to be significantly greater compared with those in normal kidney by qRT-PCR. In addition, TRAP1 expression in kidney cancer significantly correlated with lymph node metastasis and clinical stage (Pkidney cancer and correlates with patients prognosis, which may be served as a potential marker for the diagnosis and treatment of kidney cancer.

  9. Novel mutation identified in severe early-onset tumor necrosis factor receptor-associated periodic syndrome: a case report.

    Science.gov (United States)

    Radhakrishna, Suhas M; Grimm, Amy; Broderick, Lori

    2017-04-20

    Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS) is the second most common heritable autoinflammatory disease, typically presenting in pre-school aged children with fever episodes lasting 1-3 weeks. Systemic symptoms can include rash, myalgia, ocular inflammation, and serositis. Here we report an unusual presentation of TRAPS in a 7 month old girl who presented with only persistent fever. She was initially diagnosed with incomplete Kawasaki Disease and received IVIG and infliximab; however, her fevers quickly recurred. Subsequent testing revealed a urinary tract infection, but she did not improve despite appropriate therapy. As fever continued, she developed significant abdominal distension with imaging concerning for appendicitis, followed by hyperthermia and hemodynamic instability. Given her protracted clinical course and maternal history of a poorly defined inflammatory condition, an autoinflammatory disease was considered. Therapy with anakinra was initiated, resulting in rapid resolution of fever and normalization of inflammatory markers. She was found to have a previously unreported mutation, Thr90Pro, in the TNFRSF1A gene associated with TRAPS. This novel mutation was also confirmed in the patient's mother and maternal uncle. This report reviews a severe case of TRAPS in infancy associated with a novel mutation, Thr90Pro, in the TNFRSF1A gene, and emphasizes that autoinflammatory disease should be considered in the differential of infants with fever of unknown origin.

  10. Local Overexpression of V1a-Vasopressin Receptor Enhances Regeneration in Tumor Necrosis Factor-Induced Muscle Atrophy

    Directory of Open Access Journals (Sweden)

    Alessandra Costa

    2014-01-01

    Full Text Available Skeletal muscle atrophy occurs during disuse and aging, or as a consequence of chronic diseases such as cancer and diabetes. It is characterized by progressive loss of muscle tissue due to hypotrophic changes, degeneration, and an inability of the regeneration machinery to replace damaged myofibers. Tumor necrosis factor (TNF is a proinflammatory cytokine known to mediate muscle atrophy in many chronic diseases and to inhibit skeletal muscle regeneration. In this study, we investigated the role of Arg-vasopressin-(AVP-dependent pathways in muscles in which atrophy was induced by local overexpression of TNF. AVP is a potent myogenesis-promoting factor and is able to enhance skeletal muscle regeneration by stimulating Ca2+/calmodulin-dependent kinase and calcineurin signaling. We performed morphological and molecular analyses and demonstrated that local over-expression of the AVP receptor V1a enhances regeneration of atrophic muscle. By upregulating the regeneration/differentiation markers, modulating the inflammatory response, and attenuating fibrogenesis, the stimulation of AVP-dependent pathways creates a favourable environment for efficient and sustained muscle regeneration and repair even in the presence of elevated levels of TNF. This study highlights a novel in vivo role for AVP-dependent pathways, which may represent an interesting strategy to counteract muscle decline in aging or in muscular pathologies.

  11. Infliximab therapy balances regulatory T cells, tumour necrosis factor receptor 2 (TNFR2) expression and soluble TNFR2 in sarcoidosis

    Science.gov (United States)

    Hijdra, D.; Vorselaars, A. D. M.; Crommelin, H. A.; van Moorsel, C. H. M.; Grutters, J. C.; Claessen, A. M. E.

    2016-01-01

    Summary Sarcoidosis is a systemic granulomatous disease of unknown aetiology that most commonly affects the lungs. Although elevated levels of regulatory T cells (Tregs) have been reported, the extent to which they play a role in sarcoidosis pathogenesis remains unclear. Tumour necrosis factor (TNF) is thought to be one of the driving forces behind granuloma formation, illustrated by the efficacy of infliximab in severe sarcoidosis. Tregs express TNF receptor 2 (TNFR2) highly. Here, we examined the influence of infliximab therapy on Tregs and (soluble) TNFR2 levels in sarcoidosis, and correlated these with response to therapy. We observed that relative frequencies of Tregs were significantly higher in patients (n = 54) compared to healthy controls (n = 26; median 6·73 versus 4·36%; P infliximab therapy, suggesting a pathophysiological role of this T cell subset. Interestingly, sTNFR2 levels at baseline differed significantly between responders and non‐responders, making it a potential marker in predicting which patients might benefit from infliximab. PMID:27158798

  12. The role of tumor necrosis factor alpha in differentiation between malignant and non malignant pleural effusion

    Directory of Open Access Journals (Sweden)

    Heba M. Atef

    2016-07-01

    Conclusion: Pleural fluid level of TNF-α can be used in differentiating malignant from non malignant effusion. Also levels of TNF-α in the serum and pleural fluid could be useful as a complementary marker in the differential diagnosis of two most common types of exudates (tuberculous and malignant.

  13. Tigecycline reduced tumor necrosis factor alpha level and inhospital mortality in spontaneous supratentorial intracerebral hemorrhage

    Directory of Open Access Journals (Sweden)

    Mohamad Saekhu

    2016-07-01

    Full Text Available Background: The outcome of patients with spontaneous supratentorial intracerebral hemorrhage (SSICH is unsatisfactory. Inflammatory response secondary to brain injury as well as those resulted from surgical procedure were considered responsible of this outcome. This study was intended to elucidate the anti-inflammatory activity of tigecycline by measuring TNF-α level and its neuroprotective effect as represented by inhospital mortality rate.Methods: Patients with SSICH who were prepared for hematoma evacuation were randomized to receive either tigecycline (n=35 or fosfomycine (n=37 as prophylactic antibiotic. TNF-α level was measured in all subjects before surgery and postoperatively on day-1 and day-7. A repeated brain CT Scan was performed on postoperative day-7. The Glasgow outcome scale (GOS and length of stay (LOS were recorded at the time of hospital discharge. Data were analyzed using Mann-Whitney and Chi square test. Relative clinical effectiveness was measured by calculating the number needed to treat (NNT.Results: There was a significant difference regarding the proportion of subject who had  reduced TNF-α level on postoperative day-7 between the groups receiving tigecycline and fosfomycine (62% vs 29%, p=0.022. Decrease brain edema on CT control (86% vs 80%, p=0.580. Tigecycline administration showed a tendency of better clinical effectiveness in lowering inhospital mortality (17% vs 35%; p=0.083; OR=0.49; NNT=5 and worse clinical outcome / GOS ≤ 2 (20% vs 38% ; p=0.096; OR=0.41; NNT=6. LOS ≥ 15 hari ( 40% vs 27%; p=0.243; OR=1.81; NNT=8.Conclusion: Tigecycline showed anti-inflammatory and neuroprotective activities. These activities were associated with improved clinical outcome in patients with SSICH after hematoma evacuation.

  14. Transcutaneous cervical vagal nerve stimulation modulates cardiac vagal tone and tumor necrosis factor-alpha

    DEFF Research Database (Denmark)

    Brock, C; Brock, B; Aziz, Q

    2017-01-01

    The vagus nerve is a central component of cholinergic anti-inflammatory pathways. We sought to evaluate the effect of bilateral transcutaneous cervical vagal nerve stimulation (t-VNS) on validated parameters of autonomic tone and cytokines in 20 healthy subjects. 24 hours after t...

  15. MK-886 enhances tumour necrosis factor-alpha-induced differentiation and apoptosis

    Czech Academy of Sciences Publication Activity Database

    Štika, Jiří; Vondráček, Jan; Hofmanová, Jiřina; Šimek, V.; Kozubík, Alois

    2006-01-01

    Roč. 237, č. 2 (2006), s. 263-271 ISSN 0304-3835 R&D Projects: GA ČR(CZ) GA524/03/0766 Institutional research plan: CEZ:AV0Z50040507 Keywords : cell differentiation * leukaemia * HL-60 cells Subject RIV: BO - Biophysics Impact factor: 3.277, year: 2006

  16. Interleukin-6 and tumor necrosis factor-alpha gene polymorphisms in chronic idiopathic urticaria.

    Science.gov (United States)

    Tavakol, M; Amirzargar, A A; Movahedi, M; Aryan, Z; Bidoki, A Z; Gharagozlou, M; Aghamohammadi, A; Nabavi, M; Ahmadvand, A; Behniafard, N; Heidari, K; Soltani, S; Rezaei, N

    2014-01-01

    This study was performed to evaluate association of gene polymorphisms among proinflammatory cytokines and susceptibility to chronic idiopathic urticaria (CIU). Ninety patients with prolonged urticaria more than 6 weeks were included as case group. Single nucleotide polymorphisms (SNPs) of IL-6 (G/C -174, G/A nt565) and TNF-α (G/A -308, G/A -238) were evaluated, using polymerase chain reaction (PCR); and the results were compared to the control group. G allele was significantly higher in the patients at locus of -238 of promoter of TNF-α gene (p<0.001). Frequency of following genotypes were significantly lower in patients with CIU, compared to controls: AG at -308 and GA at -238 of TNF-α gene (p<0.05 and p<0.001, respectively), CG at -174 and GG at +565 of IL-6 gene (p<0.05). Additionally, following genotypes were more common among patients with CIU: GG at -308 and -238 of TNF-α gene (p<0.05 and p<0.001, respectively), GG at -174 and GA at +565 of IL-6 gene (p<0.05). Pro-inflammatory cytokine gene polymorphisms can affect susceptibility to CIU. TNF-α promoter polymorphisms as well as IL-6 gene polymorphisms are associated with CIU. Copyright © 2013 SEICAP. Published by Elsevier Espana. All rights reserved.

  17. Anti-tumour necrosis factor-alpha activity in Ixodes ricinus saliva

    Czech Academy of Sciences Publication Activity Database

    Koník, Peter; Slavíková, Veronika; Salát, Jiří; Řezníčková, Jana; Dvorožňáková, E.; Kopecký, Jan

    2006-01-01

    Roč. 28, č. 12 (2006), s. 649-656 ISSN 0141-9838 R&D Projects: GA ČR GA524/05/0811; GA MŠk(CZ) LC06009 Institutional research plan: CEZ:AV0Z60220518 Keywords : Ixodes ricinus * tick saliva * TNF Subject RIV: EC - Immunology Impact factor: 2.009, year: 2006

  18. Analysis of relationship between tumor necrosis factor alpha gene (g308a polymorphism with preterm labor

    Directory of Open Access Journals (Sweden)

    Lobat Jafarzadeh

    2013-01-01

    Conclusions: There is no significant association between PTD and either maternal or fetal TNF-α −308 polymorphism and frequency ofGAmutation is not significantly increased in mothers and neonates delivered preterm. It means that the presence of this mutation by itself does not modify the overall risk of PTD. Investigations on the combination of various polymorphisms indifferent genes are recommended to achieve more accurate results.

  19. A role for tumor necrosis factor-alpha in ischemia and ischemic preconditioning

    LENUS (Irish Health Repository)

    Watters, Orla

    2011-08-02

    Abstract During cerebral ischemia, elevation of TNF-α and glutamate to pathophysiological levels may induce dysregulation of normal synaptic processes, leading ultimately to cell death. Previous studies have shown that patients subjected to a mild transient ischemic attack within a critical time window prior to a more severe ischemic episode may show attenuation in the clinical severity of the stroke and result in a more positive functional outcome. Studies with organotypic hippocampal cultures and mixed primary hippocampal cultures have shown that prior incubation with low concentrations of glutamate and TNF-α increase the resistance of neurones to a subsequent insult from glutamate, AMPA and NMDA, while co-exposure of TNF-α and for example AMPA may have neuroprotective effects compared to cultures exposed to excitotoxic agents alone. In addition our work has shown that although glutamate and TNF-α pretreatment induces analogous levels of desensitisation of the intracellular calcium dynamics of neurons under resting conditions and in response to acute glutamate stimulation, their downstream signalling pathways involved in this response do not converge. Glutamate and TNF-α would appear to have opposing effects on resting Ca2+ levels which supports the proposal that they have distinct modes of preconditioning.

  20. Tumor necrosis factor alpha (TNF alpha) in human skin : A comparison of different antibodies for immunohistochemistry

    NARCIS (Netherlands)

    van der Laan, N; de Leij, LFMH; Buurman, W; Timens, W; ten Duis, HJ

    Conflicting results have been reported regarding the localization and presence of TNF alpha in normal human skin, To study TNF alpha expression, we tested a panel of antibodies directed against human TNF alpha, First, antibodies were tested for immunoreactivity on cytospots of isolated

  1. Reduction of Burn Progression with Topical Delivery of (Antitumor Necrosis Factor-alpha )-Hyaluronic Acid Conjugates

    Science.gov (United States)

    2012-01-01

    delivery of semapimod in a pig model,28 while systemic delivery of curcumin has shown a positive effect in reducing burn wound progression by 50% in a rat...1366–72. 48. Singer AJ, Taira BR, Lin F, Lim T, Anderson R, McClain SA, Clark RA. Curcumin reduces injury progression in a rat comb burn model. J

  2. Typical and severe tumor necrosis factor receptor-associated periodic syndrome in the absence of mutations in the TNFRSF1A gene: a case series.

    Science.gov (United States)

    Cantarini, Luca; Lucherini, Orso Maria; Cimaz, Rolando; Rigante, Donato; Baldari, Cosima Tatiana; Laghi Pasini, Franco; Galeazzi, Mauro

    2012-12-01

    Tumor necrosis factor receptor-1-associated periodic syndrome (TRAPS) is the most common autosomal dominant autoinflammatory disorder and is caused by mutations in the TNFRSF1A gene encoding the 55-kDa receptor for tumor necrosis factor (TNF)-α. TRAPS is characterized by recurrent attacks of fever, typically lasting from 1 to 3 weeks. In addition to fever, common clinical features include periorbital edema, a migratory erythematous plaque simulating erysipela with underlying myalgia, and arthralgia or arthritis. Serosal membrane inflammation is also a common feature, usually in the form of polyserositis. To date, at least 40 different TNFRSF1A mutations have been identified, but few patients with symptoms highly suggestive of TRAPS with no mutations in the TNFRSF1A gene have recently been described, thus suggesting that not all mutations are yet known or that alternative mechanisms might be involved in the pathogenesis of the disease. We report on three such patients here.

  3. Immunoreactive transforming growth factor alpha and epidermal growth factor in oral squamous cell carcinomas

    DEFF Research Database (Denmark)

    Therkildsen, M H; Poulsen, Steen Seier; Bretlau, P

    1993-01-01

    , the cells above the basal cell layer were positive for both TGF-alpha and EGF. The same staining pattern was observed in oral mucosa obtained from healthy persons. In moderately to well differentiated carcinomas, the immunoreactivity was mainly confined to the cytologically more differentiated cells, thus......Forty oral squamous cell carcinomas have been investigated immunohistochemically for the presence of transforming growth factor alpha (TGF-alpha) and epidermal growth factor (EGF). The same cases were recently characterized for the expression of EGF-receptors. TGF-alpha was detected...... previous results confirms the existence of TGF-alpha, EGF, and EGF-receptors in the majority of oral squamous cell carcinomas and their metastases....

  4. The role of tumor necrosis factor-α and TNF-α receptors in cerebral arteries following cerebral ischemia in rat

    DEFF Research Database (Denmark)

    Maddahi, Aida; Kruse, Lars S; Chen, Qing-Wen

    2011-01-01

    Tumour necrosis factor-α (TNF-α) is a pleiotropic pro-inflammatory cytokine, which is rapidly upregulated in the brain after injury. TNF-α acts by binding to its receptors, TNF-R1 (p55) and TNF-R2 (p75), on the cell surface. The aim of this study was first to investigate if there is altered expre...... expression of TNF-α and TNF-α receptors in cerebral artery walls following global or focal ischemia, and after organ culture. Secondly, we asked if the expression was regulated via activation of the MEK-ERK1/2 pathway....

  5. The role of tumor necrosis factor-α and TNF-α receptors in cerebral arteries following cerebral ischemia in rat

    DEFF Research Database (Denmark)

    Maddahi, Aida; Kruse, Lars S; Chen, Qing-Wen

    2011-01-01

    Tumour necrosis factor-a (TNF-a) is a pleiotropic pro-inflammatory cytokine, which is rapidly upregulated in the brain after injury. TNF-a acts by binding to its receptors, TNF-R1 (p55) and TNF-R2 (p75), on the cell surface. The aim of this study was first to investigate if there is altered expre...... expression of TNF-a and TNF-a receptors in cerebral artery walls following global or focal ischemia, and after organ culture. Secondly, we asked if the expression was regulated via activation of the MEK-ERK1/2 pathway....

  6. Serum interleukin-18 and soluble tumour necrosis factor receptor 2 are associated with disease severity in patients with paracoccidioidomycosis

    Science.gov (United States)

    Corvino, C L; Mamoni, R L; Fagundes, G Z Z; Blotta, M H S L

    2007-01-01

    Interleukin (IL)-18 is a proinflammatory cytokine of the IL-1 superfamily that exhibits broad functional effects in innate and acquired immune responses and which has been found in high levels in several chronic inflammatory and autoimmune diseases. Over-expression of IL-18 may promote early resolution of infection or could promote a detrimental exaggerated immune response. The aim of this study was to determine serum levels of IL-18 and other inflammatory mediators [IL-12, soluble intercellular adhesion molecule 1 (sICAM-1), soluble tumour necrosis factor receptor 1 (TNF-RI), sTNF-RII, CXC chemokine ligand 9 (CXCL9), CXCL10] at baseline and after anti-fungal therapy in serum from patients with juvenile (JF) and adult (AF) forms of paracoccidioidomycosis (PCM), as well as in healthy controls (C), and to assess their possible relationships to the severity of disease. IL-18 and sTNF-RII levels in patients with the JF of PCM were significantly higher than those in the AF and controls. In relation to sICAM-1, no difference was observed between JF and AF patients but both presented higher levels than controls. sTNF-RI levels were higher in patients with PCM than in controls, and significantly higher concentrations were detected in AF patients compared to JF patients. Moreover, IL-12 and chemokines CXCL9 and CXCL10 were also higher in patients than in controls. In JF patients IL-18 levels correlated significantly with sICAM-1 (r = 0·62, P < 0·0001), sTNF-RI (r = 0·63, P < 0·0001), sTNF-RII (r = 0·51, P = 0·02), as well as with clinical severity. The results suggest the value of serum IL-18 and sTNF-Rs levels as a parameter of PCM severity and may support a possible role for them in the pathogenesis of the disease. PMID:17302897

  7. High serum soluble tumor necrosis factor receptor 1 predicts poor treatment response in acute-stage schizophrenia.

    Science.gov (United States)

    Nishimon, Shohei; Ohnuma, Tohru; Takebayashi, Yuto; Katsuta, Narimasa; Takeda, Mayu; Nakamura, Toru; Sannohe, Takahiro; Higashiyama, Ryoko; Kimoto, Ayako; Shibata, Nobuto; Gohda, Tomohito; Suzuki, Yusuke; Yamagishi, Sho-Ichi; Tomino, Yasuhiko; Arai, Heii

    2017-06-02

    Inflammation may be involved in the pathophysiology of schizophrenia. However, few cross-sectional or longitudinal studies have examined changes in biomarker expression to evaluate diagnostic and prognostic efficacy in acute-stage schizophrenia. We compared serum inflammatory biomarker concentrations in 87 patients with acute-stage schizophrenia on admission to 105 age-, sex-, and body mass index (BMI)-matched healthy controls. The measured biomarkers were soluble tumor necrosis factor receptor 1 (sTNFR1) and adiponectin, which are associated with inflammatory responses, and pigment epithelium-derived factor (PEDF), which has anti-inflammatory properties. We then investigated biomarker concentrations and associations with clinical factors in 213 patients (including 42 medication-free patients) and 110 unmatched healthy controls to model conditions typical of clinical practice. Clinical symptoms were assessed using the Brief Psychiatric Rating Scale and Global Assessment of Function. In 121 patients, biomarker levels and clinical status were evaluated at both admission and discharge. Serum sTNFR1 was significantly higher in patients with acute-stage schizophrenia compared to matched controls while no significant group differences were observed for the other markers. Serum sTNFR1 was also significantly higher in the 213 patients compared to unmatched controls. The 42 unmedicated patients had significantly lower PEDF levels compared to controls. Between admission and discharge, sTNFR1 levels decreased significantly; however, biomarker changes did not correlate with clinical symptoms. The discriminant accuracy of sTNFR1 was 93.2% between controls and patients, showing no symptom improvement during care. Inflammation and a low-level anti-inflammatory state may be involved in both schizophrenia pathogenesis and acute-stage onset. High serum sTNFR1 in the acute stage could be a useful prognostic biomarker for treatment response in clinical practice. Copyright © 2017

  8. Expression of Tumor Necrosis Factor Receptor 2 Characterizes TLR9-Driven Formation of Interleukin-10-Producing B Cells

    Directory of Open Access Journals (Sweden)

    Olga Ticha

    2018-01-01

    Full Text Available B cell-derived interleukin-10 (IL-10 production has been described as a hallmark for regulatory function in B lymphocytes. However, there is an ongoing debate on the origin of IL-10-secreting B cells and lack of specific surface markers has turned into an important obstacle for studying human B regulatory cells. In this study, we propose that tumor necrosis factor receptor 2 (TNFR2 expression can be used for enrichment of IL-10-secreting B cells. Our data confirm that IL-10 production can be induced by TLR9 stimulation with CpG ODN and that IL-10 secretion accompanies differentiation of peripheral blood B cells into plasma blasts. We further show that CpG ODN stimulation induces TNFR2 expression, which correlates with IL-10 secretion and terminal differentiation. Indeed, flow cytometric sorting of TNFR2+ B cells revealed that TNFR2+ and TNFR2− fractions correspond to IL-10+ and IL-10− fractions, respectively. Furthermore, CpG-induced TNFR2+ B cells were predominantly found in the IgM+ CD27+ B cell subset and spontaneously released immunoglobulin. Finally, our data corroborate the functional impact of TNFR2 by demonstrating that stimulation with a TNFR2 agonist significantly augments IL-10 and IL-6 production in B cells. Altogether, our data highlight a new role for TNFR2 in IL-10-secreting human B lymphocytes along with the potential to exploit this finding for sorting and isolation of this currently ill-defined B cell subset.

  9. Tumor necrosis factor receptor 1-dependent depletion of mucus in immature small intestine: a potential role in neonatal necrotizing enterocolitis.

    Science.gov (United States)

    McElroy, Steven J; Prince, Lawrence S; Weitkamp, Jörn-Hendrik; Reese, Jeff; Slaughter, James C; Polk, D Brent

    2011-10-01

    Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in premature infants. NEC is believed to occur when intestinal bacteria invade the intestinal epithelial layer, causing subsequent inflammation and tissue necrosis. Mucins are produced and secreted by epithelial goblet cells as a key component of the innate immune system and barrier function of the intestinal tract that help protect against bacterial invasion. To better understand the role of mucins in NEC, we quantified the number of mucus-containing small intestinal goblet cells present in infants with NEC and found they had significantly fewer goblet cells and Paneth cells compared with controls. To test whether inflammation has a developmentally dependent effect on intestinal goblet cells, TNF-α was injected into mice at various stages of intestinal development. TNF-α caused a loss of mucus-containing goblet cells only in immature mice and induced Muc2 and Muc3 mRNA upregulation only in mature ileum. Only minimal changes were seen in apoptosis and in expression of markers of goblet cell differentiation. TNF-α increased small intestinal mucus secretion and goblet cell hypersensitivity to prostaglandin E2 (PGE(2)), a known mucus secretagogue produced by macrophages. These TNF-α-induced changes in mucus mRNA levels required TNF receptor 2 (TNFR2), whereas TNF-α-induced loss of mucus-positive goblet cells required TNFR1. Our findings of developmentally dependent TNF-α-induced alterations on intestinal mucus may help explain why NEC is predominantly found in premature infants, and TNF-α-induced alterations of the intestinal innate immune system and barrier functions may play a role in the pathogenesis of NEC itself.

  10. Tumor Necrosis Factor Receptor 2 Restricts the Pathogenicity of CD8(+) T Cells in Mice With Colitis.

    Science.gov (United States)

    Punit, Shivesh; Dubé, Philip E; Liu, Cambrian Y; Girish, Nandini; Washington, M Kay; Polk, D Brent

    2015-10-01

    Tumor necrosis factor receptor 2 (TNFR2, Tnfrsf1b) regulates multiple aspects of immune function, but little is known about its role in the immunopathogenesis of inflammatory bowel disease (IBD). We investigated whether TNFR2 restricts the activity of specific immune cell subtypes to protect against the development of colitis in mice. Tnfr2(-/-) mice were crossed with interleukin (Il) 10(-/-) mice, which spontaneously develop colitis, to generate Il10(-/-)Tnfr2(-/-) mice. Colonic tissues were collected from Il10(-/-)Tnfr2(-/-) mice along with Il10(-/-) mice (controls) and analyzed by flow cytometry and histology. Bone marrow was transplanted into Il10(-/-) and Il10(-/-)Tnfr2(-/-) mice from Il10(-/-) or Il10(-/-)Tnfr2(-/-) donors by intravenous injection. CD8(+) T cells were neutralized in Il10(-/-)Tnfr2(-/-) mice by intraperitoneal injection of anti-CD8 or isotype control antibodies. Colitis was induced in Rag2(-/-) mice by intravenous injections of naïve CD8(+) T cells isolated from C57BL/6 or Tnfr2(-/-) mice. Il10(-/-)Tnfr2(-/-) mice spontaneously developed more severe colitis compared with Il10(-/-) controls, characterized by selective expansion of colonic CD8(+) T cells. Transplantation of TNFR2-deficient bone marrow resulted in significantly increased incidence and severity of colitis. Transcriptome analyses showed that the expression of genes regulated by TNFR2 were specific to CD8(+) T cells and included genes associated with risk for IBD. Depletion of CD8(+) T cells from Il10(-/-)Tnfr2(-/-) mice prevented colonic inflammation. Adoptive transfer of TNFR2-null naïve CD8(+) T cells compared with CD8(+) T cells from control mice increased the severity of colitis that developed in Rag2(-/-) mice. TNFR2 protects mice from colitis by inhibiting the expansion of colonic CD8(+) T cells. TNFR2 regulates expression of genes that regulate CD8(+) T cells and have been associated with susceptibility to IBD. Disruption in TNFR2 signaling might therefore be associated

  11. ST6Gal-I sialyltransferase promotes tumor necrosis factor (TNF)-mediated cancer cell survival via sialylation of the TNF receptor 1 (TNFR1) death receptor.

    Science.gov (United States)

    Holdbrooks, Andrew T; Britain, Colleen M; Bellis, Susan L

    2018-02-02

    Activation of the tumor necrosis factor receptor 1 (TNFR1) death receptor by TNF induces either cell survival or cell death. However, the mechanisms mediating these distinct outcomes remain poorly understood. In this study, we report that the ST6Gal-I sialyltransferase, an enzyme up-regulated in numerous cancers, sialylates TNFR1 and thereby protects tumor cells from TNF-induced apoptosis. Using pancreatic and ovarian cancer cells with ST6Gal-I knockdown or overexpression, we determined that α2-6 sialylation of TNFR1 had no effect on early TNF-induced signaling events, including the rapid activation of NF-κB, c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and Akt (occurring within 15 min). However, upon extended TNF treatment (6-24 h), cells with high ST6Gal-I levels exhibited resistance to TNF-induced apoptosis, as indicated by morphological evidence of cell death and decreased activation of caspases 8 and 3. Correspondingly, at these later time points, high ST6Gal-I expressers displayed sustained activation of the survival molecules Akt and NF-κB. Additionally, extended TNF treatment resulted in the selective enrichment of clonal variants with high ST6Gal-I expression, further substantiating a role for ST6Gal-I in cell survival. Given that TNFR1 internalization is known to be essential for apoptosis induction, whereas survival signaling is initiated by TNFR1 at the plasma membrane, we examined TNFR1 localization. The α2-6 sialylation of TNFR1 was found to inhibit TNF-induced TNFR1 internalization. Thus, by restraining TNFR1 at the cell surface via sialylation, ST6Gal-I acts as a functional switch to divert signaling toward survival. These collective findings point to a novel glycosylation-dependent mechanism that regulates the cellular response to TNF and may promote cancer cell survival within TNF-rich tumor microenvironments. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

  12. Receptor-mediated endocytosis is not required for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis.

    Science.gov (United States)

    Kohlhaas, Susan L; Craxton, Andrew; Sun, Xiao-Ming; Pinkoski, Michael J; Cohen, Gerald M

    2007-04-27

    Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is selectively toxic to tumor compared with normal cells. Other members of the TNF family of death ligands (TNF, CD95L) engage their respective receptors (TNF-R1 and CD95), resulting in internalization of receptor and ligand and recruitment of adaptor proteins to the caspase activation platform known as the death-inducing signaling complex (DISC). Recently, TNF-R1 and CD95 have been shown to induce apoptosis with an absolute requirement for internalization of their corresponding receptors in the formation of a DISC. We show that TRAIL and its receptors are rapidly endocytosed in a time- and concentration-dependent manner. Blockade of receptor internalization with hyperosmotic sucrose did not inhibit TRAIL-induced apoptosis but, rather, amplified the apoptotic signaling of TRAIL. Plate-bound and soluble TRAIL induced similar levels of apoptosis. Together these results suggest that neither ligand nor receptor internalization is required for TRAIL-induced apoptosis. Internalization of TRAIL is mediated primarily by clathrin-dependent endocytosis and also by clathrin-independent pathways. Inhibition of clathrin-dependent internalization by overexpression of dominant negative forms of dynamin or AP180 did not inhibit TRAIL-induced apoptosis. Consistent with the finding that neither internalization of TRAIL nor its receptors is required for transmission of its apoptotic signal, recruitment of FADD (Fas-associated death domain) and procaspase-8 to form the TRAIL-associated DISC occurred at 4 degrees C, independent of endocytosis. Our findings demonstrate that TRAIL and TRAIL receptor 1/2, unlike TNF-TNF-R1 or CD95L-CD95, do not require internalization for formation of the DISC, activation of caspase-8, or transmission of an apoptotic signal in BJAB type I cells.

  13. The Link Between Oxidative Stress Response and Tumor Necrosis ...

    African Journals Online (AJOL)

    Thyroid hormones are essential for normal organ growth, development and function. They regulate the basal metabolic rate of different types of cells, including hepatocytes. Oxidative stress plays an essential role in the pathogenesis of thyroid disorders and disturbed tissue functions. Tumor necrosis factor-alpha (TNF-α) is a ...

  14. NOVEL CHARACTERIZATION OF bEnd.3 CELLS THAT EXPRESS LYMPHATIC VESSEL ENDOTHELIAL HYALURONAN RECEPTOR-1

    OpenAIRE

    Yuen, D.; Leu, R.; Tse, J.; Wang, S.; Chen, L.L.; Chen, L.

    2014-01-01

    Murine bEnd.3 endothelioma cell line has been widely used in vascular research and here we report the novel finding that bEnd.3 cells express lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) and vascular endothelial growth factor receptor-3 (VEGFR-3). Moreover, these cells express progenitor cell markers of Sca-1 and CD133. Upon stimulation with tumor necrosis factor-alpha (TNF-α), the bEnd.3 cells demonstrate enhanced formation of capillary-type tubes, which express LYVE-1. As the...

  15. Tumor necrosis factor receptor 1-dependent depletion of mucus in immature small intestine: a potential role in neonatal necrotizing enterocolitis

    OpenAIRE

    McElroy, Steven J.; Prince, Lawrence S.; Weitkamp, Jörn-Hendrik; Reese, Jeff; Slaughter, James C.; Polk, D. Brent

    2011-01-01

    Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in premature infants. NEC is believed to occur when intestinal bacteria invade the intestinal epithelial layer, causing subsequent inflammation and tissue necrosis. Mucins are produced and secreted by epithelial goblet cells as a key component of the innate immune system and barrier function of the intestinal tract that help protect against bacterial invasion. To better understand the role of mucins in NEC, we quant...

  16. Co-culture with bone marrow stromal cells protects PC12 neuronal cells from tumor necrosis factor-α-induced apoptosis by inhibiting the tumor necrosis factor receptor/caspase signaling pathway.

    Science.gov (United States)

    Li, Li; Wang, Jing; Tang, Ling; Yu, Xin; Sui, Yi; Zhang, Chaodong

    2015-07-01

    Bone marrow stromal cells (BMSCs), derived from the mesoderm, have been applied in the repair and reconstruction of injured tissues. The present study was conducted to explore the effects of BMSCs on cell viability of tumor necrosis factor-α (TNF-α)-stimulated PC12 cells. PC12 cells were co-cultured with BMSCs under TNF-α treatment, with normal PC12 cells as controls. Results from an MTT assay indicated that BMSCs significantly increased cell growth and proliferation of TNF-α-treated PC12 cells (survival rates were 56.71 and 76.86% for the positive control (PC) and co-culture group, respectively). Furthermore, Annexin V/propidium iodide staining and flow cytometric analysis demonstrated that TNF-α increased PC12-cell apoptosis from 3.49 to 40.74% in the negative control and PC group, and the apoptotic rate was significantly reduced upon co-culture with BMSCs to 16.97%. In addition, data from reverse transcription-quantitative polymerase chain reaction and western blot analyses illustrated that TNF-α-induced upregulation in TNF receptor (TNFR)-1 (TNFR1) and caspase-8 expression in PC12 cells were partially reversed by co-culture with BMSCs. In conclusion, the present study suggested that BMSCs protect PC12 cells against stimulation with TNF-α, which is partially mediated through the TNFR/caspase signaling pathway. The results of the present study also suggested a therapeutic use of BMSCs in clinical neurodegenerative diseases.

  17. Effect of 3-month L-arginine supplementation on insulin resistance and tumor necrosis factor activity in patients with visceral obesity.

    Science.gov (United States)

    Bogdanski, P; Suliburska, J; Grabanska, K; Musialik, K; Cieslewicz, A; Skoluda, A; Jablecka, A

    2012-06-01

    The role of tumor necrosis factor alpha (TNF-alpha), one of the adipose tissue products, in the pathogenesis of insulin resistance is well-documented. Many recent studies have shown beneficial influence of L-arginine supplementation on cardiovascular system. However, molecular mechanisms of its positive actions are not fully elucidated. The aim of the study was to evaluate the influence of L-arginine supplementation on tumor necrosis factor alpha, insulin resistance and selected anthropometric and biochemical parameters in patients with visceral obesity. 60 patients with visceral obesity were randomly assigned to either receive 9 g of L-arginine or placebo for 3 months. 20 healthy lean subjects were used as control. Selected anthropometrical measurements and blood biochemical analyses were performed at baseline and after 3-months. TNF-alpha and its soluble receptor 2 (sTNFR2) were assessed in both treated groups. Insulin resistance in the participants was evaluated according to the homeostasis model assessment-insulin resistance (HOMA-IR) protocol. The concentration of insulin, TNF-a and sTNFR2 and HOMA-IR level in both obese groups significantly exceeded these observed in the control. Basal TNF-alpha and sTNFR2 concentrations were positively correlated with basal body mass index (BMI), waist circumference, percent of body fat and HOMA-IR. We found that 3-month L-arginine supplementation resulted in significant decrease of HOMA-IR and insulin concentration. Only insignificant tendency to decrease of TNF-alpha and sTNFR2 was observed. Our results confirm TNF-alpha role in the complex pathogenesis of insulin resistance in patients with visceral obesity. 3-months L-arginine supplementation in a dose of 9 g improves insulin sensitivity in patients with visceral obesity with no impact on tumor necrosis factor alpha concentration.

  18. Comparison of drug and cell-based delivery: engineered adult mesenchymal stem cells expressing soluble tumor necrosis factor receptor II prevent arthritis in mouse and rat animal models.

    Science.gov (United States)

    Liu, Linda N; Wang, Gang; Hendricks, Kyle; Lee, Keunmyoung; Bohnlein, Ernst; Junker, Uwe; Mosca, Joseph D

    2013-05-01

    Rheumatoid arthritis (RA) is a systemic autoimmune disease with unknown etiology where tumor necrosis factor-α (TNFα) plays a critical role. Etanercept, a recombinant fusion protein of human soluble tumor necrosis factor receptor II (hsTNFR) linked to the Fc portion of human IgG1, is used to treat RA based on the rationale that sTNFR binds TNFα and blocks TNFα-mediated inflammation. We compared hsTNFR protein delivery from genetically engineered human mesenchymal stem cells (hMSCs) with etanercept. Blocking TNFα-dependent intercellular adhesion molecule-1 expression on transduced hMSCs and inhibition of nitric oxide production from TNFα-treated bovine chondrocytes by conditioned culture media from transduced hMSCs demonstrated the functionality of the hsTNFR construction. Implanted hsTNFR-transduced mesenchymal stem cells (MSCs) reduced mouse serum circulating TNFα generated from either implanted TNFα-expressing cells or lipopolysaccharide induction more effectively than etanercept (TNFα, 100%; interleukin [IL]-1α, 90%; and IL-6, 60% within 6 hours), suggesting faster clearance of the soluble tumor necrosis factor receptor (sTNFR)-TNFα complex from the animals. In vivo efficacy of sTNFR-transduced MSCs was illustrated in two (immune-deficient and immune-competent) arthritic rodent models. In the antibody-induced arthritis BalbC/SCID mouse model, intramuscular injection of hsTNFR-transduced hMSCs reduced joint inflammation by 90% compared with untransduced hMSCs; in the collagen-induced arthritis Fischer rat model, both sTNFR-transduced rat MSCs and etanercept inhibited joint inflammation by 30%. In vitro chondrogenesis assays showed the ability of TNFα and IL1α, but not interferon γ, to inhibit hMSC differentiation to chondrocytes, illustrating an additional negative role for inflammatory cytokines in joint repair. The data support the utility of hMSCs as therapeutic gene delivery vehicles and their potential to be used in alleviating inflammation

  19. The Significance of Tumor Necrosis Factor Receptor Type II in CD8+Regulatory T Cells and CD8+Effector T Cells.

    Science.gov (United States)

    Ye, Lin-Lin; Wei, Xiao-Shan; Zhang, Min; Niu, Yi-Ran; Zhou, Qiong

    2018-01-01

    Tumor necrosis factor (TNF) is a pleiotropic cytokine that has both pro-inflammatory and anti-inflammatory functions. The biological functions of TNF are mediated by two receptors, TNF receptor type I (TNFR1) and TNF receptor type II (TNFR2). TNFR1 is expressed universally on almost all cell types and has been extensively studied, whereas TNFR2 is mainly restricted to immune cells and some tumor cells and its role is far from clarified. Studies have shown that TNFR2 mediates the stimulatory activity of TNF on CD4 + Foxp3 + regulatory T cells (Tregs) and CD8 + Foxp3 + Tregs, and is involved in the phenotypic stability, proliferation, activation, and suppressive activity of Tregs. TNFR2 can also be expressed on CD8 + effector T cells (Teffs), which delivers an activation signal and cytotoxic ability to CD8 + Teffs during the early immune response, as well as an apoptosis signal to terminate the immune response. TNFR2-induced abolition of TNF receptor-associated factor 2 (TRAF2) degradation may play an important role in these processes. Consequently, due to the distribution of TNFR2 and its pleiotropic effects, TNFR2 appears to be critical to keeping the balance between Tregs and Teffs, and may be an efficient therapeutic target for tumor and autoimmune diseases. In this review, we summarize the biological functions of TNFR2 expressed on CD8 + Foxp3 + Tregs and CD8 + Teffs, and highlight how TNF uses TNFR2 to coordinate the complex events that ultimately lead to efficient CD8 + T cell-mediated immune responses.

  20. Antibodies to a soluble form of a tumor necrosis factor (TNF) receptor have TNF-like activity

    DEFF Research Database (Denmark)

    Engelmann, H; Holtmann, H; Brakebusch, C

    1990-01-01

    lack TNF-like activities, but acquire them upon cross-linking with anti-F(ab)2 antibodies, suggesting that the ability of the anti-TBPI antibodies to mimic TNF correlates with their ability to cross-link the TNF receptors. This notion was further supported by data obtained in a comparative study...

  1. Repression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL but not its receptors during oral cancer progression

    Directory of Open Access Journals (Sweden)

    Muller Susan

    2007-06-01

    Full Text Available Abstract Background TRAIL plays an important role in host immunosurveillance against tumor progression, as it induces apoptosis of tumor cells but not normal cells, and thus has great therapeutic potential for cancer treatment. TRAIL binds to two cell-death-inducing (DR4 and DR5 and two decoy (DcR1, and DcR2 receptors. Here, we compare the expression levels of TRAIL and its receptors in normal oral mucosa (NOM, oral premalignancies (OPM, and primary and metastatic oral squamous cell carcinomas (OSCC in order to characterize the changes in their expression patterns during OSCC initiation and progression. Methods DNA microarray, immunoblotting and immunohistochemical analyses were used to examine the expression levels of TRAIL and its receptors in oral epithelial cell lines and in archival tissues of NOM, OPM, primary and metastatic OSCC. Apoptotic rates of tumor cells and tumor-infiltrating lymphocytes (TIL in OSCC specimens were determined by cleaved caspase 3 immunohistochemistry. Results Normal oral epithelia constitutively expressed TRAIL, but expression was progressively lost in OPM and OSCC. Reduction in DcR2 expression levels was noted frequently in OPM and OSCC compared to respective patient-matched uninvolved oral mucosa. OSCC frequently expressed DR4, DR5 and DcR1 but less frequently DcR2. Expression levels of DR4, DR5 and DcR1 receptors were not significantly altered in OPM, primary OSCC and metastatic OSCC compared to patient-matched normal oral mucosa. Expression of proapoptotic TRAIL-receptors DR4 and DR5 in OSCC seemed to depend, at least in part, on whether or not these receptors were expressed in their parental oral epithelia. High DR5 expression in primary OSCC correlated significantly with larger tumor size. There was no significant association between TRAIL-R expression and OSSC histology grade, nodal status or apoptosis rates of tumor cells and TIL. Conclusion Loss of TRAIL expression is an early event during oral

  2. Duration and severity of symptoms and levels of plasma interleukin-1 receptor antagonist, soluble tumor necrosis factor receptor, and adhesion molecules in patients with common cold treated with zinc acetate.

    Science.gov (United States)

    Prasad, Ananda S; Beck, Frances W J; Bao, Bin; Snell, Diane; Fitzgerald, James T

    2008-03-15

    Zinc lozenges have been used for treatment of the common cold; however, the results remain controversial. Fifty ambulatory volunteers were recruited within 24 h of developing symptoms of the common cold for a randomized, double-blind, placebo-controlled trial of zinc. Participants took 1 lozenge containing 13.3 mg of zinc (as zinc acetate) or placebo every 2-3 h while awake. The subjective scores for common cold symptoms were recorded daily. Plasma zinc, soluble interleukin (IL)-1 receptor antagonist (sIL-1ra), soluble tumor necrosis factor receptor 1, soluble vascular endothelial cell adhesion molecule, and soluble intercellular adhesion molecule (sICAM)-1 were assayed on days 1 and 5. Compared with the placebo group, the zinc group had a shorter mean overall duration of cold (4.0 vs. 7.1 days; P cold symptoms. We related the improvement in cold symptoms to the antioxidant and anti-inflammatory properties of zinc.

  3. Prognostic significance of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor expression in patients with breast cancer.

    Science.gov (United States)

    Ganten, Tom M; Sykora, Jaromir; Koschny, Ronald; Batke, Emanuela; Aulmann, Sebastian; Mansmann, Ulrich; Stremmel, Wolfgang; Sinn, Hans-Peter; Walczak, Henning

    2009-10-01

    TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis upon binding to TRAIL receptors 1 and 2 (TRAIL-R1/DR4 and TRAIL-R2/DR5). TRAIL-R3 (DcR1) and TRAIL-R4 (DcR2) have no or only a truncated cytoplasmic death domain. Consequently, they cannot induce apoptosis and instead have been proposed to inhibit apoptosis induction by TRAIL. Agonists for the apoptosis-inducing TRAIL-R1 and TRAIL-R2 are currently tested in clinical trials. To determine the expression pattern of all surface-bound TRAIL receptors and their prognostic clinical value, we investigated tumour samples of 311 patients with breast cancer by immunohistochemistry. TRAIL receptor expression profiles were correlated with clinico-pathological data, disease-free survival and overall survival. TRAIL-R1 was more strongly expressed in better differentiated tumours, and correlated positively with surrogate markers of a better prognosis (hormone receptor status, Bcl-2, negative nodal status), but negatively with the expression of Her2/neu and the proliferation marker Ki67. In contrast, TRAIL-R2 and TRAIL-R4 expression correlated with higher tumour grades, higher Ki67 index, higher Her2/neu expression and a positive nodal status at the time of diagnosis, but with lower expression of Bcl-2. Thus, the TRAIL receptor expression pattern was predictive of nodal status. Patients with grade 1 and 2 tumours, who had TRAIL-R2 but no TRAIL-R1, showed a positive lymph node status in 47% of the cases. Vice versa, only 19% had a positive nodal status with high TRAIL-R1 but low TRAIL-R2. Most strikingly, TRAIL-R4 and -R2 expression negatively correlated with overall survival of breast cancer patients. Although TRAIL-R2 correlated with more aggressive tumour behaviour, mammary carcinoma could be sensitised to TRAIL-R2-induced apoptosis, suggesting that TRAIL-R2 might therefore be used to therapeutically target such tumours. Hence, determination of the TRAIL receptor expression profile may aid in defining which breast

  4. Disruption of Tumor Necrosis Factor Receptor-Associated Factor 5 Exacerbates Murine Experimental Colitis via Regulating T Helper Cell-Mediated Inflammation.

    Science.gov (United States)

    Shang, Jian; Li, Lixia; Wang, Xiaobing; Pan, Huaqin; Liu, Shi; He, Ruohang; Li, Jin; Zhao, Qiu

    2016-01-01

    Tumor necrosis factor (TNF) receptor-associated factor 5 (TRAF5) is a key mediator of TNF receptor superfamily members and is important in both T helper (Th) cell immunity and the regulation of multiple signaling pathways. To clarify TRAF5's influence on inflammatory bowel diseases (IBDs), we investigated TRAF5 deficiency's effect on dextran sulfate sodium- (DSS-) induced colitis. Colitis was induced in TRAF5 knockout (KO) mice and their wild-type (WT) littermates by administering 3% DSS orally for 7 days. The mice were then sacrificed, and their colons were removed. Our data suggested that KO mice were more susceptible to DSS-induced colitis. TRAF5 deficiency significantly enhanced IFN-γ, IL-4, and IL-17a mRNA and protein levels in the colons of DSS-fed mice, and the mRNA expression of T-bet and GATA-3 was also markedly elevated. However, ROR-α and ROR-γt mRNA levels did not differ between DSS-induced KO and WT mice. Flow cytometry showed increased frequencies of Th2 and IFN-γ/IL-17a-coproducing CD4(+) T cells in the colons of DSS-induced KO mice. Additionally, TRAF5 deficiency significantly enhanced the activation of NF-κB in CD4(+) T cells after DSS administration. These results indicated that TRAF5 deficiency significantly aggravated DSS-induced colitis, most likely by regulating Th cell-mediated inflammation.

  5. Tumour necrosis factor-induced uveitis in the Lewis rat is associated with intraocular interleukin 6 production

    NARCIS (Netherlands)

    de Vos, A. F.; van Haren, M. A.; Verhagen, C.; Hoekzema, R.; Kijlstra, A.

    1995-01-01

    Lewis rats were injected with recombinant murine tumour necrosis factor-alpha either intravitreally (0.08-50 ng) or intracardially (1 microgram). The intraocular inflammatory response induced by tumour necrosis factor was examined by slit-lamp and protein extravasation into aqueous humor was

  6. Negative Regulation of Interferon-β Production by Alternative Splicing of Tumor Necrosis Factor Receptor-Associated Factor 3 in Ducks

    Directory of Open Access Journals (Sweden)

    Xiaoqin Wei

    2018-03-01

    Full Text Available Tumor necrosis factor receptor-associated factor 3 (TRAF3, an intracellular signal transducer, is identified as an important component of Toll-like receptors and RIG-I-like receptors induced type I interferon (IFN signaling pathways. Previous studies have clarified TRAF3 function in mammals, but little is known about the role of TRAF3 in ducks. Here, we cloned and characterized the full-length duck TRAF3 (duTRAF3 gene and an alternatively spliced isoform of duTRAF3 (duTRAF3-S lacking the fragment encoding amino acids 217–319, from duck embryo fibroblasts (DEFs. We found that duTRAF3 and duTRAF3-S played different roles in regulating IFN-β production in DEFs. duTRAF3 through its TRAF domain interacted with duMAVS or duTRIF, leading to the production of IFN-β. However, duTRAF3-S, containing the TRAF domain, was unable to bind duMAVS or duTRIF due to the intramolecular binding between the N- and C-terminal of duTRAF3-S that blocked the function of its TRAF domain. Further analysis identified that duTRAF3-S competed with duTRAF3 itself for binding to duTRAF3, perturbing duTRAF3 self-association, which impaired the assembly of duTRAF3-duMAVS/duTRIF complex, ultimately resulted in a reduced production of IFN-β. These findings suggest that duTRAF3 is an important regulator of duck innate immune signaling and reveal a novel mechanism for the negative regulation of IFN-β production via changing the formation of the homo-oligomerization of wild molecules, implying a novel regulatory role of truncated proteins.

  7. Gene Expression of Tumor Necrosis Factor α and TNF-α Receptors (p55 and p75) in Nonalcoholic Steatohepatitis Patients

    International Nuclear Information System (INIS)

    Soliman, S.ET.; Abo-Madyan, A.A.

    2010-01-01

    The main objective of this study was to analyze the pathogenic role of the tumor necrosis factor (TNF-) system in the development of nonalcoholic steatohepatitis (NASH). Fifty obese patients were studied. We investigated: 1) the expression of mRNA of TNF- and their p55 and p75 receptors by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) in hepatic and adipose tissues; and 2) the relationship between TNF-, p55, and p75 and the severity of NASH. Obese patients without NASH were the control group. A remarkable increase in the expression of mRNA of TNF- was found in patients with NASH in hepatic tissue (0.65 ± 0.54) and in peripheral fat (0.43 ± 0.45); in the control samples, the mRNA expression was 0.30 ± 0.32, P < .006, and 0.28 ± 0.22, P < .016, respectively. Furthermore, we found significant increase in the mRNA levels of p55 receptor (2.94 ± 1.71 vs. 1.46 ± 1.27; P<.04); however, the mRNA expression of the p75 receptor was similar in both patients. Those patients with NASH with significant fibrosis presented an increase in the expression of mRNA TNF- in comparison with those with slight or nonexistent fibrosis. The levels of mRNA-p55 are increased in the liver tissue of NASH patients. This over expression is more elevated in patients with more advanced NASH. These findings suggest that the TNF- system may be involved in the pathogenesis of NASH.

  8. Regulation of the PKCθ-NF-κB Axis in T lymphocytes by the Tumor Necrosis Factor Receptor Family Member OX40

    Directory of Open Access Journals (Sweden)

    Takanori eSo

    2012-05-01

    Full Text Available Antigen primed T lymphocytes need to expand and persist to promote adaptive immunity. The growth and survival signals that control this are in large part provided by the NF-κB pathway in activated or effector/memory T cells. Although several membrane receptors impact NF-κB activation, signaling from OX40 (CD134, TNFRSF4, a member of the tumor necrosis factor receptor (TNFR superfamily, has proven to be important for T cell immunity and a strong contributor to NF-κB activity. PKCθ directs the TCR and CD28-dependent assembly of a CBM complex (CARMA1, BCL10, and MALT1 for efficient activation of NF-κB, raising the question of whether other membrane bound receptors that activate NF-κB also require this PKCθ-CBM axis to control TCR-independent T cell activity. We discuss here our recent data demonstrating that after ligation by OX40L (CD252, TNFSF4 expressed on antigen-presenting cells, OX40 translocates into detergent-insoluble membrane lipid microdomains (DIM or lipid rafts in T cells irrespective of TCR signals, and assembles into a novel signaling complex containing PKCθ, together with TRAF2, RIP1, the CBM complex, and the IKKα/β/γ complex. PKCθ is required for optimal NF-κB activation mediated by OX40 and thus works as an essential component of this OX40 signalosome. We also discuss the likelihood that other TNFR superfamily molecules might complex with PKCθ in T cells, and whether PKC isoforms may be critical to the function of TNFR molecules in general. 

  9. International Retrospective Chart Review of Treatment Patterns in Severe Familial Mediterranean Fever, Tumor Necrosis Factor Receptor-Associated Periodic Syndrome, and Mevalonate Kinase Deficiency/Hyperimmunoglobulinemia D Syndrome.

    Science.gov (United States)

    Ozen, Seza; Kuemmerle-Deschner, Jasmin B; Cimaz, Rolando; Livneh, Avi; Quartier, Pierre; Kone-Paut, Isabelle; Zeft, Andrew; Spalding, Steve; Gul, Ahmet; Hentgen, Veronique; Savic, Sinisa; Foeldvari, Ivan; Frenkel, Joost; Cantarini, Luca; Patel, Dony; Weiss, Jeffrey; Marinsek, Nina; Degun, Ravi; Lomax, Kathleen G; Lachmann, Helen J

    2017-04-01

    Periodic fever syndrome (PFS) conditions are characterized by recurrent attacks of fever and localized inflammation. This study examined the diagnostic pathway and treatments at tertiary centers for familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), and mevalonate kinase deficiency (MKD)/hyperimmunoglobulinemia D syndrome (HIDS). PFS specialists at medical centers in the US, the European Union, and the eastern Mediterranean participated in a retrospective chart review, providing de-identified data in an electronic case report form. Patients were treated between 2008 and 2012, with at least 1 year of followup; all had clinical and/or genetically proven disease and were on/eligible for biologic treatment. A total of 134 patients were analyzed: FMF (n = 49), TRAPS (n = 47), and MKD/HIDS (n = 38). Fever was commonly reported as severe across all indications. Other frequently reported severe symptoms were serositis for FMF patients and elevated acute-phase reactants and gastrointestinal upset for TRAPS and MKD/HIDS. A long delay from disease onset to diagnosis was seen within TRAPS and MKD/HIDS (5.8 and 7.1 years, respectively) compared to a 1.8-year delay in FMF patients. An equal proportion of TRAPS patients first received anti-interleukin-1 (anti-IL-1) and anti-tumor necrosis factor (anti-TNF) biologic agents, whereas IL-1 blockade was the main choice for FMF patients resistant to colchicine and MKD/HIDS patients. For TRAPS patients, treatment with anakinra versus anti-TNF treatments as first biologic agent resulted in significantly higher clinical and biochemical responses (P = 0.03 and P patterns and diagnostic delays highlight the need for greater awareness and improved diagnostics for PFS. This real-world treatment assessment supports the need for further refinement of treatment practices. © 2016, American College of Rheumatology.

  10. Relationship between serum tumor necrosis factor receptor-2 concentration and periodontal destruction in patients with type 2 diabetes: Cross-sectional study

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    Matić-Petrović Sanja

    2016-01-01

    Full Text Available Introduction. The role of tumor necrosis factor-α (TNFα is well documented in pathogenesis of chronic periodontitis (CP and type 2 diabetes (T2D. Considering short half-life of TNFα, tumor necrosis factor receptor-2 (TNFR2 is used as prosperous surrogate marker of TNFα activity. Objective. The aim was to detect TNFR2 serum concentration and correlate it with periodontal destruction in patients with diagnosed T2D and nondiabetics. Methods. The study included 85 patients divided into three groups: T2D + CP (group T2D, n = 34; nondiabetics + CP (Group PD, n = 27; and healthy controls (group HC, n = 24. T2D was diagnosed according to WHO criteria (2013 and periodontitis was diagnosed using International Workshop for a Classification of Periodontal Diseases and Conditions criteria (1999. TNFR2 level was measured by enzyme-linked immunosorbent assay (ELISA. Results. There was no difference in TNFR2 level among the groups (Kruskal-Wallis, p = 0.482. Significant correlation (Pearson’s correlation coefficient was observed between clinical attachment loss (CAL and TNFR2 concentration in PD group (rp = -0.460, p = 0.016. In T2D group, correlations were observed between TNFR2 concentration and CAL (rp = 0.363, p = 0.005 and periodontal inflamed surface area (PISA (rp = 0.345, p = 0.046 and periodontal epithelial surface area (PESA (rp = 0.578, p = 0.000. Conclusion. Higher concentration of TNFR2 was associated with higher CAL, PESA, and PISA scores in T2D group. Contrary to that, nondiabetics with higher values of CAL exhibited lower concentration of TNFR2, presenting potential protective effect on periodontal destruction. These results imply that diabetes may alter TNFR2 secretion originated from periodontium. [Projekat Ministarstva nauke Republike Srbije, br. 41008

  11. The role of tumor necrosis factor-α and TNF-α receptors in cerebral arteries following cerebral ischemia in rat

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    Chen Qing-Wen

    2011-08-01

    Full Text Available Abstract Background Tumour necrosis factor-α (TNF-α is a pleiotropic pro-inflammatory cytokine, which is rapidly upregulated in the brain after injury. TNF-α acts by binding to its receptors, TNF-R1 (p55 and TNF-R2 (p75, on the cell surface. The aim of this study was first to investigate if there is altered expression of TNF-α and TNF-α receptors in cerebral artery walls following global or focal ischemia, and after organ culture. Secondly, we asked if the expression was regulated via activation of the MEK-ERK1/2 pathway. Methods The hypothesis was tested in vivo after subarachnoid hemorrhage (SAH and middle cerebral artery occlusion (MCAO, and in vitro by organ culture of isolated cerebral arteries. The localization and amount of TNF-α, TNF-α receptor 1 and 2 proteins were analysed by immunohistochemistry and western blot after 24 and 48 h of organ culture and at 48 h following SAH or MCAO. In addition, cerebral arteries were incubated for 24 or 48 h in the absence or presence of a B-Raf inhibitor (SB386023-b, a MEK- inhibitor (U0126 or an NF-κB inhibitor (IMD-0354, and protein expression evaluated. Results Immunohistochemistry revealed enhanced expression of TNF-α, TNF-R1 and TNF-R2 in the walls of cerebral arteries at 48 h after MCAO and SAH compared with control. Co-localization studies showed that TNF-α, TNF-R1 and TNF-R2 were primarily localized to the cell membrane and the cytoplasm of the smooth muscle cells (SMC. There was, in addition, some expression of TNF-R2 in the endothelial cells. Immunohistochemistry and western blot analysis showed that these proteins were upregulated after 24 and 48 h in culture, and this upregulation reached an apparent maximum at 48 h of organ culture. Treatment with U0126 significantly reduced the enhanced SMC expression of TNF-α, TNF-R1 and TNF-R2 immunoreactivities after 24 and 48 h of organ culture. The Raf and NF-κB inhibitors significantly reduced organ culture induced TNF-α expression

  12. Association of transient receptor potential canonical type 3 (TRPC3) channel transcripts with proinflammatory cytokines

    DEFF Research Database (Denmark)

    Thilo, Florian; Scholze, Alexandra; Liu, Dao Yan

    2008-01-01

    necrosis factor-alpha (TNF-alpha) in monocytes from 15 patients with essential hypertension and 16 age- and sex-matched normotensive control subjects. We observed an approximately 8-fold increase of TRPC3 transcripts in monocytes from patients with essential hypertension compared to normotensive control......We investigated whether expression of non-selective cation channels of the transient receptor potential canonical (TRPC) channel family are associated with proinflammatory cytokines in monocytes. Using quantitative RT-PCR we studied the expression of TRPC3, interleukin-1beta (IL-1beta), and tumor...

  13. Soluble tumour necrosis factor (TNF)-receptor levels in serum as markers of anti-viral host reactivity

    DEFF Research Database (Denmark)

    Bartholdy, C; Nansen, A; Marker, O

    1999-01-01

    -gamma. A simple correlation between release of sTNF-Rs in vivo and macrophage activation in vitro was not present. These findings indicate that sTNF-R75 is indeed a sensitive marker of both innate and specific cell-mediated host reactivity during viral infection, but it is not correlated to a single immunological......The role of soluble receptors for TNF-alpha (sTNF-Rs) as markers of virus-induced host responses was studied by the use of murine model infections. A marked elevation in serum levels of sTNF-R75, but not sTNF-R55, was found 1 day after infection with vesicular stomatitis virus (VSV). In mice...

  14. RECEPTOR SUPERFAMILY OF TUMOR NECROSIS FACTOR Α, AND HSP90 HEAT SHOCK PROTEIN: A MOLECULAR BASIS FOR INTERACTIONS

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    N. V. Ryazantseva

    2011-01-01

    Full Text Available Abstract.  A  study  was  performed  aiming  to  investigate  interactions  between  TNFα  receptor  (TNF1 superfamily and heat shock protein Hsp90, using a Jurkat tumor cell line. The tumor cells cultured in presence of Hsp90 inhibitor (17-AAG showed increased numbers of cells, presenting surface TNFR1 and FasR, which facilitate  triggering  of  programmed  cell  death.  It  was  also  revealed  that  Hsp90  blockage  under  the  in  vitro conditions causes a decrease in FasL, while not affecting TNFα and sTNFR1 production by the tumor cells. (Med. Immunol., 2011, vol. 13, N 2-3, pp 247-252 

  15. VARIAR Study: Assessment of short-term efficacy and safety of rituximab compared to an tumor necrosis factor alpha antagonists as second-line drug therapy in patients with rheumatoid arthritis refractory to a first tumor necrosis factor alpha antagonist.

    Science.gov (United States)

    Torrente-Segarra, Vicenç; Acosta Pereira, Asunción; Morla, Rosa; Ruiz, José Miguel; Clavaguera, Teresa; Figuls, Ramon; Corominas, Hector; Geli, Carme; Roselló, Rosa; de Agustín, Juan José; Alegre, Cayetano; Pérez, Carolina; García, Angel; Rodríguez de la Serna, Arturo

    to compare the short-term efficacy and safety of rituximab (RTX) therapy versus anti-TNF in rheumatoid arthritis (RA) patients after discontinuation of a first anti-TNF agent. prospective observational multicenter study in the clinical practice setting, involving patients with severe RA refractory to a first anti-TNF agent, who received either RTX or a second anti-TNF (2TNF), comparing the efficacy endpoints, EULAR response (Good/Moderate) and safety at 6 months. 103 patients enrolled, 82 completed 6-month follow-up, 73.7% women. Baseline data for RTX and 2TNF groups, respectively: TJC, 8.6 and 6.6; SJC, 8.8 and 7.5; DAS28 score, 5.45 (±1.28) and 5.18 (±1.21) (p=0.048), ESR, 41 and 38.7mmHg; and HAQ, 1.2 and 1.0. Improvement was observed in all parameters, with no significant differences (except for a more marked reduction in ESR with RTX). There were no serious adverse events. RTX use as second-line therapy after anti-TNF failure led to improvements in the efficacy and functional variables at 6 months, with no serious adverse events. These results were comparable to those observed in patients who used a second anti-TNF agent in the same clinical scenario. Copyright © 2015 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

  16. Ciliary neurotrophic factor inhibits brain and peripheral tumor necrosis factor production and, when coadministered with its soluble receptor, protects mice from lipopolysaccharide toxicity.

    Science.gov (United States)

    Benigni, F; Villa, P; Demitri, M T; Sacco, S; Sipe, J D; Lagunowich, L; Panayotatos, N; Ghezzi, P

    1995-07-01

    The receptor of ciliary neurotrophic factor (CNTF) contains the signal transduction protein gp130, which is also a component of the receptors of cytokines such as interleukin (IL)-6, leukemia-inhibitory factor (LIF), IL-11, and oncostatin M. This suggests that these cytokines might share common signaling pathways. We previously reported that CNTF augments the levels of corticosterone (CS) and of IL-6 induced by IL-1 and induces the production of the acute-phase protein serum amyloid A (SAA). Since the elevation of serum CS is an important feedback mechanism to limit the synthesis of proinflammatory cytokines, particularly tumor necrosis factor (TNF), we have investigated the effect of CNTF on both TNF production and lipopolysaccharide (LPS) toxicity. To induce serum TNF levels, LPS was administered to mice at 30 mg/kg i.p. and CNTF was administered as a single dose of 10 micrograms/mouse i.v., either alone or in combination with its soluble receptor sCNTFR alpha at 20 micrograms/mouse. Serum TNF levels were the measured by cytotoxicity on L929 cells. In order to measure the effects of CNTF on LPS-induced TNF production in the brain, mice were injected intracerebroventricularly (i.c.v.) with 2.5 micrograms/kg LPS. Mouse spleen cells cultured for 4 hr with 1 microgram LPS/ml, with or without 10 micrograms CNTF/ml, were also analyzed for TNF production. CNTF, administered either alone or in combination with its soluble receptor, inhibited the induction of serum TNF levels by LPS. This inhibition was also observed in the brain when CNTF and LPS were administered centrally. In vitro, CNTF only marginally affected TNF production by LPS-stimulated mouse splenocytes, but it acted synergistically with dexamethasone (DEX) in inhibiting TNF production. Most importantly, CNTF administered together with sCNTFR alpha protected mice against LPS-induced mortality. These data suggest that CNTF might act as a protective cytokine against TNF-mediated pathologies both in the brain and

  17. Disruption of Tumor Necrosis Factor Receptor-Associated Factor 5 Exacerbates Murine Experimental Colitis via Regulating T Helper Cell-Mediated Inflammation

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    Jian Shang

    2016-01-01

    Full Text Available Tumor necrosis factor (TNF receptor-associated factor 5 (TRAF5 is a key mediator of TNF receptor superfamily members and is important in both T helper (Th cell immunity and the regulation of multiple signaling pathways. To clarify TRAF5’s influence on inflammatory bowel diseases (IBDs, we investigated TRAF5 deficiency’s effect on dextran sulfate sodium- (DSS- induced colitis. Colitis was induced in TRAF5 knockout (KO mice and their wild-type (WT littermates by administering 3% DSS orally for 7 days. The mice were then sacrificed, and their colons were removed. Our data suggested that KO mice were more susceptible to DSS-induced colitis. TRAF5 deficiency significantly enhanced IFN-γ, IL-4, and IL-17a mRNA and protein levels in the colons of DSS-fed mice, and the mRNA expression of T-bet and GATA-3 was also markedly elevated. However, ROR-α and ROR-γt mRNA levels did not differ between DSS-induced KO and WT mice. Flow cytometry showed increased frequencies of Th2 and IFN-γ/IL-17a-coproducing CD4+ T cells in the colons of DSS-induced KO mice. Additionally, TRAF5 deficiency significantly enhanced the activation of NF-κB in CD4+ T cells after DSS administration. These results indicated that TRAF5 deficiency significantly aggravated DSS-induced colitis, most likely by regulating Th cell-mediated inflammation.

  18. Peripheral inflammation induces tumor necrosis factor dependent AMPA receptor trafficking and Akt phosphorylation in spinal cord in addition to pain behavior.

    Science.gov (United States)

    Choi, Jeong Il; Svensson, Camilla I; Koehrn, Fred J; Bhuskute, Aditi; Sorkin, Linda S

    2010-05-01

    In the present study, intraplantar carrageenan induced increased mechanical allodynia, phosphorylation of PKB/Akt and GluR1 ser 845 (PKA site) as well as GluR1, but not GluR2 movement into neuronal membranes. This change in membrane GluR1/GluR2 ratio is indicative of Ca(2+) permeable AMPA receptor insertion. Pain behavior was reduced and biochemical changes blocked by spinal pretreatment, but not post-treatment, with a tumor necrosis factor (TNF) antagonist, Etanercept (100microg). Pain behavior was also reduced by spinal inhibition of phosphatidylinositol 3-kinase (PI-3K) (wortmannin; 1 and 5microg) and LY294002; 50 and 100microg) and Akt (Akt inhibitor IV; 3microg). Phosphorylated Akt was found exclusively in neurons in grey matter and in oligodendrocytes in white matter. Interestingly, this increase was seen first in superficial dorsal horn and alpha-motor neurons (peak 45min) and later (peak 2h post-injection) in deep dorsal horn neurons. Akt and GluR1 phosphorylation, AMPA receptor trafficking and mechanical allodynia were all TNF dependent. Whether phosphorylation of Akt and of GluR1 are in series or in parallel or upstream of pain behavior remains to be determined. Certainly, TNF-mediated GluR1 trafficking appears to play a major role in inflammatory pain and TNF-mediated effects such as these could represent a path by which glia contribute to neuronal sensitization (spinal LTP) and pathological pain. Copyright 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  19. Serial measurement of the circulating levels of tumour necrosis factor and its soluble receptors 1 and 2 for monitoring leprosy patients during multidrug treatment

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    Rosane Dias Costa

    2013-12-01

    Full Text Available Leprosy is an infectious and contagious spectral disease accompanied by a series of immunological events triggered by the host response to the aetiologic agent, Mycobacterium leprae . The induction and maintenance of the immune/inflammatory response in leprosy are linked to multiple cell interactions and soluble factors, primarily through the action of cytokines. The purpose of the present study was to evaluate the serum levels of tumour necrosis factor (TNF-α and its soluble receptors (sTNF-R1 and sTNF-R2 in leprosy patients at different stages of multidrug treatment (MDT in comparison with non-infected individuals and to determine their role as putative biomarkers of the severity of leprosy or the treatment response. ELISA was used to measure the levels of these molecules in 30 healthy controls and 37 leprosy patients at the time of diagnosis and during and after MDT. Our results showed increases in the serum levels of TNF-α and sTNF-R2 in infected individuals in comparison with controls. The levels of TNF-α, but not sTNF-R2, decreased with treatment. The current results corroborate previous reports of elevated serum levels of TNF-α in leprosy and suggest a role for sTNF-R2 in the control of this cytokine during MDT.

  20. Transmembrane Tumor Necrosis Factor Controls Myeloid-Derived Suppressor Cell Activity via TNF Receptor 2 and Protects from Excessive Inflammation during BCG-Induced Pleurisy

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    Leslie Chavez-Galan

    2017-08-01

    Full Text Available Pleural tuberculosis (TB is a form of extra-pulmonary TB observed in patients infected with Mycobacterium tuberculosis. Accumulation of myeloid-derived suppressor cells (MDSC has been observed in animal models of TB and in human patients but their role remains to be fully elucidated. In this study, we analyzed the role of transmembrane TNF (tmTNF in the accumulation and function of MDSC in the pleural cavity during an acute mycobacterial infection. Mycobacterium bovis BCG-induced pleurisy was resolved in mice expressing tmTNF, but lethal in the absence of tumor necrosis factor. Pleural infection induced MDSC accumulation in the pleural cavity and functional MDSC required tmTNF to suppress T cells as did pleural wild-type MDSC. Interaction of MDSC expressing tmTNF with CD4 T cells bearing TNF receptor 2 (TNFR2, but not TNFR1, was required for MDSC suppressive activity on CD4 T cells. Expression of tmTNF attenuated Th1 cell-mediated inflammatory responses generated by the acute pleural mycobacterial infection in association with effective MDSC expressing tmTNF and interacting with CD4 T cells expressing TNFR2. In conclusion, this study provides new insights into the crucial role played by the tmTNF/TNFR2 pathway in MDSC suppressive activity required during acute pleural infection to attenuate excessive inflammation generated by the infection.

  1. Molecular characterization and expression analysis of the first Porifera tumor necrosis factor superfamily member and of its putative receptor in the marine sponge Chondrosia reniformis.

    Science.gov (United States)

    Pozzolini, Marina; Scarfì, Sonia; Ghignone, Stefano; Mussino, Francesca; Vezzulli, Luigi; Cerrano, Carlo; Giovine, Marco

    2016-04-01

    Here we report the molecular cloning and characterization of the first Tumor Necrosis Factor homologous and of its putative receptor in the marine sponge Chondrosia reniformis: chTNF and chTNFR, respectively. The deduced chTNF amino acid sequence is a type II transmembrane protein containing the typical TNFSF domain. Phylogenetic analysis reveals that chTNF is more related to Chordata TNFs rather than to other invertebrates. chTNF and chTNFR are constitutively expressed both in the ectosome and in the choanosome of the sponge, with higher levels in the ectosome. chTNF and chTNFR mRNAs were monitored in sponge fragmorphs treated with Gram(+) or Gram(-) bacteria. chTNF was significantly upregulated in Gram(+)-treated fragmorphs as compared to controls, while chTNFR was upregulated by both treatments. Finally, the possible chTNF fibrogenic role in sponge fragmorphs was studied by TNF inhibitor treatment measuring fibrillar and non fibrillar collagen gene expression; results indicate that the cytokine is involved in sponge collagen deposition and homeostasis. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Genetic variants in toll-like receptors are not associated with rheumatoid arthritis susceptibility or anti-tumour necrosis factor treatment outcome.

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    Marieke J H Coenen

    Full Text Available BACKGROUND: Several studies point to a role of Toll-like receptors (TLRs in the development of rheumatoid arthritis (RA. We investigated if genetic variants in TLR genes are associated with RA and response to tumour necrosis factor blocking (anti-TNF medication. METHODOLOGY AND PRINCIPAL FINDINGS: 22 single nucleotide polymorphisms (SNPs in seven TLR genes were genotyped in a Dutch cohort consisting of 378 RA patients and 294 controls. Significantly associated variants were investigated in replication cohorts from The Netherlands, United Kingdom and Sweden (2877 RA patients and 2025 controls. 182 of the Dutch patients were treated with anti-TNF medication. Using these patients and a replication cohort (269 Swedish patients we analysed if genetic variants in TLR genes were associated with anti-TNF outcome. In the discovery phase of the study we found a significant association of SNPs rs2072493 in TLR5 and rs3853839 in TLR7 with RA disease susceptibility. Meta-analysis of discovery and replication cohorts did not confirm these findings. SNP rs2072493 in TLR5 was associated with anti-TNF outcome in the Dutch but not in the Swedish population. CONCLUSION: We conclude that genetic variants in TLRs do not play a major role in susceptibility for developing RA nor in anti-TNF treatment outcome in a Caucasian population.

  3. Experimental pain ratings and reactivity of cortisol and soluble tumor necrosis factor-α receptor II following a trial of hypnosis: Results of a randomized controlled pilot study

    Science.gov (United States)

    Goodin, Burel R.; Quinn, Noel B.; Kronfli, Tarek; King, Christopher D.; Page, Gayle G.; Haythornthwaite, Jennifer A.; Edwards, Robert R.; Stapleton, Laura M.; McGuire, Lynanne

    2011-01-01

    Objective Current evidence supports the efficacy of hypnosis for reducing the pain associated with experimental stimulation and various acute and chronic conditions; however, the mechanisms explaining how hypnosis exerts its effects remain less clear. The hypothalamic-pituitary-adrenal (HPA) axis and pro-inflammatory cytokines represent potential targets for investigation given their purported roles in the perpetuation of painful conditions; yet, no clinical trials have thus far examined the influence of hypnosis on these mechanisms. Design Healthy participants, highly susceptible to the effects of hypnosis, were randomized to either a hypnosis intervention or a no-intervention control. Using a cold pressor task, assessments of pain intensity and pain unpleasantness were collected prior to the intervention (Pre) and following the intervention (Post) along with pain-provoked changes in salivary cortisol and the soluble receptor of tumor necrosis factor-α (sTNFαRII). Results Compared to the no-intervention control, data analyses revealed that hypnosis significantly reduced pain intensity and pain unpleasantness. Hypnosis was not significantly associated with suppression of cortisol or sTNFαRII reactivity to acute pain from Pre to Post; however, the effect sizes for these associations were medium-sized. Conclusions Overall, the findings from this randomized controlled pilot study support the importance of a future large-scale study on the effects of hypnosis for modulating pain-related changes of the HPA axis and pro-inflammatory cytokines. PMID:22233394

  4. Role of tumour necrosis factor receptor-1 and nuclear factor-κB in production of TNF-α-induced pro-inflammatory microparticles in endothelial cells.

    Science.gov (United States)

    Lee, S K; Yang, S-H; Kwon, I; Lee, O-H; Heo, J H

    2014-09-02

    Tumour necrosis factor-α (TNF-α) is upregulated in many inflammatory diseases and is also a potent agent for microparticle (MP) generation. Here, we describe an essential role of TNF-α in the production of endothelial cell-derived microparticles (EMPs) in vivo and the function of TNF-α-induced EMPs in endothelial cells. We found that TNF-α rapidly increased blood levels of EMPs in mice. Treatment of human umbilical vein endothelial cells (HUVECs) with TNF-α also induced EMP formation in a time-dependent manner. Silencing of TNF receptor (TNFR)-1 or inhibition of the nuclear factor-κB (NF-κB) in HUVECs impaired the production of TNF-α-induced EMP. Incubation of HUVECs with PKH-67-stained EMPs showed that endothelial cells readily engulfed EMPs, and the engulfed TNF-α-induced EMPs promoted the expression of pro-apoptotic molecules and upregulated intercellular adhesion molecule-1 level on the cell surface, which led to monocyte adhesion. Collectively, our findings indicate that the generation of TNF-α-induced EMPs was mediated by TNFR1 or NF-κB and that EMPs can contribute to apoptosis and inflammation of endothelial cells.

  5. Unimpaired Autoreactive T-Cell Traffic Within the Central Nervous System During Tumor Necrosis Factor Receptor-Mediated inhibition of Experimental Autoimmune Encephalomyelitis

    Science.gov (United States)

    Korner, Heinrich; Goodsall, Anna L.; Lemckert, Frances A.; Scallon, Bernard J.; Ghrayeb, John; Ford, Andrew L.; Sedgwick, Jonathon D.

    1995-11-01

    The critical role of tumor necrosis factor (TNF) as a mediator in autoimmune inflammatory processes is evident from in vivo studies with TNF-blocking agents. However, the mechanisms by which TNF, and possibly also its homologue lymphotoxin α, contributes to development of pathology in rheumatoid arthritis and Crohn disease and in animal models like experimental autoimmune encephalomyelitis is unclear. Possibilities include regulation of vascular adhesion molecules enabling leukocyte movement into tissues or direct cytokine-mediated effector functions such as mediation of tissue damage. Here we show that administration of a TNF receptor (55 kDa)-IgG fusion protein prevented clinical signs of actively induced experimental autoimmune encephalomyelitis. Significantly, the total number of CD4^+ T lymphocytes isolated from the central nervous system of clinically healthy treated versus diseased control animals was comparable. By using a CD45 congenic model of passively transferred experimental autoimmune encephalomyelitis to enable tracking of myelin basic protein-specific effector T lymphocytes, prevention of clinical signs of disease was again demonstrated in treated animals but without quantitative or qualitative impediment to the movement of autoreactive T lymphocytes to and within the central nervous system. Thus, despite the uninterrupted movement of specific T lymphocytes into the target tissue, subsequent disease development was blocked. This provides compelling evidence for a direct effector role of TNF/lymphotoxin α in autoimmune tissue damage.

  6. Lack of Proinflammatory Cytokine Interleukin-6 or Tumor Necrosis Factor Receptor-1 Results in a Failure of the Innate Immune Response after Bacterial Meningitis.

    Science.gov (United States)

    Albrecht, Lea-Jessica; Tauber, Simone C; Merres, Julika; Kress, Eugenia; Stope, Matthias B; Jansen, Sandra; Pufe, Thomas; Brandenburg, Lars-Ove

    2016-01-01

    The most frequent pathogen that causes bacterial meningitis is the Gram-positive bacterium Streptococcus pneumoniae. By entering the brain, host cells will be activated and proinflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) are released. The goal of the current study was to examine the interaction between IL-6 and TNFR1 as receptor for TNF-α and the innate immune response in vivo in a model of Streptococcus pneumoniae-induced meningitis. For the experiments IL-6(-/-), TNFR1(-/-), and TNFR1-IL-6(-/-) KO mice were used. Our results revealed higher mortality rates and bacterial burden after infection in TNFR1(-/-), IL-6(-/-), and TNFR1-IL-6(-/-) mice and a decreased immune response including lower neutrophil infiltration in the meninges of TNFR1(-/-) and TNFR1-IL-6(-/-) mice in contrast to IL-6(-/-) and wild type mice. Furthermore, the increased mortality of TNFR1(-/-) and TNFR1-IL-6(-/-) mice correlated with decreased glial cell activation compared to IL-6(-/-) or wild type mice after pneumococcal meningitis. Altogether, the results show the importance of TNFR1 and IL-6 in the regulation of the innate immune response. The lack of TNFR1 and IL-6 results in higher mortality by weakened immune defence, whereas the lack of TNFR1 results in more severe impairment of the innate immune response than the lack of IL-6 alone.

  7. Chlorpromazine inhibits tumour necrosis factor synthesis and cytotoxicity in vitro.

    Science.gov (United States)

    Zinetti, M; Galli, G; Demitri, M T; Fantuzzi, G; Minto, M; Ghezzi, P; Alzani, R; Cozzi, E; Fratelli, M

    1995-01-01

    Chlorpromazine (CPZ) has been previously shown to protect against endotoxin [lipopolysaccharide (LPS)] lethality and inhibit the release of tumour necrosis factor in vivo. We investigated at the cellular level whether this was due to direct inhibition of tumour necrosis factor-alpha (TNF-alpha) synthesis, using LPS-stimulated THP-1 human monocytic leukemia cells. We also studied the effect of CPZ on human TNF-alpha action by assessing TNF-alpha cytotoxicity on mouse fibrosarcoma L929 cells. CPZ (1-100 microM) inhibited TNF-alpha production in THP-1 cells in a dose dependent manner by a maximum of 80%. This effect was comparable to that of two well-known inhibitory drugs, dexamethasone and cyclicAMP. Inhibition was also evident at the mRNA level. On the other hand CPZ (10-25 microM) also inhibited TNF-alpha activity: in fact it reduced the cytotoxicity of TNF-alpha on L929 cells (EC50 was increased four times) and could provide protection even as a post-treatment. CPZ inhibited TNF-induced apoptosis in L929 cells, as detected by analysis of nuclear morphology. However, since we showed that apoptosis was very limited, and was not the main mode of cell death in our conditions, this could not explain the overall protection. Since CPZ did not interfere with either the oligomerization state of TNF-alpha or its receptor binding, our data suggest that it reduced cytotoxicity by inhibiting some steps in the TNF-alpha signalling pathways. Images Figure 1 Figure 4 PMID:8550079

  8. Chlorpromazine inhibits tumour necrosis factor synthesis and cytotoxicity in vitro.

    Science.gov (United States)

    Zinetti, M; Galli, G; Demitri, M T; Fantuzzi, G; Minto, M; Ghezzi, P; Alzani, R; Cozzi, E; Fratelli, M

    1995-11-01

    Chlorpromazine (CPZ) has been previously shown to protect against endotoxin [lipopolysaccharide (LPS)] lethality and inhibit the release of tumour necrosis factor in vivo. We investigated at the cellular level whether this was due to direct inhibition of tumour necrosis factor-alpha (TNF-alpha) synthesis, using LPS-stimulated THP-1 human monocytic leukemia cells. We also studied the effect of CPZ on human TNF-alpha action by assessing TNF-alpha cytotoxicity on mouse fibrosarcoma L929 cells. CPZ (1-100 microM) inhibited TNF-alpha production in THP-1 cells in a dose dependent manner by a maximum of 80%. This effect was comparable to that of two well-known inhibitory drugs, dexamethasone and cyclicAMP. Inhibition was also evident at the mRNA level. On the other hand CPZ (10-25 microM) also inhibited TNF-alpha activity: in fact it reduced the cytotoxicity of TNF-alpha on L929 cells (EC50 was increased four times) and could provide protection even as a post-treatment. CPZ inhibited TNF-induced apoptosis in L929 cells, as detected by analysis of nuclear morphology. However, since we showed that apoptosis was very limited, and was not the main mode of cell death in our conditions, this could not explain the overall protection. Since CPZ did not interfere with either the oligomerization state of TNF-alpha or its receptor binding, our data suggest that it reduced cytotoxicity by inhibiting some steps in the TNF-alpha signalling pathways.

  9. Assessment of chronic spontaneous urticaria by serum-induced tumor necrosis factor alpha and matrix metalloproteinase-9 release

    DEFF Research Database (Denmark)

    Falkencrone, Sidsel; Bindslev-Jensen, Carsten; Skov, Per Stahl

    BACKGROUND Previous studies from our group have demonstrated that IgE-mediated basophil activation leads to release of TNFα that in turn can induce matrix metallo-proteinase-9 (MMP-9) release from monocytes. We wished to investigate if serum from chronic spontaneous urticaria-patients with auto-a....... Release levels appeared to be positive correlated to ASST reaction in ASST+ patients but not to disease severity for CSU patients in general....

  10. Serial QuantiFERON-TB Gold In-Tube testing for psoriatic patients receiving antitumor necrosis factor-alpha therapy

    Directory of Open Access Journals (Sweden)

    Chun-Yu Cheng

    2015-09-01

    Conclusion: This study demonstrated that 14.29% of psoriatic patients undergoing long-term TNF-α antagonist therapy had a QFT-GIT conversion. Although a decreased IFN-γ level and QFT-GIT reversion were observed in most cases following prophylactic therapy, the value of QFT-GIT for evaluating the effect of LTBI prophylaxis remains controversial.

  11. Diagnostic and Prognostic Particularities of the Implications of the Presence of Tumor Necrosis Factor Alpha in Patients with Periodontal Disease

    Directory of Open Access Journals (Sweden)

    Yero Ieremie Lia Maria

    2014-12-01

    Full Text Available Periodontal disease can have significant effects by increasing the circulating levels of TNF-α, therefore its prevention and treatment is important in maintaining the overall health of the body. Objective: The aim of our research was to assess the differences in the salivary concentration of TNF-α between patients with periodontal disease and those free of the disease and to studz whether it can represent an indicator of the evolution of periodontal disease. We also aimed to assess the practical applicability of the method for the determination of this cytokine in the saliva. Materials and methods: Our study included two groups of subjects, the first group consisting in patients diagnosed with periodontal disease, while the control group included subjects free of periodontal disease. TNF-α concentration was determined with the ELISA test for human TNF-α and the results were expressed in pg/ mL. The data were statistically processed with GraphPad software and the statistical nonparametric Mann-Whitney test was applied. Results: We observe nearly double values of the TNF-α salivary level in the group of patients suffering from periodontal disease compared to the subjects free of periodontal disease, which allows us to notice that saliva analysis is a useful and safely enough method for the diagnosis and follow-up in the development of periodontal disease. Conclusion: The salivary level of TNF-α in patients with periodontal disease is not only an indicator of periodontal disease progression, but also a reflection of the pathogen potential that periodontal disease may have on the overall health of the body.

  12. Ultraviolet B irradiation of skin induces mast cell degranulation and release of tumour necrosis factor-{alpha}

    Energy Technology Data Exchange (ETDEWEB)

    Walsh, L.J. [University of Queensland, Brisbane, QLD (Australia). Dept. of Dentistry, Immunopathology Unit

    1995-06-01

    In the `sunburn` response in skin, dermal blood vessels are activated and traffic of dendritic Langerhans` cells altered. While these changes have been attributed to the cytokine TNF-{alpha}, the source of this acutely released TNF has not been identified. This report demonstrates that the `sunburn` response, both in vivo and in vitro, is accompanied by rapid degranulation of cutaneous mast cells, with consequential release of intracellular stores of TNF. Epidermal keratinocytes were only minor contributors to local TNF production. Expression of the TNF-inducible CD62E (E-selectin/ELAM-1) and CD54 adhesion molecules on cutaneous endothelium occurred 2 hours following mast cell degranulation, and this event was sensitive to blockade of mast cells with disodium cromoglycate. These results indicate that TNF release in skin in the acute sunburn response can largely be attributed to mast cells. 47 refs., 5 tabs., 2 figs.

  13. Cloning, expression, purification and characterization of a single chain variable fragment specific to tumor necrosis factor alpha in Escherichia coli.

    Science.gov (United States)

    Sushma, Krishnan; Vijayalakshmi, Mookambeswaran A; Krishnan, Venkataraman; Satheeshkumar, Padikara Kutty

    2011-12-20

    Anti TNF-α molecules have been used as therapeutic agents in a variety of human diseases such as Rheumatoid arthritis, Ankylosing spondylitis, Chron's diseases, Psoriasis, etc., where high levels of TNF-α plays a destructive role. The limitations of the present TNF-α inhibitors in terms of size, tissue penetration and immunogenicity, etc., provoked the search for small anti TNF-α molecules. In the present study, a single chain variable fragment (ScFv) construct was made from a monoclonal antibody of the class IgG raised against TNF-α was used. The anti TNF-α ScFv was well expressed as soluble form in Escherichia coli BL21 (DE3), which was purified to homogeneity by commercial methacrylate monolith-convective interaction media (CIM) supports using two different chemistries, immobilized metal affinity chromatography (IMAC) with copper ions followed by anion exchange chromatography. The anti TNF-α ScFv found to be inhibiting the TNF-α mediated cytotoxicity in MCF-7 cells with an IC(50) of 8μg. Data presented here are promising and encouraging to further optimize anti TNF-α ScFv production in larger scale with higher recovery at a cheaper price for therapeutic purposes. Copyright © 2011 Elsevier B.V. All rights reserved.

  14. Expression of Tumor Necrosis Factor Alpha-Included Protein 6 Messenger RNA in Porcine Preovulatory Ovarian Follicles

    Czech Academy of Sciences Publication Activity Database

    Nagyová, Eva; Němcová, Lucie; Procházka, Radek

    2009-01-01

    Roč. 55, č. 3 (2009), s. 231-235 ISSN 0916-8818 R&D Projects: GA ČR GA523/08/0111 Institutional research plan: CEZ:AV0Z50450515 Keywords : Preovulatory Ovarian Follicles * TNFAIP6 * female fertility Subject RIV: ED - Physiology Impact factor: 1.697, year: 2009

  15. Increased pulmonary secretion of tumor necrosis factor-alpha in calves experimentally infected with bovine respiratory syncytial virus

    DEFF Research Database (Denmark)

    Rontved, C. M.; Tjørnehøj, Kirsten; Viuff, B.

    2000-01-01

    -alpha in the BAL fluid of calves killed post inoculation day (PID) 2 and 4 was at the same very low level as in the uninfected control animals. Large amounts of TNF-alpha were detected on PID 6, maximum levels of TNF-alpha were reached on PID 7, and smaller amounts of TNF-alpha were seen on PID 8. The high levels...... of the infection, as well as BRSV-infected calves free of bacteria reached the same level of TNF-alpha as animals from which bacteria were isolated from the lungs. It is concluded that significant quantities of TNF-alpha are produced in the lungs of the calves on PID 6-7 of BRSV infection. The involvement of TNF...

  16. [Association between carbonyl proteins and tumor necrosis factor alpha with muscle strength in young and older women: exploratory study].

    Science.gov (United States)

    Martínez Huenchullán, Sergio Francisco; Mancilla Solorza, Eladio Bernabé

    2015-01-01

    It has recently been proposed that there is a close relationship between oxidative stress and low-grade chronic inflammation. Both processes have been related separately to muscle function in older adults (OA). Nevertheless, it still has not been determined if this relationship is present particularly in OA. The objective of this study was to determine the relationship between the plasma levels of TNF-α and carbonyl proteins (CP) and muscle strength in a group of young and older women. An exploratory study was conducted on 13 older and 8 young women, in whom the plasma levels of CP and TNF-α were measured. Muscle strength was measured by handgrip test, quadriceps voluntary maximal isometric strength, arm curl, and the 30 second sit to stand test. There were no differences in the plasma levels of CP and TNF-α between the groups, but there was relationship between the biomarkers only in the OA group. A non-linear relationship was observed between CP and quadriceps voluntary maximal isometric strength only in the OA group (R(2)=36.2; P=.038). For TNF-α there were no significant association with any of the applied tests. There is an association between CP and quadriceps voluntary maximal isometric strength only in the OA group, which could indicate a deleterious action of oxidative stress on muscle function, particularly in aging. Copyright © 2015 SEGG. Published by Elsevier Espana. All rights reserved.

  17. Serum levels of interleukin-6, tumor necrosis factor-alpha and interferon-gama in infants with and without dengue

    OpenAIRE

    Restrepo,Berta Nelly; Isaza,Diana María; Salazar,Clara Lina; Ramírez,Ruth; Ospina,Marta; Alvarez,Luis Gonzalo

    2008-01-01

    This study compared the serum levels of IL-6, TNF-alpha and IFN-gamma, in children under 1 year of age with and without dengue. Sera were collected from a total of 41 children living in the Department of Antioquia, Colombia (27 patients with dengue and 14 controls). The results showed higher cytokine levels in children with dengue than without dengue, with statistically significant differences for IL-6 and IFN-gamma. No statistically significant differences were found between clinical forms, ...

  18. Substance P ameliorates tumor necrosis factor-alpha-induced endothelial cell dysfunction by regulating eNOS expression in vitro.

    Science.gov (United States)

    Piao, Jiyuan; Hong, Hyun Sook; Son, Youngsook

    2018-04-01

    The aim of this study was to explore the beneficial effects of SP on NO production and inflammation-induced vascular endothelium cell death. To mimic the inflammatory environment, TNF-α was treated with HUVECs, and SP was added prior to TNF-α to determine its protective effect. WST-1 assay was performed to detect cell viability. NO level in conditioned medium was measured by Griess Reagent System. The protein level of cleaved caspase-3, eNOS, and phosphorylated Akt was detected by Western blot analysis. TNF-α declined endothelial cell viability by downregulating Akt and NO production. TNF-α-induced cell death was reliably restored by NO, confirming the requirement of NO for cell survival. By contrast, pretreatment of SP attenuated TNF-α-induced cellular apoptosis, accompanied by an increase in the phosphorylation of Akt, eNOS expression, and NO production. Blockage of NK-1R, phosphorylated Akt or eNOS by CP-96345, A6730, or L-NAME entirely eliminated the effect of SP. SP can protect the vascular endothelium against inflammation-induced damage through modulation of the Akt/eNOS/NO signaling pathway. © 2018 John Wiley & Sons Ltd.

  19. Inhibitory effects of bisbenzylisoquinolines on synthesis of the inflammatory cytokines interleukin-1 and tumour necrosis factor-alpha

    Directory of Open Access Journals (Sweden)

    W. Kim Seow

    1993-01-01

    Full Text Available Synthesis of IL-1β and TNFα by human monocytesmacrophages was significantly inhibited by eleven bisbenzylisoquinolines and one half-molecule (benzylisoquinoline, with IC50 values in the μM range. The results indicate that these compounds may have value in the therapy of human diseases where these inflammatory cytokines have a central role in pathogenesis.

  20. Activation of nuclear factor-kappa B via endogenous tumor necrosis factor alpha regulates survival of axotomized adult sensory neurons

    NARCIS (Netherlands)

    Fernyhough, P; Smith, DR; Schapansky, J; Van Der Ploeg, R; Gardiner, NJ; Tweed, CW; Kontos, A; Freeman, L; Purves-Tyson, TD; Glazner, GW

    2005-01-01

    Embryonic dorsal root ganglion (DRG) neurons die after axonal damage in vivo, and cultured embryonic DRG neurons require exogenous neurotrophic factors that activate the neuroprotective transcription factor nuclear factor-kappaB(NF-kappaB) for survival. In contrast, adult DRG neurons survive

  1. Tumor necrosis factor alpha and interleukin-1 beta modulate calcium and nitric oxide signaling in mechanically stimulated osteocytes

    NARCIS (Netherlands)

    Bakker, A.D.; Da Silva, V.C.; Krishan, R.; Bacabac, R.G.; Blaauboer, M.E.; Lin, Y.C.; Marcantonio, R.A.C.; Cirelli, J.A.; Klein-Nulend, J.

    2009-01-01

    Objective: Inflammatory diseases often coincide with reduced bone mass. Mechanoresponsive osteocytes regulate bone mass by maintaining the balance between bone formation and resorption. Despite its biologic significance, the effect of inflammation on osteocyte mechanoresponsiveness is not

  2. Interleukin-17 induces hyperresponsive interleukin-8 and interleukin-6 production to tumor necrosis factor-alpha in structural lung cells

    NARCIS (Netherlands)

    van den Berg, Arjen; Kuiper, Mathys; Snoek, Mieke; Timens, Wim; Postma, Dirkje S.; Jansen, Henk M.; Lutter, René

    2005-01-01

    Lung epithelial cells contribute to local inflammation by the production of pro-inflammatory mediators like interleukin (IL)-8 and IL-6. Although their production depends on gene transcription, previous studies showed that post-transcriptional mechanisms modulate IL-8 and IL-6 production. Human lung

  3. Synthesis of Tumor Necrosis Factor Alpha Induced Protein 6 in Porcine Preovulatory Follicles; A Study with A38 Antibody

    Czech Academy of Sciences Publication Activity Database

    Nagyová, Eva; Camaioni, A.; Procházka, Radek; Day, A. J.; Salustri, A.

    2008-01-01

    Roč. 78, - (2008), s. 903-909 ISSN 0006-3363 R&D Projects: GA ČR GA305/05/0960 Grant - others:Program of Scientific and Technological Cooperation between Czech Republic and Italy(CZ) 52/ZV2 Institutional research plan: CEZ:AV0Z50450515 Keywords : cumulus cells * extracellular matrix * hyaluronan Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.469, year: 2008

  4. Evaluation of tumor necrosis factor alpha serum level in obese and lean women with clomiphene citrate resistant polycystic ovary disease

    Directory of Open Access Journals (Sweden)

    Emaduldin Seyam

    2017-09-01

    Conclusion: TNF-α serum level has come significantly higher in all women with PCOD, especially in those resistant to CC. Androgenic obesity with higher W/H ratio has shown a positive correlation with TNF-α level, which could consider it a good severity index of PCOD status, and an informative predictor of CCR before its use.

  5. DLG1/SAP97 modulates transforming growth factor alpha bioavailability.

    Science.gov (United States)

    Surena, Anne-Laure; de Faria, Giselle P; Studler, Jeanne-Marie; Peiretti, Franck; Pidoux, Morgane; Camonis, Jacques; Chneiweiss, Hervé; Formstecher, Etienne; Junier, Marie-Pierre

    2009-02-01

    TGFalpha and its receptor EGFR participate in the development of a wide range of tumors including gliomas, the main adult primary brain tumors. TGFalpha soluble form results from the cleavage by the metalloprotease TACE/ADAM17 of the extracellular part of its transmembrane precursor, pro-TGFalpha. To gain insights into the mechanisms underlying TGFalpha bioavailability, a yeast two-hybrid screen was performed to identify proteins interacting with pro-TGFalpha intracellular domain (ICD). DLG1/SAP97 (Discs Large Gene 1 or Synapse Associated Protein 97) was found to interact with both pro-TGFalpha and TACE ICDs through distinct PDZ domains. An in vivo pro-TGFalpha-DLG1-TACE complex was detected in U251 glioma cells and in gliomas-derived tumor initiating cells. Interaction between DLG1 and TACE diminished in response to stimulations promoting pro-TGFalpha shedding. Manipulation of DLG1 levels revealed dual actions of DLG1 on pro-TGFalpha shedding, favoring approximation of pro-TGFalpha and TACE, while limiting TACE full shedding activity. These results show that DLG1 participates in the control of TGFalpha bioavailability through its dynamic interaction with the growth factor precursor and TACE.

  6. Interleukin 6 Present in Inflammatory Ascites from Advanced Epithelial Ovarian Cancer Patients Promotes Tumor Necrosis Factor Receptor 2-Expressing Regulatory T Cells

    Directory of Open Access Journals (Sweden)

    Nirmala Chandralega Kampan

    2017-11-01

    Full Text Available BackgroundEpithelial ovarian cancer (EOC remains a highly lethal gynecological malignancy. Ascites, an accumulation of peritoneal fluid present in one-third of patients at presentation, is linked to poor prognosis. High levels of regulatory T cells (Tregs in ascites are correlated with tumor progression and reduced survival. Malignant ascites harbors high levels of Tregs expressing the tumor necrosis factor receptor 2 (TNFR2, as well as pro-inflammatory factors such as interleukin 6 (IL-6 and tumor necrosis factor (TNF. IL-6 is also associated with poor prognosis. Herein, we study the effect of IL-6 and TNF present in ascites on the modulation of TNFR2 expression on T cells, and specifically Tregs.MethodsAscites and respective peripheral blood sera were collected from 18 patients with advanced EOC and soluble biomarkers, including IL-6, sTNFR2, IL-10, TGF-β, and TNF, were quantified using multiplexed bead-based immunoassay. Peripheral blood mononuclear cells (PBMC from healthy donors were incubated with cell-free ascites for 48 h (or media as a negative control. In some experiments, IL-6 or TNF within the ascites were neutralized by using monoclonal antibodies. The phenotype of TNFR2+ Tregs and TNFR2− Tregs were characterized post incubation in ascites. In some experiments, cell sorted Tregs were utilized instead of PBMC.ResultsHigh levels of immunosuppressive (sTNFR2, IL-10, and TGF-β and pro-inflammatory cytokines (IL-6 and TNF were present in malignant ascites. TNFR2 expression on all T cell subsets was higher in post culture in ascites and highest on CD4+CD25hiFoxP3+ Tregs, resulting in an increased TNFR2+ Treg/effector T cell ratio. Furthermore, TNFR2+ Tregs conditioned in ascites expressed higher levels of the functional immunosuppressive molecules programmed cell death ligand-1, CTLA-4, and GARP. Functionally, TNFR2+ Treg frequency was inversely correlated with interferon-gamma (IFN-γ production by effector T cells, and was

  7. Interleukin 6 Present in Inflammatory Ascites from Advanced Epithelial Ovarian Cancer Patients Promotes Tumor Necrosis Factor Receptor 2-Expressing Regulatory T Cells.

    Science.gov (United States)

    Kampan, Nirmala Chandralega; Madondo, Mutsa Tatenda; McNally, Orla M; Stephens, Andrew N; Quinn, Michael A; Plebanski, Magdalena

    2017-01-01

    Epithelial ovarian cancer (EOC) remains a highly lethal gynecological malignancy. Ascites, an accumulation of peritoneal fluid present in one-third of patients at presentation, is linked to poor prognosis. High levels of regulatory T cells (Tregs) in ascites are correlated with tumor progression and reduced survival. Malignant ascites harbors high levels of Tregs expressing the tumor necrosis factor receptor 2 (TNFR2), as well as pro-inflammatory factors such as interleukin 6 (IL-6) and tumor necrosis factor (TNF). IL-6 is also associated with poor prognosis. Herein, we study the effect of IL-6 and TNF present in ascites on the modulation of TNFR2 expression on T cells, and specifically Tregs. Ascites and respective peripheral blood sera were collected from 18 patients with advanced EOC and soluble biomarkers, including IL-6, sTNFR2, IL-10, TGF-β, and TNF, were quantified using multiplexed bead-based immunoassay. Peripheral blood mononuclear cells (PBMC) from healthy donors were incubated with cell-free ascites for 48 h (or media as a negative control). In some experiments, IL-6 or TNF within the ascites were neutralized by using monoclonal antibodies. The phenotype of TNFR2 + Tregs and TNFR2 - Tregs were characterized post incubation in ascites. In some experiments, cell sorted Tregs were utilized instead of PBMC. High levels of immunosuppressive (sTNFR2, IL-10, and TGF-β) and pro-inflammatory cytokines (IL-6 and TNF) were present in malignant ascites. TNFR2 expression on all T cell subsets was higher in post culture in ascites and highest on CD4 + CD25 hi FoxP3 + Tregs, resulting in an increased TNFR2 + Treg/effector T cell ratio. Furthermore, TNFR2 + Tregs conditioned in ascites expressed higher levels of the functional immunosuppressive molecules programmed cell death ligand-1, CTLA-4, and GARP. Functionally, TNFR2 + Treg frequency was inversely correlated with interferon-gamma (IFN-γ) production by effector T cells, and was uniquely able to suppress TNFR2

  8. Expression of osteoprotegerin, receptor activator of nuclear factor kappa-B ligand, tumor necrosis factor-related apoptosis-inducing ligand, stromal cell-derived factor-1 and their receptors in epithelial metastatic breast cancer cell lines

    Directory of Open Access Journals (Sweden)

    Labovsky Vivian

    2012-06-01

    Full Text Available Abstract Background While breast cancer (BC is the major cause of death among women worldwide, there is no guarantee of better patient survival because many of these patients develop primarily metastases, despite efforts to detect it in its early stages. Bone metastasis is a common complication that occurs in 65-80 % of patients with disseminated disease, but the molecular basis underlying dormancy, dissemination and establishment of metastasis is not understood. Our objective has been to evaluate simultaneously osteoprotegerin (OPG, receptor activator of nuclear factor kappa B ligand (RANKL, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, stromal cell-derived factor-1 (SDF-1, and their receptors (R in 2 human BC cell lines, MDA-MB-231 and MCF-7. Methods OPG, RANKL, TRAIL and SDF-1 expression and release, in addition to the expression of their receptors has been investigated using immunofluorescence, immunocytochemistry and ELISA analyses. Results MCF-7 cells released higher levels of OPG in conditioned media (CM than MDA-MB-231 cells; 100 % of both types of cell expressed OPG, RANKL, TRAIL and SDF-1. Moreover, 100 % in both lines expressed membrane RANKL and RANK, whereas only 50 % expressed CXCR4. Furthermore, 100 % expressed TRAIL-R1 and R4, 30-50 % TRAIL-R2, and 40-55 % TRAIL-R3. Conclusions MCF-7 and MDA-MB-231 cells not only released OPG, but expressed RANKL, TRAIL and SDF-1. The majority of the cells also expressed RANK, CXCR4 and TRAIL-R. Since these ligands and their receptors are implicated in the regulation of proliferation, survival, migration and future bone metastasis during breast tumor progression, assessment of these molecules in tumor biopsies of BC patients could be useful in identifying patients with more aggressive tumors that are also at risk of bone metastasis, which may thus improve the available options for therapeutic intervention.

  9. The effect of angiotensin receptor blockers on C-reactive protein and other circulating inflammatory indices in man

    Science.gov (United States)

    Alessandra, Del Fiorentino; Cianchetti, Silvana; Celi, Alessandro; Dell’Omo, Giulia; Pedrinelli, Roberto

    2009-01-01

    Anti-inflammatory properties may contribute to the pharmacological effects of angiotensin II receptor blockers (ARBs), a leading therapeutic class in the management of hypertension and related cardiovascular and renal diseases. That possibility, supported by consistent evidence from in-vitro and animal studies showing pro-inflammatory properties of angiotensin II, has been evaluated clinically by measuring the effect of ARBs on C-reactive protein and other circulating indices of inflammation (e-selectin, adhesion molecules, interleukin-6, tissue necrosis factor-alpha, monocyte chemoattractant protein-1) of potential clinical relevance, a body of evidence that this paper aims to review. PMID:19436669

  10. The SMAC mimetic birinapant attenuates lipopolysaccharide-induced liver injury by inhibiting the tumor necrosis factor receptor-associated factor 3 degradation in Kupffer cells.

    Science.gov (United States)

    Liu, Hongxiang; Liao, Rui; He, Kun; Zhu, Xiwen; Li, Peizhi; Gong, Jianping

    2017-05-01

    It was demonstrated that second mitochondria-derived activator of caspases (SMAC) mimetic inhibites tumor necrosis factor receptor-associated factor 3 (TRAF3) degradation and the mitogen-activated protein kinase (MAPK) signaling pathway activation induced by lipopolysaccharide (LPS) in vitro. However, the effect of Smac mimetic in vivo is not clear. The present study was to investigate the role of Smac mimetic in LPS-induced liver injury in mice and its possible mechanism. An animal model of LPS-induced liver injury was established by intraperitoneally injecting mice with 10mg/kg LPS pretreatment with or without Smac mimetic birinapant (30mg/kg body weight). Birinapant significantly improved the survival rate of endotoxemic mice (P<0.05) and attenuated LPS-induced liver pathologic damage and inflammatory response. IL-1 and TNF-α levels in the serum were markedly decreased in birinapant pretreatment mice compared with control mice (P<0.05).The cellular inhibitor of apoptosis protein 1 (cIAP1) expression in liver resident macrophage (Kupffer cells, KCs) was significantly decreased in the Birinapant group compared to the Vehicle group (P<0.05). At the same time, total TRAF3 protein abundance in KCs rapidly declined after LPS stimulation in the Vehicle group. However, it remained constant in the Birinapant group. Moreover, K48-linked polyubiquitination of TRAF3 in KCs was markedly impressed in the birinapant group compared with the control group. At last, the JNK and p38 MAPK activation in KCs was significantly inhibited by birinapant pretreatment (P<0.05). These results suggested that birinapant attenuated liver injury and improved survival rates in endotoxemic mice by inhibited the expression of cIAP1, degradation of TRAF3 and aviation of MAPK signaling pathway. Copyright © 2017 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  11. Myosin light chain kinase expression induced via tumor necrosis factor receptor 2 signaling in the epithelial cells regulates the development of colitis-associated carcinogenesis.

    Directory of Open Access Journals (Sweden)

    Masahiro Suzuki

    Full Text Available It has been suggested that prolonged inflammatory bowel diseases (IBD may lead to colitis-associated carcinogenesis (CAC. We previously observed that the NF-κB activation in colonic epithelial cells is associated with increased tumor necrosis factor receptor 2 (TNFR2 expression in CAC development. However, the mechanism by which epithelial NF-κB activation leading to CAC is still unclear. Myosin light chain kinase (MLCK has been reported to be responsible for the epithelial permeability associated with TNF signaling. Therefore we focused on the role of MLCK expression via TNFR2 signaling on CAC development. Pro-tumorigenic cytokines such as IL-1β, IL-6 and MIP-2 production as well as INF-γ and TNF production at the lamina propria were increased in the setting of colitis, and further in tumor tissues in associations with up-regulated TNFR2 and MLCK expressions in the epithelial cells of a CAC model. The up-regulated MLCK expression was observed in TNF-stimulated colonic epithelial cells in a dose-dependent fashion in association with up-regulation of TNFR2. Silencing TNFR2, but not TNFR1, resulted in restoration of epithelial tight junction (TJ associated with decreased MLCK expression. Antibody-mediated blockade of TNF signaling also resulted in restoration of TJ in association with suppressed MLCK expression, and interestingly, similar results were observed with suppressing TNFR2 and MLCK expressions by inhibiting MLCK in the epithelial cells. Silencing of MLCK also resulted in suppressed TNFR2, but not TNFR1, expression, suggesting that the restored TJ leads to reduced TNFR2 signaling. Such suppression of MLCK as well as blockade of TNFR2 signaling resulted in restored TJ, decreased pro-tumorigenic cytokines and reduced CAC development. These results suggest that MLCK may be a potential target for the prevention of IBD-associated tumor development.

  12. Molecular cloning of feline tumour necrosis factor receptor type I (TNFR I) and expression of TNFR I and TNFR II in lymphoid cells in cats.

    Science.gov (United States)

    Mizuno, T; Goto, Y; Baba, K; Masuda, K; Ohno, K; Tsujimoto, H

    2003-04-01

    Tumour necrosis factor (TNF)-alpha is a pro-inflammatory cytokine produced by many types of cells. It has been shown that two distinct TNF receptors (TNFRs), TNFR type I (TNFR I) and TNFR type II (TNFR II), have different functions in signal transduction, which is possibly associated with the development of a variety of diseases. In this study, we isolated a feline TNFR I cDNA clone and analysed the expression of TNFR I and TNFR II mRNA in feline lymphoid cells. The deduced amino acid sequence of feline TNFRI cDNA showed 75.8, 62.5 60.9 and 72.1% similarity with those of its human, mouse, rat, and pig counterparts, respectively. The feline TNFR I cDNA was shown to encode extracellular, transmembrane and intracellular domains fundamentally conserved in the homologues of other species. Expression of TNFR I and TNFR II mRNAs was shown to be up-regulated in feline peripheral blood mononuclear cells (PBMC) by stimulation with concanavalin A. Five of six feline lymphoma cell lines were shown to express both TNFR I and TNFR II mRNAs. The expression of TNFR I in PBMC was up-regulated in cats infected with feline immunodeficiency virus (FIV), whereas the expression of TNFR II in PBMC was not different between FIV-infected cats and uninfected cats. The present study indicate that expression of TNFR I and TNFR II may be associated with disease progression, especially in retrovirus infections in cats.

  13. Lack of Proinflammatory Cytokine Interleukin-6 or Tumor Necrosis Factor Receptor-1 Results in a Failure of the Innate Immune Response after Bacterial Meningitis

    Directory of Open Access Journals (Sweden)

    Lea-Jessica Albrecht

    2016-01-01

    Full Text Available The most frequent pathogen that causes bacterial meningitis is the Gram-positive bacterium Streptococcus pneumoniae. By entering the brain, host cells will be activated and proinflammatory cytokines like interleukin-6 (IL-6 and tumor necrosis factor-α (TNF-α are released. The goal of the current study was to examine the interaction between IL-6 and TNFR1 as receptor for TNF-α and the innate immune response in vivo in a model of Streptococcus pneumoniae-induced meningitis. For the experiments IL-6−/−, TNFR1−/−, and TNFR1-IL-6−/− KO mice were used. Our results revealed higher mortality rates and bacterial burden after infection in TNFR1−/−, IL-6−/−, and TNFR1-IL-6−/− mice and a decreased immune response including lower neutrophil infiltration in the meninges of TNFR1−/− and TNFR1-IL-6−/− mice in contrast to IL-6−/− and wild type mice. Furthermore, the increased mortality of TNFR1−/− and TNFR1-IL-6−/− mice correlated with decreased glial cell activation compared to IL-6−/− or wild type mice after pneumococcal meningitis. Altogether, the results show the importance of TNFR1 and IL-6 in the regulation of the innate immune response. The lack of TNFR1 and IL-6 results in higher mortality by weakened immune defence, whereas the lack of TNFR1 results in more severe impairment of the innate immune response than the lack of IL-6 alone.

  14. Tumor necrosis factor α promotes replication and pathogenicity of rat cytomegalovirus

    NARCIS (Netherlands)

    Horzinek, M.C.; Haagmans, B.L.; Stals, F.S.; Meide, P.H. van der; Bruggeman, C.A.; Schijns, Virgil E.C.J.

    1994-01-01

    We investigated the role of tumor necrosis factor alpha (TNF-α) in the pathogenesis of rat cytomegalovirus (RCMV) infection. TNF-α levels found in the sera of radiation-immunosuppressed rats in the course of infection (> 350 pg/ml) correlated with the development of RCMV disease. Administration of

  15. Cannabidiol ameliorates cognitive and motor impairments in bile-duct ligated mice via 5-HT1A receptor activation.

    Science.gov (United States)

    Magen, I; Avraham, Y; Ackerman, Z; Vorobiev, L; Mechoulam, R; Berry, E M

    2010-02-01

    We aimed to demonstrate the involvement of 5-HT(1A) receptors in the therapeutic effect of cannabidiol, a non-psychoactive constituent of Cannabis sativa, in a model of hepatic encephalopathy induced by bile-duct ligation (BDL) in mice. Cannabidiol (5 mg x kg(-1); i.p.) was administered over 4 weeks to BDL mice. Cognition and locomotion were evaluated using the eight-arm maze and the open field tests respectively. Hippocampi were analysed by RT-PCR for expression of the genes for tumour necrosis factor-alpha receptor 1, brain-derived neurotrophic factor (BDNF) and 5-HT(1A) receptor. N-(2-(4-(2-methoxy-phenyl)-1-piperazin-1-yl)ethyl)-N-(2-pyridyl) cyclohexanecarboxamide (WAY-100635), a 5-HT(1A) receptor antagonist (0.5 mg x kg(-1)), was co-administered with cannabidiol. Liver function was evaluated by measuring plasma liver enzymes and bilirubin. Cannabidiol improved cognition and locomotion, which were impaired by BDL, and restored hippocampal expression of the tumour necrosis factor-alpha receptor 1 and the BDNF genes, which increased and decreased, respectively, following BDL. It did not affect reduced 5-HT(1A) expression in BDL mice. All the effects of cannabidiol, except for that on BDNF expression, were blocked by WAY-100635, indicating 5-HT(1A) receptor involvement in cannabidiol's effects. Cannabidiol did not affect the impaired liver function in BDL. The behavioural outcomes of BDL result from both 5-HT(1A) receptor down-regulation and neuroinflammation. Cannabidiol reverses these effects through a combination of anti-inflammatory activity and activation of this receptor, leading to improvement of the neurological deficits without affecting 5-HT(1A) receptor expression or liver function. BDNF up-regulation by cannabidiol does not seem to account for the cognitive improvement.

  16. Effect of Wenhua Juanbi Recipe () on expression of receptor activator of nuclear factor kappa B ligand, osteoprotegerin, and tumor necrosis factor receptor superfamily member 14 in rats with collagen-induced arthritis.

    Science.gov (United States)

    Liu, Xi-de; Wang, Yun-Qing; Cai, Long; Ye, Li-Hong; Wang, Fang; Feng, Ying-Ying

    2017-03-01

    To study the effect of Wenhua Juanbi Recipe (, WJR) on expression of receptor activator of nuclear factor kappa B ligand (RANKL), osteoprotegerin (OPG), and tumor necrosis factor receptor superfamily member 14 (TNFRSF14, also known as LIGHT) in rats with collagen-induced arthritis (CIA). CIA rats were generated by subcutaneous injection of bovine collagen type-II at the tail base. Sixty CIA rats were randomly assigned (10 animals/group) to: model, methotrexate (MTX)-treated (0.78 mg/kg body weight), and WJR-treated (22.9 g/kg) groups. Healthy normal rats (n=10) were used as the normal control. Treatments or saline were administered once daily by oral gavage. Rats were sacrifificed at day 28 post-treatment and knee synovium and peripheral blood serum were collected. Toe swelling degree and expression of RANKL, OPG, and LIGHT were determined by Western blot and immunohistochemistry. Compared with the normal group, toe swelling degree was signifificantly increased in the model group (P<0.01). After treatment, toe swelling degree decreased signifificantly in the WJR and MTX groups compared with the model group (P<0.01). Compared with the normal group, expression of RANKL and LIGHT were signifificantly increased and OPG signifificantly decreased in peripheral blood and synovium of the model group (P<0.01). Conversely, RANKL and LIGHT expression were signifificantly reduced and OPG increased in the WJR and MTX groups compared with the model group (P<0.01). No statistically significant difference existed between WJR and MTX groups. WJR likely acts by reducing RANKL expression and increasing OPG expression, thus inhibiting RANKL/RANK interaction and reducing LIGHT expression, thereby inhibiting osteoclast formation/activation to block bone erosion.

  17. Tumor Necrosis Factor (TNF) Receptor Superfamily Member 1b on CD8+ T Cells and TNF Receptor Superfamily Member 1a on Non-CD8+ T Cells Contribute Significantly to Upper Genital Tract Pathology Following Chlamydial Infection.

    Science.gov (United States)

    Manam, Srikanth; Thomas, Joshua D; Li, Weidang; Maladore, Allison; Schripsema, Justin H; Ramsey, Kyle H; Murthy, Ashlesh K

    2015-06-15

    We demonstrated previously that tumor necrosis factor α (TNF-α)-producing Chlamydia-specific CD8(+) T cells cause oviduct pathological sequelae. In the current study, we used wild-type C57BL/6J (WT) mice with a deficiency in genes encoding TNF receptor superfamily member 1a (TNFR1; TNFR1 knockout [KO] mice), TNF receptor superfamily member 1b (TNFR2; TNFR2 KO mice), and both TNFR1 and TNFR2 (TNFR1/2 double KO [DKO] mice) and mix-match adoptive transfers of CD8(+) T cells to study chlamydial pathogenesis. TNFR1 KO, TNFR2 KO, and TNFR1/2 DKO mice displayed comparable clearance of primary or secondary genital Chlamydia muridarum infection but significantly reduced oviduct pathology, compared with WT animals. The Chlamydia-specific total cellular cytokine response in splenic and draining lymph nodes and the antibody response in serum were comparable between the WT and KO animals. However, CD8(+) T cells from TNFR2 KO mice displayed significantly reduced activation (CD11a expression and cytokine production), compared with TNFR1 KO or WT animals. Repletion of TNFR2 KO mice with WT CD8(+) T cells but not with TNFR2 KO CD8(+) T cells and repletion of TNFR1 KO mice with either WT or TNFR1 KO CD8(+) T cells restored oviduct pathology to WT levels in both KO groups. Collectively, these results demonstrate that TNFR2-bearing CD8(+) T cells and TNFR1-bearing non-CD8(+) T cells contribute significantly to oviduct pathology following genital chlamydial infection. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  18. Stimulation of nuclear receptor REV-ERBs regulates tumor necrosis factor-induced expression of proinflammatory molecules in C6 astroglial cells

    Energy Technology Data Exchange (ETDEWEB)

    Morioka, Norimitsu, E-mail: mnori@hiroshima-u.ac.jp; Tomori, Mizuki; Zhang, Fang Fang; Saeki, Munenori; Hisaoka-Nakashima, Kazue; Nakata, Yoshihiro

    2016-01-08

    Under physiological conditions, astrocytes maintain homeostasis in the CNS. Following inflammation and injury to the CNS, however, activated astrocytes produce neurotoxic molecules such as cytokines and chemokines, amplifying the initial molecular-cellular events evoked by inflammation and injury. Nuclear receptors REV-ERBα and REV-ERBβ (REV-ERBs) are crucial in the regulation of inflammation- and metabolism-related gene transcription. The current study sought to elucidate a role of REV-ERBs in rat C6 astroglial cells on the expression of inflammatory molecules following stimulation with the neuroinflammatory cytokine tumor necrosis factor (TNF). Stimulation of C6 cells with TNF (10 ng/ml) significantly increased the mRNA expression of CCL2, interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), and matrix metalloprotease (MMP)-9, but not fibroblast growth factor-2 (FGF-2), cyclooxygenase-2 (COX-2) and MMP-2. Treatment with either REV-ERB agonists GSK4112 or SR9009 significantly blocked TNF-induced upregulation of CCL2 mRNA and MMP-9 mRNA, but not IL-6 mRNA and iNOS mRNA expression. Furthermore, treatment with RGFP966, a selective histone deacetylase 3 (HDAC3) inhibitor, potently reversed the inhibitory effects of GSK4112 on TNF-induced expression of MMP-9 mRNA, but not CCL2 mRNA. Expression of Rev-erbs mRNA in C6 astroglial cells, primary cultured rat cortical and spinal astrocytes was confirmed by reverse transcription polymerase chain reaction. Together, the findings demonstrate an anti-inflammatory effect, downregulating of MMP-9 and CCL2 transcription, of astroglial REV-ERBs activation through HDAC3-dependent and HDAC3-independent mechanisms. - Highlights: • Rev-erbα mRNA and Rev-erbβ mRNA are expressed in C6 astroglial cells. • TNF increases the expression of CCL2, IL-6, MMP-9 and iNOS mRNA. • REV-ERB activation inhibits CCL2 mRNA and MMP-9 mRNA expression. • HDAC3 activity is involved in the inhibitory effect of REV-ERB on MMP-9 induction.

  19. Common gene variants in the tumor necrosis factor (TNF and TNF receptor superfamilies and NF-kB transcription factors and non-Hodgkin lymphoma risk.

    Directory of Open Access Journals (Sweden)

    Sophia S Wang

    Full Text Available A promoter polymorphism in the pro-inflammatory cytokine tumor necrosis factor (TNF (TNF G-308A is associated with increased non-Hodgkin lymphoma (NHL risk. The protein product, TNF-alpha, activates the nuclear factor kappa beta (NF-kappaB transcription factor, and is critical for inflammatory and apoptotic responses in cancer progression. We hypothesized that the TNF and NF-kappaB pathways are important for NHL and that gene variations across the pathways may alter NHL risk.We genotyped 500 tag single nucleotide polymorphisms (SNPs from 48 candidate gene regions (defined as 20 kb 5', 10 kb 3' in the TNF and TNF receptor superfamilies and the NF-kappaB and related transcription factors, in 1946 NHL cases and 1808 controls pooled from three independent population-based case-control studies. We obtained a gene region-level summary of association by computing the minimum p-value ("minP test". We used logistic regression to compute odds ratios and 95% confidence intervals for NHL and four major NHL subtypes in relation to SNP genotypes and haplotypes. For NHL, the tail strength statistic supported an overall relationship between the TNF/NF-kappaB pathway and NHL (p = 0.02. We confirmed the association between TNF/LTA on chromosome 6p21.3 with NHL and found the LTA rs2844484 SNP most significantly and specifically associated with the major subtype, diffuse large B-cell lymphoma (DLBCL (p-trend = 0.001. We also implicated for the first time, variants in NFKBIL1 on chromosome 6p21.3, associated with NHL. Other gene regions identified as statistically significantly associated with NHL included FAS, IRF4, TNFSF13B, TANK, TNFSF7 and TNFRSF13C. Accordingly, the single most significant SNPs associated with NHL were FAS rs4934436 (p-trend = 0.0024, IRF4 rs12211228 (p-trend = 0.0026, TNFSF13B rs2582869 (p-trend = 0.0055, TANK rs1921310 (p-trend = 0.0025, TNFSF7 rs16994592 (p-trend = 0.0024, and TNFRSF13C rs6002551 (p-trend = 0.0074. All associations were

  20. Stimulation of nuclear receptor REV-ERBs regulates tumor necrosis factor-induced expression of proinflammatory molecules in C6 astroglial cells

    International Nuclear Information System (INIS)

    Morioka, Norimitsu; Tomori, Mizuki; Zhang, Fang Fang; Saeki, Munenori; Hisaoka-Nakashima, Kazue; Nakata, Yoshihiro

    2016-01-01

    Under physiological conditions, astrocytes maintain homeostasis in the CNS. Following inflammation and injury to the CNS, however, activated astrocytes produce neurotoxic molecules such as cytokines and chemokines, amplifying the initial molecular-cellular events evoked by inflammation and injury. Nuclear receptors REV-ERBα and REV-ERBβ (REV-ERBs) are crucial in the regulation of inflammation- and metabolism-related gene transcription. The current study sought to elucidate a role of REV-ERBs in rat C6 astroglial cells on the expression of inflammatory molecules following stimulation with the neuroinflammatory cytokine tumor necrosis factor (TNF). Stimulation of C6 cells with TNF (10 ng/ml) significantly increased the mRNA expression of CCL2, interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), and matrix metalloprotease (MMP)-9, but not fibroblast growth factor-2 (FGF-2), cyclooxygenase-2 (COX-2) and MMP-2. Treatment with either REV-ERB agonists GSK4112 or SR9009 significantly blocked TNF-induced upregulation of CCL2 mRNA and MMP-9 mRNA, but not IL-6 mRNA and iNOS mRNA expression. Furthermore, treatment with RGFP966, a selective histone deacetylase 3 (HDAC3) inhibitor, potently reversed the inhibitory effects of GSK4112 on TNF-induced expression of MMP-9 mRNA, but not CCL2 mRNA. Expression of Rev-erbs mRNA in C6 astroglial cells, primary cultured rat cortical and spinal astrocytes was confirmed by reverse transcription polymerase chain reaction. Together, the findings demonstrate an anti-inflammatory effect, downregulating of MMP-9 and CCL2 transcription, of astroglial REV-ERBs activation through HDAC3-dependent and HDAC3-independent mechanisms. - Highlights: • Rev-erbα mRNA and Rev-erbβ mRNA are expressed in C6 astroglial cells. • TNF increases the expression of CCL2, IL-6, MMP-9 and iNOS mRNA. • REV-ERB activation inhibits CCL2 mRNA and MMP-9 mRNA expression. • HDAC3 activity is involved in the inhibitory effect of REV-ERB on MMP-9 induction.

  1. Histamine H1-receptor antagonists inhibit nuclear factor-kappaB and activator protein-1 activities via H1-receptor-dependent and -independent mechanisms.

    Science.gov (United States)

    Roumestan, C; Henriquet, C; Gougat, C; Michel, A; Bichon, F; Portet, K; Jaffuel, D; Mathieu, M

    2008-06-01

    Histamine H1-receptor antagonists are used to relieve the symptoms of an immediate allergic reaction. They have additional anti-inflammatory effects that could result from an inhibition of the transcription factors activator protein-1 (AP-1) and nuclear factor-kappa B (NF-kappaB). The implication of the H1-receptor in these effects is controversial. Diphenhydramine is a first-generation H1-receptor antagonist while mizolastine and desloratadine are second-generation compounds. Mizolastine is also an inhibitor of 5-lipoxygenase (5-LO), an enzyme that has been involved in NF-kappaB activation. We measured the ability of antihistamines to reverse histamine-induced smooth muscle contraction, an effect that involves the H1-receptor. We then investigated whether these drugs affect NF-kappaB and AP-1 activities in A549 lung epithelial cells, and whether this potential regulation involves H1-receptor and 5-LO. Muscle tone was measured on tracheal segments of guinea-pigs. The H1-receptor was overexpressed by transfection and detected by Western blotting and immunofluorescence microscopy. NF-kappaB and AP-1 activities were assessed by reporter gene assays in cells overexpressing or not overexpressing the H1-receptor. Production of regulated upon activation, normal T cell expressed andsecreted (RANTES), a chemokine whose expression is induced through NF-kappaB, was measured using an immunoassay. H1-receptor antagonists reversed histamine-induced contraction in a dose-dependent manner. Induction of AP-1 and NF-kappaB activities by histamine and the down-regulatory effect of antihistamines required overexpression of the H1-receptor. In contrast, when tumour necrosis factor-alpha and a phorbol ester were used to stimulate NF-kappaB and AP-1 activities, respectively, repression of these activities did not involve the H1-receptor. Indeed, repression was triggered only by a subset of H1-receptor antagonists and was not stronger after overexpression of the H1-receptor. Mizolastine

  2. Differential effects of decoy receptor- and antibody-mediated tumour necrosis factor blockage on FoxP3 expression in responsive arthritis patients

    DEFF Research Database (Denmark)

    Ryder, L Rebekka; Ryder, Lars P; Bartels, Else M

    2013-01-01

    Our aim was to clarify if anti-tumour necrosis factor (TNF) drugs have effect on expression of three splice forms of FoxP3 mRNA in blood CD4+ T cells from rheumatoid arthritis (RA) patients compared with healthy controls. Forty-five rheumatoid arthritis patients treated with anti-TNF therapy were...

  3. Tumor necrosis factor (TNF) receptor shedding controls thresholds of innate immune activation that balance opposing TNF functions in infectious and inflammatory diseases

    DEFF Research Database (Denmark)

    Xanthoulea, Sofia; Pasparakis, Manolis; Kousteni, Stavroula

    2004-01-01

    Tumor necrosis factor (TNF) is a potent cytokine exerting critical functions in the activation and regulation of immune and inflammatory responses. Due to its pleiotropic activities, the amplitude and duration of TNF function must be tightly regulated. One of the mechanisms that may have evolved ...... shedding as a mechanism setting up thresholds of cytokine function to balance resistance and susceptibility to disease. Assessment of p55TNFR shedding may thus be of prognostic value in infectious, inflammatory, and autoimmune diseases....

  4. Oral clefts, tranforming growth factor alpha gene variants, and maternal smoking

    DEFF Research Database (Denmark)

    Christensen, Kaare; Olsen, Jørn; Nørgaard-Pedersen, Bent

    1999-01-01

    Studies in the United States have indicated that maternal first trimester smoking and infant transforming growth factor alpha (TGFA) locus mutations are associated with non-syndromic cleft lip and/or palate (CLP) and that a synergistic effect of these two risk factors occurs. Based on a Danish case-control......, and no synergistic effect with smoking was observed. The "rare" TGFA allele occurred in 25% of both cases and controls compared with an average of 14% in other white control groups. Furthermore, the frequency of CLP in Scandinavia is among the highest in the world. Hence, it is possible that the previously reported...

  5. Programmed necrosis and necroptosis – molecular mechanisms

    Directory of Open Access Journals (Sweden)

    Agata Giżycka

    2015-12-01

    Full Text Available Programmed necrosis has been proven vital for organism development and homeostasis maintenance. Its regulatory effects on functional activity of the immune system, as well as on pathways regulating the death mechanisms in cells with diminished apoptotic activity, including malignant cells, have been confirmed. There is also increasing evidence indicating necrosis involvement in many human pathologies. Contrary to previous beliefs, necrosis is not only a passive, pathological, gene-independent process. However, the current knowledge regarding molecular regulation of programmed necrosis is scarce. In part this is due to the multiplicity and complexity of signaling pathways involved in programmed necrosis, as well as the absence of specific cellular markers identifying this process, but also the ambiguous and imprecise international terminology. This review presents the current state of the art on molecular mechanisms of programmed necrosis. In particular, its specific and frequent form, necroptosis, is discussed. The role of RIP1 and RIP3 kinases in this process is presented, as well as the diverse pathways induced by ligation of tumor necrosis factor α, to its receptor, TNFR1, i.e. cell survival, apoptosis or necroptosis.

  6. Cytokine-mediated downregulation of vasopressin V(1A) receptors during acute endotoxemia in rats.

    Science.gov (United States)

    Bucher, Michael; Hobbhahn, Jonny; Taeger, Kai; Kurtz, Armin

    2002-04-01

    The reduced pressure response to vasopressin during acute sepsis has directed our interest to the regulation of vasopressin V(1A) receptors. Rats were injected with lipopolysaccharide for induction of experimental gram-negative sepsis. V(1A) receptor gene expression was downregulated in the liver, lung, kidney, and heart during endotoxemia. Inasmuch as the concentrations of proinflammatory cytokines such as interleukin-1beta, tumor necrosis factor-alpha, and interferon-gamma were highly increased during sepsis, the influence of these cytokines on V(1A) receptor expression was investigated in primary cultures of hepatocytes and in the aortic vascular smooth muscle cell line A7r5. V(1A) receptor expression was downregulated by the cytokines in a nitric oxide-independent manner. Blood pressure dose-response studies after injection of endotoxin showed a diminished responsiveness to the selective V(1) receptor agonist Phe(2),Ile(3),Orn(8)-vasopressin. Our data show that sepsis causes a downregulation of V(1A) receptors and suggest that this effect is likely mediated by proinflammatory cytokines. We propose that this downregulation of V(1A) receptors contributes to the attenuated responsiveness of blood pressure in response to vasopressin and, therefore, contributes to the circulatory failure in septic shock.

  7. Upregulation of neurokinin-1 receptor expression in the lungs of patients with sarcoidosis.

    LENUS (Irish Health Repository)

    O'Connor, Terence M

    2012-02-03

    Substance P (SP) is a proinflammatory neuropeptide that is secreted by sensory nerves and inflammatory cells. Increased levels of SP are found in sarcoid bronchoalveolar lavage fluid. SP acts by binding to the neurokinin-1 receptor and increases secretion of tumor necrosis factor-alpha in many cell types. We sought to determine neurokinin-1 receptor expression in patients with sarcoidosis compared with normal controls. Neurokinin-1 receptor messenger RNA and protein expression were below the limits of detection by reverse transcriptase-polymerase chain reaction and immunohistochemistry in peripheral blood mononuclear cells of healthy volunteers (n = 9) or patients with stage 1 or 2 pulmonary sarcoidosis (n = 10), but were detected in 1\\/9 bronchoalveolar lavage cells of controls compared with 8\\/10 patients with sarcoidosis (p = 0.012) and 2\\/9 biopsies of controls compared with 9\\/10 patients with sarcoidosis (p = 0.013). Immunohistochemistry localized upregulated neurokinin-1 receptor expression to bronchial and alveolar epithelial cells, macrophages, lymphocytes, and sarcoid granulomas. The patient in whom neurokinin-1 receptor was not detected was taking corticosteroids. Incubation of the type II alveolar and bronchial epithelial cell lines A549 and SK-LU 1 with dexamethasone downregulated neurokinin-1 receptor expression. Upregulated neurokinin-1 receptor expression in patients with sarcoidosis may potentiate substance P-induced proinflammatory cytokine production in patients with sarcoidosis.

  8. Tumor necrosis factor and its p55 and p75 receptors are not required for axonal lesion-induced microgliosis in mouse fascia dentata

    DEFF Research Database (Denmark)

    Fenger, Christina; Drojdahl, Nina; Wirenfeldt, Martin

    2006-01-01

    and terminal degeneration in mice, we studied the effect of TNF and its p55 and p75 receptors on axonal lesion-induced microglial activation in fascia dentata following transection of the perforant path (PP) projection. Unexpectedly, cell counting showed that the axonal lesion-induced microglial response...... maximum. However, in spite of the induction of TNF mRNA, TNF protein level remained at base-line in fascia dentata using immunohistochemistry and ELISA. In conclusion, the results showed a lower than expected lesion-induced increase in TNF protein, and that neither TNF nor its receptors were required...... for the axonal lesion-induced microglial morphological transformation and proliferation or for the initial clearance of degenerated myelin in the PP-deafferented fascia dentata....

  9. Characterization of a relationship between the T-lymphocyte derived differentiation inducing factor (DIF) and lymphotoxin:A common receptor system for DIF, lymphotoxin and tumor necrosis factor downregulated by phorbol diesters

    International Nuclear Information System (INIS)

    Gullberg, U.; Lantz, M.; Nilsson, E.; Peetre, C.; Olsson, I.; Adolf, G.

    1987-01-01

    Here we describe results which show that recombinant lymphotoxin (rLT), like the T-lymphocyte derived differentiation inducing factor (DIF), inhibited the clonogenic growth of some myeloid leukemia cell lines by concentrations of 1 to 30 pmol/l. Wild type HL-60 cells were resistant at these concentrations but responded with differentiation into monocyte-like cells at higher concentrations. An antigenic relationship between DIF and LT was indicated because a neutralizing monoclonal anti-LT antibody bound to and neutralized both differentiation and growth inhibitory effects of DIF. An activity, which cochromatographed with DIF during all purification steps, competed with binding of both rLT and recombinant tumor necrosis factor (rTNF) to HL-60 cells. By use of radioiodinated ligand, 2100 binding sites for rLT were detected on HL-60 cells with a K d of of 330 pmol/l. At 37 deg. C bound ligand was transferred to lysosomes, followed by degradation. rTNF and rLT were shown to compete for binding sites on HL-60 cells. Receptors for both rLT and rTNF were downregulated by activators of protein kinase C such as phorbol diester or diacylglycerol; the number of cell surface receptors decreased while the K d remained unchanged. Our observations demonstrate a functional and antigenic relationship between DIF and LT and indicate that TNF, LT and DIF share binding sites on myeloid leukemia cells that are downregulated by activation of protein kinase-C. (author)

  10. Synthetic Nanoparticles That Promote Tumor Necrosis Factor Receptor 2 Expressing Regulatory T Cells in the Lung and Resistance to Allergic Airways Inflammation

    Directory of Open Access Journals (Sweden)

    Rohimah Mohamud

    2017-12-01

    Full Text Available Synthetic glycine coated 50 nm polystyrene nanoparticles (NP (PS50G, unlike ambient NP, do not promote pulmonary inflammation, but instead, render lungs resistant to the development of allergic airway inflammation. In this study, we show that PS50G modulate the frequency and phenotype of regulatory T cells (Treg in the lung, specifically increasing the proportion of tumor necrosis factor 2 (TNFR2 expressing Treg. Mice pre-exposed to PS50G, which were sensitized and then challenged with an allergen a month later, preferentially expanded TNFR2+Foxp3+ Treg, which further expressed enhanced levels of latency associated peptide and cytotoxic T-lymphocyte associated molecule-4. Moreover, PS50G-induced CD103+ dendritic cell activation in the lung was associated with the proliferative expansion of TNFR2+Foxp3+ Treg. These findings provide the first evidence that engineered NP can promote the selective expansion of maximally suppressing TNFR2+Foxp3+ Treg and further suggest a novel mechanism by which NP may promote healthy lung homeostasis.

  11. Postneonatal Mortality and Liver Changes in Cloned Pigs Associated with Human Tumor Necrosis Factor Receptor I-Fc and Human Heme Oxygenase-1 Overexpression

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    Geon A. Kim

    2017-01-01

    Full Text Available Soluble human tumor necrosis factor (shTNFRI-Fc and human heme oxygenase 1 (hHO-1 are key regulators for protection against oxidative and inflammatory injury for xenotransplantation. Somatic cells with more than 10 copy numbers of shTNFRI-Fc and hHO-1 were employed in somatic cell nuclear transfer to generate cloned pigs, thereby resulting in seven cloned piglets. However, produced piglets were all dead within 24 hours after birth. Obviously, postnatal death with liver apoptosis was reported in the higher copy number of shTNFRI-Fc and hHO-1 piglets. In liver, the transcript levels of ferritin heavy chain, light chain, transferrin, and inducible nitric oxide synthase were significantly highly expressed compared to those of lower copy number of shTNFRI-Fc and hHO-1 piglets (P<0.05. Also, H2O2 contents were increased, and superoxide dismutase was significantly lower in the higher copy number of shTNFRI-Fc and hHO-1 piglets (P<0.05. These results indicate that TNFRI-Fc and hHO-1 overexpression may apparently induce free iron in the liver and exert oxidative stress by enhancing reactive oxygen species production and block normal postneonatal liver metabolism.

  12. Association of the gene expression variation of tumor necrosis factor-α and expressions changes of dopamine receptor genes in progression of diabetic severe foot ulcers

    Directory of Open Access Journals (Sweden)

    Hajar Vaseghi

    2017-11-01

    Full Text Available Objective(s:Regulation of pro-inflammatory factors such as TNF-, which are secreted by the immune cells through induction of their several receptors including dopamine receptors (especially DRD2 and DRD3 is one of the noticeable problems in diabetic severe foot ulcer healing. This study was conducted to evaluate the alteration of TNF- in plasma as well as DRD2 and DRD3 changes in PBMCs of diabetics with severe foot ulcers. Materials and Methods: Peripheral blood samples were collected from 31 subjects with ulcers, 29 without ulcers, and 25 healthy individuals. Total mRNA was extracted from PBMCs for the study of DRD2, DRD3, and TNF- gene expression variations. Expression patterns of these genes were evaluated by real-time PCR. Consequently, concentration of TNF- was investigated in plasma. Results: Significant decrease in gene expression and plasma concentration of TNF- in PBMCs was observed in both patient groups at P Conclusion: We concluded that DRD2 and DRD3 expression alteration and presence of new DRD3 transcripts can be effective in reduction of TNF-α expression as a pro-inflammatory factor. Performing complementary studies, may explain that variations in DRD2 and DRD3 are prognostic and effective markers attributed to the development of diabetes severe foot ulcers.

  13. HIV-1 Tat C-mediated regulation of tumor necrosis factor receptor-associated factor-3 by microRNA 32 in human microglia

    Directory of Open Access Journals (Sweden)

    Mishra Ritu

    2012-06-01

    Full Text Available Abstract Background HIV-1 Tat protein is known to be associated with neuroinflammation, a condition that develops in almost half of patients infected with HIV-1. HIV-1 Tat can alter glial neuroprotective functions, leading to neurotoxicity within the CNS. HIV-1 Tat is known to be secreted from productively infected cells and can affect neighboring uninfected cells by modulating cellular gene expression in a bystander fashion. Methods We were interested to study whether exogenous exposure to HIV-1 Tat-C protein perturbs the microRNA (miRNA expression profile of human microglial cells, leading to altered protein expression. We used protein expression and purification, miRNA overexpression, miRNA knockdown, transfection, site-directed mutagenesis, real-time PCR, luciferase assay and western blotting techniques to perform our study. Results HIV-1 Tat-C treatment of human microglial cells resulted in a dose-dependent increase in miR-32 expression. We found that tumor necrosis factor-receptor–associated factor 3 TRAF3 is a direct target for miR-32, and overexpression of miR-32 in CHME3 cells decreased TRAF3 both at the mRNA and the protein level. Recovery of TRAF3 protein expression after transfection of anti-miR-32 and the results of the luciferase reporter assay provided direct evidence of TRAF3 regulation by miR-32. We found that the regulation of interferon regulatory factor 3 (IRF3 and IRF7 is controlled by cellular levels of TRAF3 protein in microglial cells, as after overexpression of miR-32 and application of anti-miR-32, expression levels of IRF3 and IRF7 were inversely regulated by expression levels of TRAF3. Thus, our results suggest a novel miRNA mediated mechanism for regulation of TRAF3 in human microglial cells exposed to HIV-1 Tat C protein. These results may help to elucidate the detrimental neuroinflammatory consequences of HIV-1 Tat C protein in bystander fashion. Conclusion HIV-1 Tat protein can modulate TRAF3 expression through

  14. Molecular characterization and evolutionary analysis of horse BAFF-R, a tumor necrosis factor receptor related to B-cell survival.

    Science.gov (United States)

    Wu, Haitao; Chen, Shanshan; Liu, Meng; Xu, Xingzhou; Ji, Xuemei; Gao, Kai; Tian, Aiying; Ke, Zhen; Zhang, Jianrong; Zhao, Bo; Zhang, Shuangquan

    2014-01-01

    B-cell survival depends on signals induced by B-cell activating factor (BAFF) that binds to the BAFF receptor (BAFF-R). Herein, a BAFF-R homolog was identified in a horse (Equus caballus). The horse BAFF-R gene, located on chromosome 28, spans 1444 base pairs and encodes a 183-amino acid protein. The protein is structurally conserved, in which the DxL motif plays an important role in binding to BAFF. Furthermore, the horse BAFF-R extracellular domain was expressed and purified, which specifically bound to His6-sBAFF and had the capability of blocking the function of His6-sBAFF in vitro. Finally, evolutionary analyses indicated that some codon sites of BAFF-R evolve with positive selection and that the genetic relationship among a horse, Chiroptera, and Caniformia are the closest. Copyright © 2013 Elsevier B.V. All rights reserved.

  15. Tumor Necrosis Factor Receptor Superfamily, Member 1B Haplotypes Increase or Decrease the Risk of Inflammatory Bowel Diseases in a New Zealand Caucasian Population

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    Lynnette R. Ferguson

    2009-01-01

    Full Text Available Inflammatory bowel diseases (IBDs comprising Crohn disease (CD and ulcerative colitis (UC are chronic inflammatory conditions with polygenic susceptibility. Interactions between TNF-alpha and TNF-alpha receptor play a fundamental role in inflammatory response. This study investigates the role that selected single nucleotide polymorphisms (SNPs and haplotypes in the TNF-alpha receptor (TNSFRSF1B gene play in the risk of IBD in a New Zealand Caucasian population. DNA samples from 388 CD, 405 UC, 27 indeterminate colitis patients, and 293 randomly selected controls, from Canterbury, New Zealand were screened for 3 common SNPs in TNSFRSF1B: rs1061622 (c.676T>C, rs1061624 (c.∗1663A>G, and rs3397 (c.∗1690T>C, using TaqMan technologies. Carrying the rs1061624 variant decreased the risk of UC in the left colon (OR 0.73, 95% CI=0.54–1.00 and of being a smoker at diagnosis (OR 0.62; 95% CI=0.40–0.96. Carrying the rs3397 variant decreased the risk of penetrating CD (OR 0.62, 95% CI=0.40–0.95. Three marker haplotype analyses revealed highly significant differences between CD patients and control subjects (χ2=29.9, df=7, P=.0001 and UC cases and controls (χ2=46.3, df=7, P<.0001. We conclude that carrying a 3-marker haplotype in the TNSFRSF1B gene may increase (e.g., haplotype of GGC was 2.9-fold more in the CD or UCpatients or decrease (e.g., TGT was 0.47-fold less in UC patients the risk of IBD in a New Zealand Caucasian population.

  16. Association of transforming growth-factor alpha gene polymorphisms with nonsyndromic cleft palate only (CPO)

    Energy Technology Data Exchange (ETDEWEB)

    Shiang, R. (Univ. of California, Irvine, CA (United States)); Lidral, A.C.; Ardinger, H.H.; Murray, J.C.; Romitti, P.A.; Munger, R.G.; Buetow, K.H.

    1993-10-01

    Genetic analysis and tissue-specific expression studies support a role for transforming growth-factor alpha (TGFA) in craniofacial development. Previous studies have confirmed an association of alleles for TGFA with nonsyndromic cleft lip with or without cleft palate (CL/P) in humans. The authors carried out a retrospective association study to determine whether specific allelic variants of the TGFA gene are also associated with cleft palate only (CPO). The PCR products from 12 overlapping sets of primers to the TGFA cDNA were examined by using single-strand conformational polymorphism analysis. Four DNA polymorphic sites for TGFA were identified in the 3[prime] untranslated region of the TGFA gene. These variants, as well as previously identified RFLPs for TGFA, were characterized in case and control populations for CPO by using X[sup 2] analysis. A significant association between alleles of TGFA and CPO was identified which further supports a role for this gene as one of the genetic determinants of craniofacial development. Sequence analysis of the variants disclosed a cluster of three variable sites within 30 bp of each other in the 3[prime] untranslated region previously associated with an antisense transcript. These studies extend the role for TGFA in craniofacial morphogenesis and support an interrelated mechanism underlying nonsyndromic forms of CL/P. 46 refs., 3 figs., 3 tabs.

  17. Adenosine inhibits neutrophil vascular endothelial growth factor release and transendothelial migration via A2B receptor activation.

    LENUS (Irish Health Repository)

    Wakai, A

    2012-02-03

    The effects of adenosine on neutrophil (polymorphonuclear neutrophils; PMN)-directed changes in vascular permeability are poorly characterized. This study investigated whether adenosine modulates activated PMN vascular endothelial growth factor (vascular permeability factor; VEGF) release and transendothelial migration. PMN activated with tumour necrosis factor-alpha (TNF-alpha, 10 ng\\/mL) were incubated with adenosine and its receptor-specific analogues. Culture supernatants were assayed for VEGF. PMN transendothelial migration across human umbilical vein endothelial cell (HUVEC) monolayers was assessed in vitro. Adhesion molecule receptor expression was assessed flow cytometrically. Adenosine and some of its receptor-specific analogues dose-dependently inhibited activated PMN VEGF release. The rank order of potency was consistent with the affinity profile of human A2B receptors. The inhibitory effect of adenosine was reversed by 3,7-dimethyl-1-propargylxanthine, an A2 receptor antagonist. Adenosine (100 microM) or the A2B receptor agonist 5\\'-N-ethylcarboxamidoadenosine (NECA, 100 microM) significantly reduced PMN transendothelial migration. However, expression of activated PMN beta2 integrins and HUVEC ICAM-1 were not significantly altered by adenosine or NECA. Adenosine attenuates human PMN VEGF release and transendothelial migration via the A2B receptor. This provides a novel target for the modulation of PMN-directed vascular hyperpermeability in conditions such as the capillary leak syndrome.

  18. The Mediterranean diet pattern and its main components are associated with lower plasma concentrations of tumor necrosis factor receptor 60 in patients at high risk for cardiovascular disease.

    Science.gov (United States)

    Urpi-Sarda, Mireia; Casas, Rosa; Chiva-Blanch, Gemma; Romero-Mamani, Edwin Saúl; Valderas-Martínez, Palmira; Salas-Salvadó, Jordi; Covas, María Isabel; Toledo, Estefanía; Andres-Lacueva, Cristina; Llorach, Rafael; García-Arellano, Ana; Bulló, Monica; Ruiz-Gutierrez, Valentina; Lamuela-Raventos, Rosa M; Estruch, Ramon

    2012-06-01

    Adherence to a Mediterranean diet (MD) is associated with a reduced risk of coronary heart disease. However, the molecular mechanisms involved are not fully understood. The aim of this study was to compare the effects of 2 MD with those of a low-fat-diet (LFD) on circulating inflammatory biomarkers related to atherogenesis. A total of 516 participants included in the Prevention with Mediterranean Diet Study were randomized into 3 intervention groups [MD supplemented with virgin olive oil (MD-VOO); MD supplemented with mixed nuts (MD-Nuts); and LFD]. At baseline and after 1 y, participants completed FFQ and adherence to MD questionnaires, and plasma concentrations of inflammatory markers including intercellular adhesion molecule-1(ICAM-1), IL-6, and 2 TNF receptors (TNFR60 and TNFR80) were measured by ELISA. At 1 y, the MD groups had lower plasma concentrations of IL-6, TNFR60, and TNFR80 (P < 0.05), whereas ICAM-1, TNFR60, and TNFR80 concentrations increased in the LFD group (P < 0.002). Due to between-group differences, participants in the 2 MD groups had lower plasma concentrations of ICAM-1, IL-6, TNFR60, and TNFR80 compared to those in the LFD group (P ≤ 0.028). When participants were categorized in tertiles of 1-y changes in the consumption of selected foods, those in the highest tertile of virgin olive oil (VOO) and vegetable consumption had a lower plasma TNFR60 concentration compared with those in tertile 1 (P < 0.02). Moreover, the only changes in consumption that were associated with 1-y changes in the geometric mean TNFR60 concentrations were those of VOO and vegetables (P = 0.01). This study suggests that a MD reduces TNFR concentrations in patients at high cardiovascular risk.

  19. Orofacial clefts, parental cigarette smoking, and transforming growth factor-alpha gene variants

    Energy Technology Data Exchange (ETDEWEB)

    Shaw, G.M.; Wasserman, C.R.; O`Malley, C.D. [California Birth Defects Monitoring Program, Emeryville, CA (United States)] [and others

    1996-03-01

    Results of studies determine whether women who smoke during early pregnancy are at increased risk of delivering infants with orofacial clefts have been mixed, and recently a gene-environment interaction between maternal smoking, transforming growth factor-alpha (TGFa), and clefting has been reported. Using a large population-based case-control study, we investigated whether parental periconceptional cigarette smoking was associated with an increased risk for having offspring with orofacial clefts. We also investigated the influence of genetic variation of the TGFa locus on the relation between smoking and clefting. Parental smoking information was obtained from telephone interviews with mothers of 731 (84.7% of eligible) orofacial cleft case infants and with mothers of 734 (78.2%) nonmalformed control infants. DNA was obtained from newborn screening blood spots and genotyped for the allelic variants of TGFa. We found that risks associated with maternal smoking were most elevated for isolated cleft lip with or without cleft palate, (odds ratio 2.1 [95% confidence interval 1.3-3.6]) and for isolated cleft palate (odds ratio 2.2 [1.1-4.5]) when mothers smoked {ge} 20 cigarrettes/d. These risks for white infants ranged from 3-fold to 11-fold across phenotypic groups. Paternal smoking was not associated with clefting among the offspring of nonsmoking mothers, and passive smoke exposures were associated with at most slightly increased risks. This study offers evidence that the risk for orofacial clefting in infants may be influenced by maternal smoke exposures alone as well as in combination (gene-environment interaction) with the presence of the uncommon TGFa allele. 56 refs., 5 tabs.

  20. Tumour necrosis factor-alpha increases extravasation of virus particles into tumour tissue by activating the Rho A/Rho kinase pathway

    Czech Academy of Sciences Publication Activity Database

    Seki, T.; Carroll, F.; Illingworth, S.; Green, N.; Cawood, R.; Bachtarzi, H.; Šubr, Vladimír; Fisher, K. D.; Seymour, L. W.

    2011-01-01

    Roč. 156, č. 3 (2011), s. 381-389 ISSN 0168-3659 Institutional research plan: CEZ:AV0Z40500505 Keywords : drug delivery * adenovirus * vascular permeability Subject RIV: CD - Macromolecular Chemistry Impact factor: 5.732, year: 2011

  1. Benzo[a]pyrene and tumor necrosis factor-alpha coordinately increase genotoxic damage and the production of proinflammatory mediators in alveolar epithelial type II cells

    Czech Academy of Sciences Publication Activity Database

    Umannová, Lenka; Machala, M.; Topinka, Jan; Schmuczerová, Jana; Krčmář, P.; Neča, J.; Šujanová, Klára; Kozubík, Alois; Vondráček, Jan

    2011-01-01

    Roč. 206, č. 2 (2011), s. 121-129 ISSN 0378-4274 R&D Projects: GA ČR(CZ) GAP503/11/1227 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702; CEZ:AV0Z50390512; CEZ:AV0Z50390703 Keywords : DNA adducts * proinflammatory cytokines * COX -2 Subject RIV: BO - Biophysics Impact factor: 3.230, year: 2011

  2. Respiratory mechanics and plasma levels of tumor necrosis factor alpha and interleukin 6 are affected by gas humidification during mechanical ventilation in dogs.

    Directory of Open Access Journals (Sweden)

    Claudia Hernández-Jiménez

    Full Text Available The use of dry gases during mechanical ventilation has been associated with the risk of serious airway complications. The goal of the present study was to quantify the plasma levels of TNF-alpha and IL-6 and to determine the radiological, hemodynamic, gasometric, and microscopic changes in lung mechanics in dogs subjected to short-term mechanical ventilation with and without humidification of the inhaled gas. The experiment was conducted for 24 hours in 10 dogs divided into two groups: Group I (n = 5, mechanical ventilation with dry oxygen dispensation, and Group II (n = 5, mechanical ventilation with oxygen dispensation using a moisture chamber. Variance analysis was used. No changes in physiological, hemodynamic, or gasometric, and radiographic constants were observed. Plasma TNF-alpha levels increased in group I, reaching a maximum 24 hours after mechanical ventilation was initiated (ANOVA p = 0.77. This increase was correlated to changes in mechanical ventilation. Plasma IL-6 levels decreased at 12 hours and increased again towards the end of the study (ANOVA p>0.05. Both groups exhibited a decrease in lung compliance and functional residual capacity values, but this was more pronounced in group I. Pplat increased in group I (ANOVA p = 0.02. Inhalation of dry gas caused histological lesions in the entire respiratory tract, including pulmonary parenchyma, to a greater extent than humidified gas. Humidification of inspired gases can attenuate damage associated with mechanical ventilation.

  3. Respiratory mechanics and plasma levels of tumor necrosis factor alpha and interleukin 6 are affected by gas humidification during mechanical ventilation in dogs.

    Science.gov (United States)

    Hernández-Jiménez, Claudia; García-Torrentera, Rogelio; Olmos-Zúñiga, J Raúl; Jasso-Victoria, Rogelio; Gaxiola-Gaxiola, Miguel O; Baltazares-Lipp, Matilde; Gutiérrez-González, Luis H

    2014-01-01

    The use of dry gases during mechanical ventilation has been associated with the risk of serious airway complications. The goal of the present study was to quantify the plasma levels of TNF-alpha and IL-6 and to determine the radiological, hemodynamic, gasometric, and microscopic changes in lung mechanics in dogs subjected to short-term mechanical ventilation with and without humidification of the inhaled gas. The experiment was conducted for 24 hours in 10 dogs divided into two groups: Group I (n = 5), mechanical ventilation with dry oxygen dispensation, and Group II (n = 5), mechanical ventilation with oxygen dispensation using a moisture chamber. Variance analysis was used. No changes in physiological, hemodynamic, or gasometric, and radiographic constants were observed. Plasma TNF-alpha levels increased in group I, reaching a maximum 24 hours after mechanical ventilation was initiated (ANOVA p = 0.77). This increase was correlated to changes in mechanical ventilation. Plasma IL-6 levels decreased at 12 hours and increased again towards the end of the study (ANOVA p>0.05). Both groups exhibited a decrease in lung compliance and functional residual capacity values, but this was more pronounced in group I. Pplat increased in group I (ANOVA p = 0.02). Inhalation of dry gas caused histological lesions in the entire respiratory tract, including pulmonary parenchyma, to a greater extent than humidified gas. Humidification of inspired gases can attenuate damage associated with mechanical ventilation.

  4. Alopecia induced by tumour necrosis factor-alpha antagonists: description of 52 cases and disproportionality analysis in a nationwide pharmacovigilance database.

    Science.gov (United States)

    Béné, Johana; Moulis, Guillaume; Auffret, Marine; Lefevre, Guillaume; Coquerelle, Pascal; Coupe, Patrick; Péré, Patrice; Gautier, Sophie

    2014-08-01

    The aim of this research was to describe the cases of TNF-α antagonist-related alopecia reported in the French Pharmacovigilance Database (FPVD) and to investigate the association between exposure to TNF-α antagonists and occurrence of alopecia. All spontaneous reports of TNF-α antagonist-related alopecia recorded in the FPVD between January 2000 and April 2012 were colligated and described. We conducted disproportionality analyses (case/non-case method) to assess the link between the occurrence of alopecia and exposure to TNF-α antagonists. Cases were all reports of alopecia and non-cases were all other reports recorded during the study period. Exposure to TNF-α antagonists was sought in cases and in non-cases. Reporting odds ratios (RORs) were calculated to assess the association. Docetaxel was used as positive control and acetaminophen as negative control. We performed sensitivity analyses excluding cases of androgenic alopecia and those occurring in psoriatic patients. Among 282 590 spontaneous reports of adverse drug reactions (ADRs) collated in the FPVD, 1068 cases (alopecia reports) were identified. Of these cases, 52 (4.9%) occurred during exposure to TNF-α antagonists (18 involved infliximab, 17 adalimumab, 15 etanercept and 2 certolizumab). Exposure to TNF-α antagonists was more frequent among alopecia reports than among other ADR reports for all TNF-α antagonists pooled (ROR 3.0, 95% CI 2.3, 4.0) as well as for each antagonist separately, with similar values. Sensitivity analyses yielded similar results. The RORs were 29.9 (95% CI 25.3, 35.5) with docetaxel and 0.3 (95% CI 0.2, 0.4) with acetaminophen. The present study confirms a strong link between TNF-α antagonist exposure (class effect) and the occurrence of alopecia. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  5. [Spontaneous and mitogen-induced production of proinflammatory cytokines (interleukin-1 and tumor necrosis factor-alpha) in patients with chronic chlamydia infection of urogenital system].

    Science.gov (United States)

    Driians'ka, V Ie; Drannik, H M; Vashchenko, S M; Fesenkova, V I; Papakina, V S

    2004-03-01

    The article contributes to studying functional activity of mononuclear and macrophage immune cells by spontaneous and induced production of IL-1 and TNF-alpha cytokines in patients with chronic urogenital clamidiosis. The patients with monoinfection were shown to have high level of IL-1 and low level of TNF-alpha, while the patients with mixed infection of urogenital tract presented with the high production of TNF-alpha. The cells activation raise cytokines production not to the level observed among healthy persons. It suggests decreasing compensatory regulation in yet higher activated cells.

  6. Peptidylarginine deiminase 2 is required for tumor necrosis factor alpha-induced citrullination and arthritis, but not neutrophil extracellular trap formation

    DEFF Research Database (Denmark)

    Bawadekar, Mandar; Shim, Daeun; Johnson, Chad J

    2017-01-01

    Citrullination, the post-translational conversion of arginines to citrullines, may contribute to rheumatoid arthritis development given the generation of anti-citrullinated protein antibodies (ACPAs). However, it is not known which peptidylarginine deiminase (PAD) catalyzes the citrullination seen...... and pathological scoring were all reduced in the absence of PAD2. Thus, PAD2 contributes to TNFα-induced citrullination and arthritis, but is not required for NETosis. In contrast, PAD4, which is critical for NETosis, is dispensable for generalized citrullination supporting the possibility that NETs may...

  7. Spironolactone inhibits production of proinflammatory cytokines, including tumour necrosis factor-alpha and interferon-gamma, and has potential in the treatment of arthritis

    DEFF Research Database (Denmark)

    Bendtzen, K; Hansen, P R; Rieneck, K

    2003-01-01

    and interleukin 6 (70-90% inhibition). Release of these cytokines was also suppressed when testing whole blood from RA patients receiving 50 mg spironolactone twice daily, indicating that pharmaceutical use of the drug may suppress the release of inflammatory cytokines. Spironolactone therapy was generally well...

  8. Beneficial effect of treatment with a monoclonal anti-tumor necrosis factor-alpha antibody on markers of coagulation and fibrinolysis in patients with active Crohn's disease

    NARCIS (Netherlands)

    Hommes, DW; van Dullemen, HM; Levi, M; Van der Ende, A; Woody, J; Tytgat, GNJ; van Deventer, SJH

    1997-01-01

    Crohn's disease has frequently been associated with coagulation abnormalities, causing intravascular deposition of fibrin and local infarction which can subsequently compromise the gut mucosa. Also, arterial and venous thromboembolic complications of larger vessels appear to be associated with

  9. Staphylococcus aureus alpha-toxin induces apoptosis in peripheral blood mononuclear cells : role of endogenous tumour necrosis factor-alpha and the mitochondrial death pathway

    NARCIS (Netherlands)

    Haslinger, Bettina; Strangfeld, Katrin; Peters, Georg; Schulze-Osthoff, Klaus; Sinha, Bhanu

    2003-01-01

    Staphylococcus aureus infections can result in septic and toxic shock with depletion of immune cells and massive cytokine production. Recently, we showed that, in S. aureus-infected Jurkat T cells, alpha-toxin is the major mediator of caspase activation and apoptosis. Here, we investigated the

  10. LPS-stimulated tumor necrosis factor-alpha and interleukin-6 mRNA and cytokine responses following acute psychological stress.

    Science.gov (United States)

    Huang, Chun-Jung; Stewart, Jennifer K; Franco, R Lee; Evans, Ronald K; Lee, Zendra P; Cruz, Tracey Dawson; Webb, Heather E; Acevedo, Edmund O

    2011-11-01

    The purpose of this study was to examine the effect of acute psychological stress on LPS-stimulated TNF-α and IL-6 mRNA expression. Twenty-one healthy male subjects participated in 20 min of acute stress. Blood samples for norepinephrine and LPS-stimulated TNF-α and IL-6 cytokines and mRNA were drawn prior to, immediately after and 1-h after stress. Stress-induced increases in anxiety scores, cortisol, plasma norepinephrine, and heart rate demonstrated that the experimental protocol elicited an acute stress response. LPS-stimulated TNF-α mRNA decreased significantly immediately post-stress and partially recovered at 1h post-stress, whereas LPS-stimulated IL-6 mRNA exhibited a significant change across time, with an increase immediately after stress and a decrease 1h after stress. Trends in LPS-stimulated TNF-α and IL-6 cytokine concentrations followed the patterns of mRNA expression. A negative correlation of body mass index (BMI) and percent change of LPS-stimulated TNF-α mRNA was observed immediately post-stress, and BMI positively correlated with percent change of LPS-stimulated IL-6 cytokine levels immediately following stress. These findings demonstrated that acute psychological stress affects LPS-stimulated IL-6 and TNF-α gene expression. These results also indicate that BMI may impact the effects of psychological stress on cytokine responses to immune challenge. Further examination of the effects of stress on synthesis of other cellular cytokines and investigation of the association of BMI and stress responses will provide a more clear representation of the cytokine responses to acute psychological stress. In addition, studies examining the influence of gender on the response of immune cell subsets to acute stress and the possible mediating effect of BMI are warranted. Published by Elsevier Ltd.

  11. Induction of cytokine (interleukin-1alpha and tumor necrosis factor-alpha) and chemokine (CCL20, CCL27, and CXCL8) alarm signals after allergen and irritant exposure

    NARCIS (Netherlands)

    Spiekstra, S.W.; Toebak, M.J.; Sampat-Sardjoepersad, S.; van Beek, P.J; Boorsma, D.M.; Stoof, T.J.; von Blomberg, B.M.; Scheper, R.J.; Bruynzeel, D.P.; Rustemeyer, T.; Gibbs, S.

    2005-01-01

    The immune system is called into action by alarm signals generate from injured tissues. We examined the nature of these alarm signals after exposure of skin residential cells to contact allergens (nickel sulfate and potassium dichromate) and a contact irritant [sodium dodecyl sulfate (SDS)]. Nickel

  12. Hantaan Virus Nucleocapsid Protein Binds to Importin alpha Proteins and Inhibits Tumor Necrosis Factor Alpha-Induced Activation of Nuclear Factor Kappa B

    Science.gov (United States)

    2008-11-19

    bipartite) stretches of the basic amino acids arginine and lysine (21). There are some reports of viral proteins, including VP24 of Ebola virus and ORF6...nucleus by importin 3 and importin 4. J. Biol. Chem. 280:15942–15951. 7. Fagerlund, R., K. Melen, L. Kinnunen, and I. Julkunen. 2002. Arginine / lysine ...out- comes correlate with the levels of TNF- (24). Recently, studies have begun to focus on the ability of han- taviruses to antagonize the innate

  13. Tumor necrosis factor-alpha potentiates genotoxic effects of benzo[a]pyrene in rat liver epithelial cells through upregulation of cytochrome P450 1B1 expression

    Czech Academy of Sciences Publication Activity Database

    Umannová, Lenka; Machala, M.; Topinka, Jan; Nováková, Zuzana; Milcová, Alena; Kozubík, Alois; Vondráček, Jan

    2008-01-01

    Roč. 640, 1-2 (2008), s. 162-169 ISSN 0027-5107 R&D Projects: GA ČR(CZ) GA524/05/0595 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702; CEZ:AV0Z50390512; CEZ:AV0Z50390703 Keywords : TNF-alpha * BaP * CYP1B1 Subject RIV: BO - Biophysics Impact factor: 3.198, year: 2008

  14. Gestational Day-Dependent Expression of Interleukin-10 and Tumor Necrosis Factor-alpha in Porphyromonas gingivalis-infected Pregnant Rats

    Directory of Open Access Journals (Sweden)

    Banun Kusumawardani

    2014-04-01

    Full Text Available Normal 0 false false false IN X-NONE X-NONE MicrosoftInternetExplorer4 Fetal growth restriction remains a major cause of neonatal morbidity and mortality. Porphyromonas gingivaliscan induce placental inflammatory response resulting in fetal growth restriction. Objective: This study aimed to evaluate the potential utility of the pro-inflammatory cytokine TNF-α and anti-inflammatory cytokine IL-10 in rat placental tissues to understand whether these events were causally related. Methods: Female rats were infected with live-Porphyromonas gingivalis at concentration of 2x109 cells/ml into subgingival sulcus area of the maxillary first molar before and/or during pregnancy. They were sacrificed on gestational day (GD-14 and GD20. The expression of TNF-α and IL-10 in macrophages and trophoblast cells were detected by immunohistochemistry. Results: A higher expression of TNF-α was found in spongiotrophoblast of the Pg-BD group on GD14 (6.30±1.16, and in trophoblastic giant cells of Pg-D group on GD20 (5.50±1.35. Furthermore, a higher expression of IL-10 was found in trophoblastic giant cells of the Pg-BD group on GD14 (4.50±1.51 and in syncytiotrophoblasts of Pg-BD group on GD20 (8.70±2.67. Conclusion: The expression of TNF-α on GD14 and GD20 were accompanied by increased expression of IL-10. The placental pathologic conditions induced by Porphyromonas gingivalis can be inhibited by elevated expression of IL-10 in macrophages and trophoblast cells.DOI: 10.14693/jdi.v20i3.199

  15. Experimental study of cerebrospinal fluid tumor necrosis factor-alpha release in penicillin- and cephalosporin-resistant pneumococcal meningitis treated with different antibiotic schedules

    Directory of Open Access Journals (Sweden)

    M. Vivas

    2017-08-01

    Conclusion: CSF TNF-α levels were significantly lower in rabbits treated with daptomycin than in rabbits treated with ceftriaxone. Daptomycin avoided the inflammatory peak after administration observed in ceftriaxone-treated rabbits. The use of daptomycin plus dexamethasone achieved a significantly larger reduction in CSF TNF-α levels.

  16. Tumour necrosis factor-alpha (TNF-alpha) transcription and translation in the CD4+ T cell-transplanted scid mouse model of colitis

    DEFF Research Database (Denmark)

    Williams, A M; Whiting, C V; Bonhagen, K

    1999-01-01

    The adoptive transfer of activated CD4+ alpha/beta T cell blasts from the spleens of immunocompetent C.B-17+/+ or BALB/cdm2 mice into C.B-17scid/scid (scid) mice induces a colitis in the scid recipient within 8 weeks, which progresses to severe disease within 16 weeks. T cells isolated from...

  17. Gestational Day-Dependent Expression of Interleukin-10 and Tumor Necrosis Factor-alpha in Porphyromonas gingivalis-infected Pregnant Rats

    OpenAIRE

    Banun Kusumawardani; Marsetyawan HNE Soesatyo; Djaswadi Dasuki; Widya Asmara

    2014-01-01

    Fetal growth restriction remains a major cause of neonatal morbidity and mortality. Porphyromonas gingivaliscan induce placental inflammatory response resulting in fetal growth restriction. Objective: This study aimed to evaluate the potential utility of the pro-inflammatory cytokine TNF-α and anti-inflammatory cytokine IL-10 in rat placental tissues to understand whether these events were causally related. Methods: Female rats were infected with live-Porphyromonas gingivalis at concentratio...

  18. Polymorphisms in the tumor necrosis factor alpha and interleukin 1-beta promoters with possible gene regulatory functions increase the risk of preterm birth

    DEFF Research Database (Denmark)

    Hollegaard, Mads Vilhelm; Grove, Jakob; Thorsen, Poul

    2008-01-01

    >C and IL1B -511 C>T rare alleles (C and T) have an increased risk of preterm birth with OR 3.1 (95\\% CI: 1.0-10.3) and OR 6.4 (95\\% CI: 1.3-60.5), respectively. Two estimated TNFA haplotypes were associated with preterm birth with OR 3.1 (p=0.037) and OR 2.7 (p=0.045). Conclusion. Polymorphisms...... in the cytokine genes TNFA and IL1B may increase the risk of preterm birth, possibly by a dysregulation of the immune system in pregnancy....

  19. Polymorphisms in the tumor necrosis factor alpha and interleukin 1-beta promoters with possible gene regulatory functions increase the risk of preterm birth

    DEFF Research Database (Denmark)

    Hollegaard, Mads Vilhelm; Grove, Jakob; Thorsen, Poul

    2008-01-01

    >C and IL1B -511 C>T rare alleles (C and T) have an increased risk of preterm birth with OR 3.1 (95% CI: 1.0-10.3) and OR 6.4 (95% CI: 1.3-60.5), respectively. Two estimated TNFA haplotypes were associated with preterm birth with OR 3.1 (p=0.037) and OR 2.7 (p=0.045). CONCLUSION: Polymorphisms...... in the cytokine genes TNFA and IL1B may increase the risk of preterm birth, possibly by a dysregulation of the immune system in pregnancy....

  20. Interferon beta 1, an intermediate in the tumor necrosis factor alpha- induced increased MHC class I expression and an autocrine regulator of the constitutive MHC class I expression

    OpenAIRE

    1987-01-01

    In conclusion, our observations indicate that the constitutive MHC class I expression is regulated by autocrine production of IFN-beta 1. TNF-alpha acts as an enhancer of the autocrine production of IFN-beta 1, and consequently as an enhancer of the MHC class I expression and viral protection.

  1. Tumor Necrosis Factor Alpha and Insulin-Like Growth Factor 1 Induced Modifications of the Gene Expression Kinetics of Differentiating Skeletal Muscle Cells.

    Directory of Open Access Journals (Sweden)

    Swanhild U Meyer

    Full Text Available TNF-α levels are increased during muscle wasting and chronic muscle degeneration and regeneration processes, which are characteristic for primary muscle disorders. Pathologically increased TNF-α levels have a negative effect on muscle cell differentiation efficiency, while IGF1 can have a positive effect; therefore, we intended to elucidate the impact of TNF-α and IGF1 on gene expression during the early stages of skeletal muscle cell differentiation.This study presents gene expression data of the murine skeletal muscle cells PMI28 during myogenic differentiation or differentiation with TNF-α or IGF1 exposure at 0 h, 4 h, 12 h, 24 h, and 72 h after induction. Our study detected significant coregulation of gene sets involved in myoblast differentiation or in the response to TNF-α. Gene expression data revealed a time- and treatment-dependent regulation of signaling pathways, which are prominent in myogenic differentiation. We identified enrichment of pathways, which have not been specifically linked to myoblast differentiation such as doublecortin-like kinase pathway associations as well as enrichment of specific semaphorin isoforms. Moreover to the best of our knowledge, this is the first description of a specific inverse regulation of the following genes in myoblast differentiation and response to TNF-α: Aknad1, Cmbl, Sepp1, Ndst4, Tecrl, Unc13c, Spats2l, Lix1, Csdc2, Cpa1, Parm1, Serpinb2, Aspn, Fibin, Slc40a1, Nrk, and Mybpc1. We identified a gene subset (Nfkbia, Nfkb2, Mmp9, Mef2c, Gpx, and Pgam2, which is robustly regulated by TNF-α across independent myogenic differentiation studies.This is the largest dataset revealing the impact of TNF-α or IGF1 treatment on gene expression kinetics of early in vitro skeletal myoblast differentiation. We identified novel mRNAs, which have not yet been associated with skeletal muscle differentiation or response to TNF-α. Results of this study may facilitate the understanding of transcriptomic networks underlying inhibited muscle differentiation in inflammatory diseases.

  2. Plasma L-cystine/L-glutamate imbalance increases tumor necrosis factor-alpha from CD14+ circulating monocytes in patients with advanced cirrhosis.

    Directory of Open Access Journals (Sweden)

    Eiji Kakazu

    Full Text Available BACKGROUND AND AIMS: The innate immune cells can not normally respond to the pathogen in patients with decompensated cirrhosis. Previous studies reported that antigen-presenting cells take up L-Cystine (L-Cys and secrete substantial amounts of L-Glutamate (L-Glu via the transport system Xc- (4F2hc+xCT, and that this exchange influences the immune responses. The aim of this study is to investigate the influence of the plasma L-Cys/L-Glu imbalance observed in patients with advanced cirrhosis on the function of circulating monocytes. METHODS: We used a serum-free culture medium consistent with the average concentrations of plasma amino acids from patients with advanced cirrhosis (ACM, and examined the function of CD14+ monocytes or THP-1 under ACM that contained 0-300 nmol/mL L-Cys with LPS. In patients with advanced cirrhosis, we actually determined the TNF-alpha and xCT mRNA of monocytes, and evaluated the correlation between the plasma L-Cys/L-Glu ratio and TNF-alpha. RESULTS: The addition of L-Cys significantly increased the production of TNF alpha from monocytes under ACM. Monocytes with LPS and THP-1 expressed xCT and a high level of extracellular L-Cys enhanced L-Cys/L-Glu antiport, and the intracellular GSH/GSSG ratio was decreased. The L-Cys transport was inhibited by excess L-Glu. In patients with advanced cirrhosis (n = 19, the TNF-alpha and xCT mRNA of monocytes were increased according to the Child-Pugh grade. The TNF-alpha mRNA of monocytes was significantly higher in the high L-Cys/L-Glu ratio group than in the low ratio group, and the plasma TNF-alpha was significantly correlated with the L-Cys/L-Glu ratio. CONCLUSIONS: A plasma L-Cys/L-Glu imbalance, which appears in patients with advanced cirrhosis, increased the TNF-alpha from circulating monocytes via increasing the intracellular oxidative stress. These results may reflect the immune abnormality that appears in patients with decompensated cirrhosis.

  3. Discovery of novel hydroxamates as highly potent tumor necrosis factor-[alpha] converting enzyme inhibitors. Part II: Optimization of the S3′ pocket

    Energy Technology Data Exchange (ETDEWEB)

    Mazzola Jr., Robert D.; Zhu, Zhaoning; Sinning, Lisa; McKittrick, Brian; Lavey, Brian; Spitler, James; Kozlowski, Joseph; Neng-Yang, Shih; Zhou, Guowei; Guo, Zhuyan; Orth, Peter; Madison, Vincent; Sun, Jing; Lundell, Daniel; Niu, Xiaoda (SPRI)

    2010-10-01

    A series of cyclopropyl hydroxamic acids were prepared. Many of the compounds displayed picomolar affinity for the TACE enzyme while maintaining good to excellent selectivity profiles versus MMP-1, -2, -3, -7, -14, and ADAM-10. X-ray analysis of an inhibitor in the TACE active site indicated that the molecules bound to the enzyme in the S1{prime}-S3{prime} pocket.

  4. Tumor necrosis factor-alpha but not interleukin-1 beta or interleukin-8 concentrations correlate with angiogenic activity of peritoneal fluid from patients with minimal to mild endometriosis

    NARCIS (Netherlands)

    Maas, J. W.; Calhaz-Jorge, C.; ter Riet, G.; Dunselman, G. A.; de Goeij, A. F.; Struijker-Boudier, H. A.

    2001-01-01

    OBJECTIVE: To assess the angiogenic activity of peritoneal fluid in women with minimal to mild endometriosis and to investigate the relationship between this activity and the concentration of macrophage-derived angiogenic factors and clinical variables, such as phase of menstrual cycle, type of

  5. Induction of Mdr1b expression by tumor necrosis factor-alpha in rat liver cells is independent of p53 but requires NF-kappa B signaling

    NARCIS (Netherlands)

    Ros, J.E.; Schuetz, JD; Geuken, M; Streetz, K; Moshage, H; Kuipers, F; Manns, MP; Jansen, PLM; Trautwein, C; Muller, M

    The multidrug resistance protein Mdr1b in rats is upregulated during liver regeneration after partial hepatectomy or after endotoxin treatment. We hypothesize that up-regulation of Mdr1b in these models is TNF-alpha -dependent. The mechanism of Mdr1b activation by TNF-alpha is unknown as TNF-alpha

  6. Induction of Mdr1b expression by tumor necrosis factor-alpha in rat liver cells is independent of p53 but requires NF-kappaB signaling

    NARCIS (Netherlands)

    Ros, J. E.; Schuetz, J. D.; Geuken, M.; Streetz, K.; Moshage, H.; Kuipers, F.; Manns, M. P.; Jansen, P. L.; Trautwein, C.; Müller, M.

    2001-01-01

    The multidrug resistance protein Mdr1b in rats is up-regulated during liver regeneration after partial hepatectomy or after endotoxin treatment. We hypothesize that up-regulation of Mdr1b in these models is TNF-alpha-dependent. The mechanism of Mdr1b activation by TNF-alpha is unknown as TNF-alpha

  7. Canadian Association of Gastroenterology Clinical Practice Guidelines: The Use of Tumour Necrosis Factor-Alpha Antagonist Therapy in Crohn’s Disease

    Directory of Open Access Journals (Sweden)

    Daniel C Sadowski

    2009-01-01

    Full Text Available BACKGROUND: Guidelines regarding the use of infliximab in Crohn’s disease were previously published by the Canadian Association of Gastroenterology in 2004. However, recent clinical findings and drug developments warrant a review and update of these guidelines.

  8. Anti-Interleukin-1 Beta/Tumor Necrosis Factor-Alpha IgY Antibodies Reduce Pathological Allergic Responses in Guinea Pigs with Allergic Rhinitis.

    Science.gov (United States)

    Wei-Xu, Hu; Wen-Yun, Zhou; Xi-Ling, Zhu; Zhu, Wen; Li-Hua, Wu; Xiao-Mu, Wu; Hui-Ping, Wei; Wen-Ding, Wang; Dan, He; Qin, Xiang; Guo-Zhu, Hu

    2016-01-01

    This study aims to determine whether the combined blockade of IL-1β and TNF-α can alleviate the pathological allergic inflammatory reaction in the nasal mucosa and lung tissues in allergic rhinitis (AR) guinea pigs. Healthy guinea pigs treated with saline were used as the healthy controls. The AR guinea pigs were randomly divided into (1) the AR model group treated with intranasal saline; (2) the 0.1% nonspecific IgY treatment group; (3) the 0.1% anti-TNF-α IgY treatment group; (4) the 0.1% anti-IL-1β IgY treatment group; (5) the 0.1% combined anti-IL-1β and TNF-α IgY treatment group; and (6) the fluticasone propionate treatment group. The inflammatory cells were evaluated using Wright's staining. Histopathology was examined using hematoxylin-eosin staining. The results showed that the number of eosinophils was significantly decreased in the peripheral blood, nasal lavage fluid, and bronchoalveolar lavage fluid (P guinea pigs. The data suggest that topical blockade of IL-1β and TNF-α could reduce pathological allergic inflammation in the nasal mucosa and lung tissues in AR guinea pigs.

  9. Cytokines interleukin-1beta and tumor necrosis factor-alpha regulate different transcriptional and alternative splicing networks in primary beta-cells

    DEFF Research Database (Denmark)

    Ortis, Fernanda; Naamane, Najib; Flamez, Daisy

    2010-01-01

    OBJECTIVE: Cytokines contribute to pancreatic beta-cell death in type 1 diabetes. This effect is mediated by complex gene networks that remain to be characterized. We presently utilized array analysis to define the global expression pattern of genes, including spliced variants, modified by the cy...

  10. Cytotoxic macrophage-released tumour necrosis factor-alpha (TNF-α) as a killing mechanism for cancer cell death after cold plasma activation

    Science.gov (United States)

    Kaushik, Nagendra Kumar; Kaushik, Neha; Min, Booki; Choi, Ki Hong; Hong, Young June; Miller, Vandana; Fridman, Alexander; Choi, Eun Ha

    2016-03-01

    The present study aims at studying the anticancer role of cold plasma-activated immune cells. The direct anti-cancer activity of plasma-activated immune cells against human solid cancers has not been described so far. Hence, we assessed the effect of plasma-treated RAW264.7 macrophages on cancer cell growth after co-culture. In particular, flow cytometer analysis revealed that plasma did not induce any cell death in RAW264.7 macrophages. Interestingly, immunofluorescence and western blot analysis confirmed that TNF-α released from plasma-activated macrophages acts as a tumour cell death inducer. In support of these findings, activated macrophages down-regulated the cell growth in solid cancer cell lines and induced cell death in vitro. Together our findings suggest plasma-induced reactive species recruit cytotoxic macrophages to release TNF-α, which blocks cancer cell growth and can have the potential to contribute to reducing tumour growth in vivo in the near future.

  11. Variability in tumor necrosis factor-alpha, nitric oxide, and xanthine oxidase responses to endotoxin challenge in heifers: Effect of estrous cycle stage

    Science.gov (United States)

    The severity of host response to some disease agents differs between sexes and this dimorphism has been attributed to the immunomodulating effects of steroid hormones. Our objective was to determine in heifers whether the phase of estrous cycle affected immune response mediators after endotoxin cha...

  12. Interferon-gamma and tumor necrosis factor-alpha sensitize primarily resistant human endometrial stromal cells to Fas-mediated apoptosis

    DEFF Research Database (Denmark)

    Fluhr, Herbert; Krenzer, Stefanie; Stein, Gerburg M

    2007-01-01

    of Fas by an agonistic anti-Fas antibody. Incubation of ESCs with the early embryonic signal human chorionic gonadotropin (hCG, CGB) does not influence their reaction to Fas stimulation. The sensitizing effect of IFN-gamma and TNF-alpha was accompanied by a significant upregulation of Fas and FLICE......The subtle interaction between the implanting embryo and the maternal endometrium plays a pivotal role during the process of implantation. Human endometrial stromal cells (ESCs) express Fas and the implanting trophoblast cells secrete Fas ligand (FASLG, FasL), suggesting a possible role for Fas...

  13. Involvement of matrix metalloproteinases and their inhibitors in peripheral synovitis and down-regulation by tumor necrosis factor alpha blockade in spondylarthropathy

    NARCIS (Netherlands)

    Vandooren, Bernard; Kruithof, Elli; Yu, David T. Y.; Rihl, Markus; Gu, Jieruo; de Rycke, Leen; van den Bosch, Filip; Veys, Eric M.; de Keyser, Filip; Baeten, Dominique

    2004-01-01

    OBJECTIVE: To investigate the role of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in spondylarthropathy (SpA) synovitis. METHODS: Paired samples of synovial biopsy tissue as well as serum and synovial fluid (SF) from 41 patients with SpA and 20

  14. Inhibition of tumor necrosis factor alpha-stimulated monocyte adhesion to human aortic endothelial cells by AMP-activated protein kinase.

    Science.gov (United States)

    Ewart, Marie-Ann; Kohlhaas, Christine F; Salt, Ian P

    2008-12-01

    Proatherosclerotic adhesion of leukocytes to the endothelium is attenuated by NO. As AMP-activated protein kinase (AMPK) regulates endothelial NO synthesis, we investigated the modulation of adhesion to cultured human aortic endothelial cells (HAECs) by AMPK. HAECs incubated with the AMPK activator, AICAR, or expressing constitutively active AMPK demonstrated reduced TNFalpha-stimulated adhesion of promonocytic U-937 cells. Rapid inhibition of TNFalpha-stimulated U-937 cell adhesion by AICAR was NO-dependent, associated with unaltered cell surface adhesion molecule expression, and reduced MCP-1 secretion by HAECs. In contrast, inhibition of TNFalpha-stimulated U-937 cell adhesion by prolonged AMPK activation was NO-independent and associated with reduced cell surface adhesion molecule expression. AMPK activation in HAECs inhibits TNFalpha-stimulated leukocyte adhesion by a rapid NO-dependent mechanism associated with reduced MCP-1 secretion and a late NO-independent mechanism whereby adhesion molecule expression, in particular E-selectin, is suppressed.

  15. Evaluation of accuracy and uncertainty of ELISA assays for the determination of interleukin-4, interleukin-5, interferon-gamma and tumor necrosis factor-alpha

    DEFF Research Database (Denmark)

    Borg, Lone; Kristiansen, Jesper; Christensen, Jytte M

    2002-01-01

    , and robustness. Traceability was ensured by the use of World Health Organization International Standards (WHO IS). An uncertainty budget, which combined the contribution from all known uncertainty components, was established for each cytokine ELISA. The between-run relative analytical standard deviation (RSDA...... for each of the cytokines. The combined relative standard uncertainty (U(result)/C(result)) was 28%, 22-62%, 28% and 24% for the IL-4, IL-5, IFN-gamma and TNF-alpha results, respectively. The major contributions to uncertainty came from the relative analytical standard deviation and from the uncertainty...... by the ELISAs are very limited. The task of evaluating measurement uncertainty would be much easier if producers of international reference standards reported the uncertainty of the value of standards. The model for evaluating uncertainty presented in this paper is applicable to other types of assays...

  16. Tumor necrosis factor-alpha (TNF-alpha) concentrations from whole blood cultures correlate with isolated peripheral blood mononuclear cell cultures

    Science.gov (United States)

    Many cellular immune assays are impractical because they require labor-intensive isolation of cells from their natural environment. The objectives of this study were to determine the relationship between cell culture supernatant TNF-alpha from isolated peripheral blood mononuclear cells (PBMC) and w...

  17. Leukemia inhibitory factor is produced by myelin-reactive T cells from multiple sclerosis patients and protects against tumor necrosis factor-alpha-induced oligodendrocyte apoptosis

    NARCIS (Netherlands)

    Vanderlocht, J; Hellings, N; Hendriks, JJA; Vandenabeele, F; Moreels, M; Buntinx, M; Hoekstra, D; Antel, JP; Stinissen, P

    In multiple sclerosis (MS), damage to oligodendrocytes is believed to be caused by an aberrant immune response initiated by autoreactive T cells. Increasing evidence indicates that these T cells are not exclusively detrimental but might also exert protective effects. We report for the first time

  18. Alpha beta but not gamma delta T cell clones in synovial fluids of patients with reactive arthritis show active transcription of tumour necrosis factor alpha and interferon gamma

    NARCIS (Netherlands)

    Rihl, M.; Gu, J.; Baeten, D.; Märker-Hermann, E.; Goodall, J. C.; Gaston, J. S. H.; Kuipers, J. G.; Zeidler, H.; Yu, D. T. Y.

    2004-01-01

    OBJECTIVE: To compare the cytokine expression profile of three CD8+, three CD4+, and three gammadelta+ T cell clones all derived from the synovial fluids of three patients with reactive arthritis (ReA). METHODS: Complementary DNA based microarrays containing the specific sequence of 56 cytokine

  19. Relationship of interleukin-6 and tumor necrosis factor-alpha with muscle mass and muscle strength in elderly men and women : the Health ABC Study

    NARCIS (Netherlands)

    Visser, Marjolein; Pahor, Marco; Taaffe, Dennis R; Goodpaster, Bret H; Simonsick, Eleanor M; Newman, Anne B; Nevitt, Michael; Harris, Tamara B

    BACKGROUND: A decline in muscle mass and muscle strength characterizes normal aging. As clinical and animal studies show a relationship between higher cytokine levels and low muscle mass, the aim of this study was to investigate whether markers of inflammation are associated with muscle mass and

  20. Spironolactone inhibits production of proinflammatory cytokines, including tumour necrosis factor-alpha and interferon-gamma, and has potential in the treatment of arthritis

    DEFF Research Database (Denmark)

    Bendtzen, K; Hansen, P R; Rieneck, K

    2003-01-01

    tolerated, although treatment had to be stopped in two adults on concomitant methotrexate therapy. Sixteen patients (76%) responded favourably. American College of Rheumatology criteria (ACR)20 or better was achieved in six of nine RA patients; four reached ACR70. Eight of nine JIA patients improved...

  1. Impact of anti-tumour necrosis factor alpha treatment on admissions to hospital and days of sick leave in patients with ankylosing spondylitis.

    Science.gov (United States)

    Listing, J; Brandt, J; Rudwaleit, M; Zink, A; Sieper, J; Braun, J

    2004-12-01

    To analyse the impact of infliximab treatment on the number of hospital inpatient days and days of sick leave in patients with active ankylosing spondylitis (AS). The data of a 2 year open extension study of a 12 week, double blind, randomised, placebo controlled trial, in which all patients with AS were treated with 5 mg/kg infliximab, were used to investigate the effect of anti-TNF treatment on admissions to hospital and days of sick leave. All patients were interviewed at baseline and at regular intervals during the study to collect this information by questionnaires. Patients who completed 2 years of treatment (n = 49) and those who did not (n = 20) were analysed separately. Sick leave analysis was restricted to currently employed patients (n = 38). During the 12 months before the screening visit, 20/49 (41%) completers had been admitted to hospital. After 1 and 2 years of treatment this percentage was reduced to 5/49 (10%; ppatients with active AS reduces some important costs of AS, but additional studies with detailed cost calculations are needed.

  2. Tumor Necrosis Factor-Alpha −308 G>A Polymorphism, Adherence to Mediterranean Diet, and Risk of Overweight/Obesity in Young Women

    Directory of Open Access Journals (Sweden)

    Martina Barchitta

    2014-01-01

    Full Text Available The present study was conducted in order to (i characterize the adherence to the Mediterranean diet (MD pattern and fatty acids (FAs intakes and (ii explore interactions between TNFA −308 G>A polymorphism and adherence to MD and FAs intakes, respectively, on overweight/obesity risk. From 2010 to 2013, 380 healthy women were enrolled, and MD score (MDS and FAs intakes were evaluated by a Food Frequencies Questionnaire in relation to nutritional status. TNFA −308 G/A polymorphism was characterized using PCR-RFLP. A total of 32.6% of women were overweight or obese. Lower mean MDS values were more observed in the younger age group than in the older age group (3.60 versus 4.45. The risk of being overweight/obese was 3.5-fold increased due to poor adherence to MD and was about twofold increased in less educated women. Furthermore, younger age was associated with poor adherence to MD. No evidence for an independent effect of the polymorphism on overweight/obesity risk was found. There was no evidence of biological interaction from the gene-diet interaction analyses. Young women, less educated and with poor adherence to MD, are a target group for the nutritional interventions that aimed to control the obesity risk, thus improving the adherence to MD and particularly the intake of unsaturated FAs.

  3. Association of Obesity and Breast Cancer Risk: The Role of Estrogen, Tumor Necrosis Factor-alpha, and Adiponectin as Risk factors (preliminary study

    Directory of Open Access Journals (Sweden)

    Ampi Retnowarnadi

    2009-04-01

    Full Text Available BACKGROUND: Breast cancer is the most frequent cancer diagnosed among women. Many factors influence the carcinogenesis of breast cancer. The aim of this study to analyze the role of obesity (waist circumference and body mass index, serum Estradiol levels, TNF-α, and Adiponectin in the occurrence of breast cancer. METHODS: This was observational study with case control design. Eleven breast cancer patients as cases and twelve Fibroadenoma Mammae (FAM patients as controls were analyzed. The serum Estrogen, TNF-α and Adiponectin were examined in their association with breast cancer risk. RESULTS: Women with breast tumor and waist circumference >80 cm have significantly higher breast cancer risk than women with breast tumor and waist circumference 2.30 pg/ml have higher breast cancer risk (19.25 times than women with breast tumor and have lower serum TNF-α levels (95% CI=1.77-209.55, p=0.015. Whereas, women with breast tumor and lower Adiponectin/TNF-α ratio (80 cm and low Adiponectin/TNF-α ratio in women with breast tumor are significantly associated with an increased risk for breast cancer. KEYWORDS: obesity, breast cancer, adiponectin/TNF-α ratio.

  4. Cytotoxic macrophage-released tumour necrosis factor-alpha (TNF-α) as a killing mechanism for cancer cell death after cold plasma activation

    International Nuclear Information System (INIS)

    Kaushik, Nagendra Kumar; Kaushik, Neha; Min, Booki; Choi, Ki Hong; Hong, Young June; Choi, Eun Ha; Miller, Vandana; Fridman, Alexander

    2016-01-01

    The present study aims at studying the anticancer role of cold plasma-activated immune cells. The direct anti-cancer activity of plasma-activated immune cells against human solid cancers has not been described so far. Hence, we assessed the effect of plasma-treated RAW264.7 macrophages on cancer cell growth after co-culture. In particular, flow cytometer analysis revealed that plasma did not induce any cell death in RAW264.7 macrophages. Interestingly, immunofluorescence and western blot analysis confirmed that TNF-α released from plasma-activated macrophages acts as a tumour cell death inducer. In support of these findings, activated macrophages down-regulated the cell growth in solid cancer cell lines and induced cell death in vitro. Together our findings suggest plasma-induced reactive species recruit cytotoxic macrophages to release TNF-α, which blocks cancer cell growth and can have the potential to contribute to reducing tumour growth in vivo in the near future. (paper)

  5. Tumor necrosis factor-alpha and the cytokine network in psoriasis Fator de necrose tumoral-alfa e a rede de citocinas na psoriase

    Directory of Open Access Journals (Sweden)

    Arles Martins Brotas

    2012-10-01

    Full Text Available New molecular methods of research have greatly expanded the knowledge about the role of cytokines in several diseases, including psoriasis. The work orchestrated by these peptides is essential for the communication between resident inflammatory cells (keratinocytes and endothelial cells and infiltrating cells (neutrophils, lymphocytes, Langerhans cells. This is a complex network due to redundancy, synergism and, sometimes, the antagonism of cytokines, which prevents full understanding of the pathogenesis of the disease. Currently, it seems premature to try to establish a main actor, but TNFalpha participates in all stages of psoriatic plaque development, as we shall see.A introdução de novos métodos moleculares de investigação ampliou muito o conhecimento sobre o papel das citocinas em diversas doenças, entre elas a psoríase. O trabalho orquestrado desses polipeptídeos é fundamental na comunicação entre as células inflamatórias residentes (queratinócitos e células endoteliais e infiltrantes (neutrófilos, linfócitos, células de Langerhans. Trata-se de uma rede complexa devido à redundância, ao sinergismo e, por vezes, ao antagonismo das citocinas, o que dificulta a compreensão da fisiopatogenia da doença a partir de um mecanismo linear. No momento atual, parece precoce tentar estabelecer um regente, mas o TNF-alfa se destaca em todos os passos do desenvolvimento da placa psoriásica, como veremos a seguir.

  6. Human rheumatoid arthritis tissue production of IL-17A drives matrix and cartilage degradation: synergy with tumour necrosis factor-alpha, Oncostatin M and response to biologic therapies.

    LENUS (Irish Health Repository)

    Moran, Ellen M

    2009-01-01

    INTRODUCTION: The aim of this study was to examine IL-17A in patients, following anti-TNF-alpha therapy and the effect of IL-17A on matrix turnover and cartilage degradation. METHODS: IL-17A expression was examined by ELISA and immunohistology in the rheumatoid arthritis (RA) joints. RA whole synovial tissue explant (RA ST), primary synovial fibroblasts (RASFC), human cartilage and chondrocyte cultures were stimulated with IL-17A +\\/- TNF-alpha and Oncostatin M (OSM). Matrix metalloproteinase (MMP) and tissue inhibitor (TIMP-1) were assessed by ELISA and zymography. Cartilage proteoglycan release was assessed histologically by Safranin-O staining. Clinical parameters, IL-17A, MMP\\/TIMP were assessed in patients pre\\/post biologic therapy. RESULTS: IL-17A levels were higher in RA vs osteoarthritis (OA)\\/normal joints (P < 0.05). IL-17A up-regulated MMP-1, -2, -9, and -13 in RA ST, RASFC, cartilage and chondrocyte cultures (P < 0.05). In combination with TNF-alpha and OSM, IL-17A shifted the MMP:TIMP-1 ratio in favor of matrix degradation (all P < 0.05). Cartilage proteoglycan depletion in response to IL-17A was mild; however, in combination with TNF-alpha or OSM showed almost complete proteoglycan depletion. Serum IL-17A was detected in 28% of patients commencing biologic therapy. IL-17A negative patients demonstrated reductions post therapy in serum MMP1\\/TIMP4, MMP3\\/TIMP1 and MMP3\\/TIMP4 ratios and an increase in CS846 (all P < 0.05). No significant changes were observed in IL-17A positive patients. CONCLUSIONS: IL-17A is produced locally in the inflamed RA joint. IL-17A promotes matrix turnover and cartilage destruction, especially in the presence of other cytokines, mimicking the joint environment. IL-17A levels are modulated in vivo, following anti-TNF therapy, and may reflect changes in matrix turnover.

  7. A role for b-cell-depleting agents in treating psoriatic skin lesions induced by tumor necrosis factor-alpha antagonists: A case report and literature review

    Directory of Open Access Journals (Sweden)

    Ancuta Codrina Mihaela

    2014-01-01

    Full Text Available Despite recent advances in understanding the pathological pathways, clinical pattern and management opportunities for new-onset psoriasis as a paradoxical adverse event in patients receiving TNF inhibitors for their immune-mediated disorder, there is a subset of patients who are either partial responders or non-responders, whatever the therapeutic scenario. We present the case of new-onset psoriasis and severe alopecia development in a case study of long-standing rheumatoid arthritis (RA treated with adalimumab (ADA and leflunomide. Since skin lesions and alopecia are resistant to the classic protocol (topical treatment, ADA discontinuation and RA becomes highly active, rituximab (RTX was started. Dramatic improvement in joint disease, total remission of alopecia and partial remission of pustular psoriasis were described after the first RTX cycle. Although B-cell-depleting agents result in controversial effects on psoriatic skin lesions, this is the first case of ADA-induced psoriasis and alopecia that improved under RTX, suggesting a possible role in treating such a patient population.

  8. Prospective comparison of preference and efficacy of adalimumab and infliximab for treating ulcerative colitis naive to antitumor necrosis factor therapy.

    Science.gov (United States)

    Mizoshita, Tsutomu; Katano, Takahito; Tanida, Satoshi; Hirano, Atsuyuki; Miyaki, Tomokatsu; Ozeki, Keiji; Suzuki, Yuka; Sugimura, Naomi; Kataoka, Hiromi; Joh, Takashi

    2017-08-01

    There have been few reports on 2 tumor necrosis factor alpha inhibitors, infliximab and adalimumab, with respect to patient preference and efficacy in ulcerative colitis (UC).We used questionnaires to evaluate the preference and reasons for drug choice between infliximab and adalimumab in UC patients naive to antitumor necrosis factor alpha therapy. We also analyzed the efficacy of infliximab and adalimumab prospectively and endoscopically before treatment and at 14 and 54 weeks.Of the 25 UC patients, infliximab and adalimumab were chosen by 10 (40%) and 15 (60%), respectively. Patients who favored infliximab considered "fear of syringes" (7/10, 70%) as the most important influencing factor, whereas patients who favored adalimumab considered "ease of administration" (10/15, 66.7%) and "time required for therapy" (10/15, 66.7%) as the most important factors. There were no statistical differences in remission induction and maintenance between the infliximab and adalimumab groups with regard to response, remission, mucosal healing, steroid-free, and steroid-free remission rates at weeks 14 and 54.The efficacy of adalimumab in remission induction and maintenance was equivalent to that of infliximab in UC patients naive to antitumor necrosis factor alpha therapy in this prospective study, but more patients preferred adalimumab.

  9. Serotonin 5-HT2A receptor activation blocks TNF-α mediated inflammation in vivo.

    Directory of Open Access Journals (Sweden)

    Felix Nau

    Full Text Available Tumor necrosis factor alpha (TNF-α plays a key role in inflammation, and its production and signaling contribute to many inflammatory related diseases. Recently, we discovered that selective activation of serotonin 5-HT2A receptors with the agonist (R-DOI produces a super-potent blockade of proinflammatory markers in primary rat aortic smooth muscle cells. Here, we demonstrate that systemic administration of (R-DOI can block the systemic effects of TNF-α in whole animal, with potent anti-inflammatory effects in the aortic arch and small intestine. This includes blockade of TNF-α-induced expression of pro-inflammatory cell adhesion (Icam-1, Vcam-1, cytokine (Il-6, IL-1b, and chemokine (Mcp-1, Cx3cl1 genes, and expression of VCAM-1 protein in the intestine. Further, systemic (R-DOI also prevents the TNF-α-induced increase of circulating IL-6. Importantly, utilizing receptor selective antagonists, we have demonstrated that the mechanism underlying the systemic anti-inflammatory effects of (R-DOI is activation of serotonin 5-HT2A receptors. Our results highlight a powerful new role for the serotonin 5-HT2A receptor in inflammatory processes, and indicate that agonism of serotonin receptors may represent an effective and novel approach to develop powerful small molecule therapeutics for inflammatory diseases and conditions such as atherosclerosis and inflammatory bowel disease.

  10. Serotonin 5-HT2A receptor activation blocks TNF-α mediated inflammation in vivo.

    Science.gov (United States)

    Nau, Felix; Yu, Bangning; Martin, David; Nichols, Charles D

    2013-01-01

    Tumor necrosis factor alpha (TNF-α) plays a key role in inflammation, and its production and signaling contribute to many inflammatory related diseases. Recently, we discovered that selective activation of serotonin 5-HT2A receptors with the agonist (R)-DOI produces a super-potent blockade of proinflammatory markers in primary rat aortic smooth muscle cells. Here, we demonstrate that systemic administration of (R)-DOI can block the systemic effects of TNF-α in whole animal, with potent anti-inflammatory effects in the aortic arch and small intestine. This includes blockade of TNF-α-induced expression of pro-inflammatory cell adhesion (Icam-1, Vcam-1), cytokine (Il-6, IL-1b), and chemokine (Mcp-1, Cx3cl1) genes, and expression of VCAM-1 protein in the intestine. Further, systemic (R)-DOI also prevents the TNF-α-induced increase of circulating IL-6. Importantly, utilizing receptor selective antagonists, we have demonstrated that the mechanism underlying the systemic anti-inflammatory effects of (R)-DOI is activation of serotonin 5-HT2A receptors. Our results highlight a powerful new role for the serotonin 5-HT2A receptor in inflammatory processes, and indicate that agonism of serotonin receptors may represent an effective and novel approach to develop powerful small molecule therapeutics for inflammatory diseases and conditions such as atherosclerosis and inflammatory bowel disease.

  11. Angiotensin II type 2 receptor agonist Compound 21 attenuates pulmonary inflammation in a model of acute lung injury

    Directory of Open Access Journals (Sweden)

    Menk M

    2018-05-01

    Full Text Available Mario Menk, Jan Adriaan Graw, Clarissa von Haefen, Hendrik Steinkraus, Burkhard Lachmann, Claudia D Spies, David Schwaiberger Department of Anesthesiology and Operative Intensive Care Medicine, Charité – University Medicine Berlin, FreieUniversität Berlin, Humboldt-Universitätzu Berlin, and Berlin Institute of Health, Germany Purpose: Although the role of the angiotensin II type 2 (AT2 receptor in acute lung injury is not yet completely understood, a protective role of this receptor subtype has been suggested. We hypothesized that, in a rodent model of acute lung injury, stimulation of the AT2 receptor with the direct agonist Compound 21 (C21 might have a beneficial effect on pulmonary inflammation and might improve pulmonary gas exchange. Materials and methods: Male adult rats were divided into a treatment group that received pulmonary lavage followed by mechanical ventilation (LAV, n=9, a group receiving pulmonary lavage, mechanical ventilation, and direct stimulation of the AT2 receptor with C21 (LAV+C21, n=9, and a control group that received mechanical ventilation only (control, n=9. Arterial blood gas analysis was performed every 30 min throughout the 240-min observation period. Lung tissue and plasma samples were obtained at 240 min after the start of mechanical ventilation. Protein content and surface activity of bronchoalveolar lavage fluid were assessed and the wet/dry-weight ratio of lungs was determined. Transcriptional and translational regulation of pro- and antiinflammatory cytokines IL-1β, tumor necrosis factor-alpha, IL-6, IL-10, and IL-4 was determined in lungs and in plasma. Results: Pulmonary lavage led to a significant impairment of gas exchange, the formation of lung edema, and the induction of pulmonary inflammation. Protein content of lavage fluid was increased and contained washed-out surfactant. Direct AT2 receptor stimulation with C21 led to a significant inhibition of tumor necrosis factor-alpha and IL-6

  12. Subcutaneous encapsulated fat necrosis

    DEFF Research Database (Denmark)

    Aydin, Dogu; Berg, Jais O

    2016-01-01

    We have described subcutaneous encapsulated fat necrosis, which is benign, usually asymptomatic and underreported. Images have only been published on two earlier occasions, in which the necrotic nodules appear "pearly" than the cloudy yellow surface in present case. The presented image may help f...

  13. Tumor Necrosis Factor Receptor-associated Protein 1 (TRAP1) Mutation and TRAP1 Inhibitor Gamitrinib-triphenylphosphonium (G-TPP) Induce a Forkhead Box O (FOXO)-dependent Cell Protective Signal from Mitochondria.

    Science.gov (United States)

    Kim, Hyunjin; Yang, Jinsung; Kim, Min Ju; Choi, Sekyu; Chung, Ju-Ryung; Kim, Jong-Min; Yoo, Young Hyun; Chung, Jongkyeong; Koh, Hyongjong

    2016-01-22

    TRAP1 (tumor