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Sample records for cell il-6 expression

  1. Genetic polymorphism directs IL-6 expression in fibroblasts but not selected other cell types.

    Science.gov (United States)

    Noss, Erika H; Nguyen, Hung N; Chang, Sook Kyung; Watts, Gerald F M; Brenner, Michael B

    2015-12-01

    Interleukin (IL)-6 blockade is an effective treatment for rheumatoid arthritis (RA), and synovial fibroblasts are a major IL-6 producer in the inflamed joint. We found that human RA and osteoarthritis (OA) synovial fibroblasts derived from independent donors reproducibly segregated into low, medium, and high IL-6 producers, independent of stimulus, cell passage, or disease state. IL-6 expression pattern correlated strongly with total mRNA expression, not mRNA stability, suggesting transcriptional rather than posttranscriptional regulation. High-fibroblast IL-6 expression was significantly associated with the IL-6 proximal promoter single nucleotide polymorphism (SNP) rs1800795 minor allele (CC) genotype. In contrast, no association between this SNP and IL-6 production was detected in CD14(+) monocytes, another major producer of synovial IL-6. Luciferase expression assays confirmed that this SNP was associated with differential IL-6 expression in fibroblasts. To date, several association studies examining rs1800795 allele frequency and disease risk have reported seemingly conflicting results ranging from no association to association with either the major or minor allele across a spectrum of conditions, including cancer and autoimmune, cardiovascular, infectious, and metabolic diseases. This study points to a prominent contribution from promoter genetic variation in fibroblast IL-6 regulation, but not in other IL-6-producing cell types. We propose that some of the heterogeneity in these clinical studies likely reflects the cellular source of IL-6 in specific diseases, much of which may be produced by nonhematopoietic cells. These results highlight that functional analysis of disease-associated SNPs on gene expression and pathologic processes must consider variation in diverse cell types.

  2. Phenylmethimazole and a thiazole derivative of phenylmethimazole inhibit IL-6 expression by triple negative breast cancer cells.

    Science.gov (United States)

    Noori, Mahboubeh S; O'Brien, John D; Champa, Zachary J; Deosarkar, Sudhir P; Lanier, Olivia L; Qi, Chunyan; Burdick, Monica M; Schwartz, Frank L; Bergmeier, Stephen C; McCall, Kelly D; Goetz, Douglas J

    2017-03-23

    Inhibition of interleukin-6 (IL-6) holds significant promise as a therapeutic approach for triple negative breast cancer (TNBC). We previously reported that phenylmethimazole (C10) reduces IL-6 expression in several cancer cell lines. We have identified a more potent derivative of C10 termed COB-141. In the present work, we tested the hypothesis that C10 and COB-141 inhibit TNBC cell expressed IL-6 and investigated the potential for classical IL-6 pathway induced signaling within TNBC cells. A panel of TNBC cell lines (MDA-MB-231, Hs578T, MDA-MB-468) was used. Enzyme linked immunosorbent assays (ELISA) revealed that C10 and COB-141 inhibit MDA-MB-231 cell IL-6 secretion, with COB-141 being ~6.5 times more potent than C10. Therefore, the remainder of the study focused on COB-141 which inhibited IL-6 secretion, and was found, via quantitative real time polymerase chain reaction (QRT-PCR), to inhibit IL-6 mRNA in the TNBC panel. COB-141 had little, if any, effect on metabolic activity indicating that the IL-6 inhibition is not via a toxic effect. Flow cytometric analysis and QRT-PCR revealed that the TNBC cell lines do not express the IL-6 receptor (IL-6Rα). Trans-AM assays suggested that COB-141 exerts its inhibitory effect, at least in part, by reducing NF-κB (p65/p50) DNA binding. In summary, COB-141 is a potent inhibitor of TNBC cell expressed IL-6 and the inhibition does not appear to be due to non-specific toxicity. The TNBC cell lines do not have an intact classical IL-6 signaling pathway. COB-141's inhibitory effect may be due, at least in part, to reducing NF-κB (p65/p50) DNA binding.

  3. Neurotrophins regulate bone marrow stromal cell IL-6 expression through the MAPK pathway.

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    Fariba Rezaee

    Full Text Available BACKGROUND: The host's response to infection is characterized by altered levels of neurotrophins and an influx of inflammatory cells to sites of injured tissue. Progenitor cells that give rise to the differentiated cellular mediators of inflammation are derived from bone marrow progenitor cells where their development is regulated, in part, by cues from bone marrow stromal cells (BMSC. As such, alteration of BMSC function in response to elevated systemic mediators has the potential to alter their function in biologically relevant ways, including downstream alteration of cytokine production that influences hematopoietic development. METHODOLOGY/PRINCIPAL FINDINGS: In the current study we investigated BMSC neurotrophin receptor expression by flow cytometric analysis to determine differences in expression as well as potential to respond to NGF or BDNF. Intracellular signaling subsequent to neurotrophin stimulation of BMSC was analyzed by western blot, microarray analysis, confocal microscopy and real-time PCR. Analysis of BMSC Interleukin-6 (IL-6 expression was completed using ELISA and real-time PCR. CONCLUSION: BMSC established from different individuals had distinct expression profiles of the neurotrophin receptors, TrkA, TrkB, TrkC, and p75(NTR. These receptors were functional, demonstrated by an increase in Akt-phosphorylation following BMSC exposure to recombinant NGF or BDNF. Neurotrophin stimulation of BMSC resulted in increased IL-6 gene and protein expression which required activation of ERK and p38 MAPK signaling, but was not mediated by the NFkappaB pathway. BMSC response to neurotrophins, including the up-regulation of IL-6, may alter their support of hematopoiesis and regulate the availability of inflammatory cells for migration to sites of injury or infection. As such, these studies are relevant to the growing appreciation of the interplay between neurotropic mediators and the regulation of hematopoiesis.

  4. Preliminary evidence that overexpression of nuclear factor for IL6 expression (NF—IL6) in NIH3T3 cells may be related to malignant transformation

    Institute of Scientific and Technical Information of China (English)

    ZHUMINSHENG; DINGGANLIU; 等

    1994-01-01

    NF-IL6 is a member of c/EBP family and has multiple functions in regulation of cellular gene expression.We have constructed NF-IL6 expression plasmids and trans·fected the NIH3T3 cells with them.The sense NF-IL6 transfectants showed significantly increased tumorigenicity,and the stable integration of NF-IL6 cDNA into cellular DNA and its expression were demonstrated.Our results suggest that NF-IL6 may be related to tumorigenesis.

  5. HBV X Gene Transfection Upregulates IL-1β and IL-6 Gene Expression and Induces Rat Glomerular Mesangial Cell Proliferation

    Institute of Scientific and Technical Information of China (English)

    Hongzhu LU; Jianhua ZHOU

    2008-01-01

    The X gene of HBV encodes a 17-KD protein, termed HBx, which has been shown to function as a transcriptional trans-activator of a variety of viral and cellular promoter/enhancer elements. The aim of this study was to investigate the effect of HBx on gene expression of interleukin (IL)-1β and IL-6, and proliferation of rat mesangial cells in vitro. The X gene of HBV was amplified by PCR assay, and inserted into the eukaryotic expression vector pCI-neo. The structure of recombinant pCI-neo-X plasmid was proved by restrict endonuclease digestion and sequencing analysis. pCI-neo-X was transfected into cultured rat mesangial cell line in vitro via liposome. HBx expression in transfected mesangial cells was detected by Western blot. The IL-1β and IL-6 mRNA expression in those cells was assayed by semiquantitative RT-PCR. Mesangial cell proliferation was tested by MTT. The results showed that HBx was obviously expressed in cultured mesangial cell line at 36th and 48th h after transfection. The expression of IL-1β and IL-6 mRNA was simultaneously increased. The cell proliferation was also obvious at the same time. It was concluded that HBx gene transfection could induce IL-1β and IL-6 gene expression and mesangial cell proliferation. HBx may play a critical role in mesangial cell proliferation through upregulation of the IL-1β and IL-6 gene expression.

  6. IL-6 upregulation contributes to the reduction of miR-26a expression in hepatocellular carcinoma cells

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    Zhang, Yafei [People' s Liberation Army, Department of Oncology, Wuhan General Hospital of Guangzhou Command, Wuhan (China); Third Military Medical University, Department of Gastroenterology, Southwest Hospital, Chongqing (China); Zhang, Bicheng [People' s Liberation Army, Department of Oncology, Wuhan General Hospital of Guangzhou Command, Wuhan (China); Zhang, Anran [Third Military Medical University, Department of Gastroenterology, Southwest Hospital, Chongqing (China); Li, Xiaohua [Fourth Military Medical University, State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xi' an (China); Liu, Jian; Zhao, Jie; Zhao, Yong; Gao, Jianfei [People' s Liberation Army, Department of Oncology, Wuhan General Hospital of Guangzhou Command, Wuhan (China); Fang, Dianchun [Third Military Medical University, Department of Gastroenterology, Southwest Hospital, Chongqing (China); Rao, Zhiguo [People' s Liberation Army, Department of Oncology, Wuhan General Hospital of Guangzhou Command, Wuhan (China)

    2012-09-28

    A recent study showed that miR-26a is downregulated in hepatocellular carcinoma tissues and that this downregulation is an independent predictor of survival. Interestingly, the same study also reported that miR-26a downregulation causes a concomitant elevation of IL-6 expression. Because miR-26a expression was found to be transcriptionally downregulated by oncogene c-Myc in various cancers, and the expression of c-Myc was increased by IL-6 stimulation, we hypothesized that IL-6 contributes to reduction of miR-26a in hepatocellular carcinoma. Serum IL-6 was measured by ELISA and miR-26a was detected by qRT-PCR. The data of 30 patients with hepatocellular carcinoma who had undergone surgical tumor resection revealed that serum IL-6 could be considered to be a predictor of survival up to 5 years for hepatocellular carcinoma patients (log-rank test, P < 0.05). We observed that the serum IL-6 concentration was inversely correlated with miR-26a expression in cancerous tissues (Pearson correlation test, r = -0.651, P < 0.01). Furthermore, by in vitro experiments with HepG2 cells, we showed that IL-6 stimulation can lead to miR-26a suppression via c-Myc activation, whereas in normal hepatocyte LO2 cells incubation with IL-6 had no significant effect on miR-26a expression. Taken together, these results indicate that miR-26a reduction in hepatocellular carcinoma might be due to IL-6 upregulation.

  7. Piperine inhibits IL-1β-induced IL-6 expression by suppressing p38 MAPK and STAT3 activation in gastric cancer cells.

    Science.gov (United States)

    Xia, Yong; Khoi, Pham Ngoc; Yoon, Hyun Joong; Lian, Sen; Joo, Young Eun; Chay, Kee Oh; Kim, Kyung Keun; Jung, Young Do

    2015-01-01

    Piperine, a kind of natural alkaloid found in peppers, has been reported to exhibit anti-oxidative and anti-tumor activities, both in vitro and in vivo. Interleukin-6 (IL-6) is an important cytokine that activates the signal transduction, promotes tumor cell metastasis, and induces malignancy, including in gastric cancer. However, the effects of piperine on IL-6 expression in gastric cancer cells have not yet been well defined. In this study, we investigated the effects of piperine on the IL-6 expression, and examined the underlying signaling pathways via RT-PCR, promoter studies and Western blotting in human gastric cancer TMK-1 cells. Our results showed that piperine inhibited interleukin-1β (IL-1β)-induced IL-6 expression in a dose-dependent manner. In addition, piperine also inhibited IL-6 promoter activity. Experiments with mitogen-activated protein kinase (MAPK) inhibitors and dominant negative mutant p38 MAPK indicated that p38 MAPK was essential for IL-6 expression in the TMK-1 cells. Additionally, signal transducer and activator of transcription 3 (STAT3) was also involved in the IL-1β-induced IL-6 expression in gastric cancer cells. Piperine inhibited IL-1β-induced p38 MAPK and STAT3 activation and, in turn, blocked the IL-1β-induced IL-6 expression. Furthermore, gastric cancer cells pretreated with IL-1β showed markedly enhanced invasiveness, which was partially abrogated by treatment with IL-6 siRNA, piperine, and inhibitors of p38 MAPK and STAT3. These results suggest that piperine may exert at least part of its anti-cancer effect by controlling IL-6 expression through the suppression of p38 MAPK and STAT3.

  8. Mast cell-derived TNF-α and histamine modify IL-6 and IL-8 expression and release from cutaneous tumor cells

    DEFF Research Database (Denmark)

    Artuc, Metin; Guhl, Sven; Babina, Magda

    2011-01-01

    The coincidence of skin tumors and elevated mast cell (MC) numbers has been known for many years. However, it has remained controversial whether, in this context, MCs promote or inhibit tumor growth. Addressing this problem, different melanoma and squamous cell carcinoma cell lines were co-cultivated...... with primary, dermal MC for 24 h and gene or protein expression of cytokines tumor necrosis factor (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8) estimated. Co-culture with MCs led to an increase in IL-8 gene expression and IL-8 protein release from melanoma cells and IL-6 and IL-8 gene expression...... and protein release from squamous cell carcinoma cells, respectively. Moreover induction of IL-6 and IL-8 was primarily regulated by MC-derived TNF-α. Our data suggest an interplay between MCs and tumor cells, which results in altered cytokine release and may, thus, have an impact on tumor growth, invasion...

  9. Effects of 17β-Estradiol on the Expression of IL-6, IL-11 and NF-κB in Human MG-63 Osteoblast-like Cell Line

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    In order to characterize the effects of 17β-estradiol (17β-E2) on the expression of IL-6,IL-11 and NF-κB in the human MG-63 osteoblast-likecell line, the expression of IL-6 was detected by RT-PCR, Northern blot and Western blot. The expression of IL-11 was determined by RT-PCR, and NF-κB by Western blot. The results showed that 17β-E2 down-regulated the expression of IL-6 mRNA and protein, IL-11 mRNA and NF-κB protein in MG-63 cells. It was suggested that the expression of NF-κB, IL-6 and IL-11 in MG-63 cells could be suppressed by 17β-E2, and this might lend support to estrogen replacement therapy in postmenopausal women.

  10. Bacterial flagellin induces IL-6 expression in human basophils.

    Science.gov (United States)

    Jeon, Jun Ho; Ahn, Ki Bum; Kim, Sun Kyung; Im, Jintaek; Yun, Cheol-Heui; Han, Seung Hyun

    2015-05-01

    Binding of allergen to IgE on basophils positively affects allergic inflammation by releasing inflammatory mediators. Recently, basophils were shown to express pattern-recognition receptors, such as toll-like receptors (TLRs), for recognizing microbe-associated molecular patterns (MAMPs) that are independent of allergen-IgE binding. In this study, we investigated whether MAMP alone can induce IL-6 production in a human basophil cell line, KU812. Stimulation with flagellin in the absence of allergen-IgE association induced IL-6 expression in KU812 cells, while stimulation with lipoteichoic acid, peptidoglycan, or poly I:C did not under the same condition. Flagellin-induced IL-6 expression was also observed in human primary basophils. Flow cytometric analysis showed that KU812 cells expressed flagellin-recognizing TLR5 both on the cell surface and in the cytoplasm while TLR2 and TLR3 were observed only in the cytoplasm. We further demonstrated that although flagellin augmented the phosphorylation of mitogen-activated protein kinases including p38 kinase, ERK, and JNK, flagellin-induced IL-6 production was attenuated by inhibitors for p38 kinase and ERK, but not by JNK inhibitors. In addition, flagellin enhanced phosphorylation of signaling molecules including CREB, PKCδ, and AKT. The inhibitors for PKA and PKC also showed inhibitory effects. Interestingly, flagellin-induced IL-6 production was further enhanced by pretreatment with inhibitors for PI3K, implying that PI3K negatively affects the flagellin-induced IL-6 production. Furthermore, DNA binding activities of NF-κB, AP-1, and CREB, which play pivotal roles in the induction of IL-6 gene expression, were increased by flagellin. These results suggest that flagellin alone is sufficient to induce IL-6 gene expression via TLR5 signaling pathways in human basophils.

  11. Growth of triple-negative breast cancer cells relies upon coordinate autocrine expression of the proinflammatory cytokines IL-6 and IL-8.

    Science.gov (United States)

    Hartman, Zachary C; Poage, Graham M; den Hollander, Petra; Tsimelzon, Anna; Hill, Jamal; Panupinthu, Nattapon; Zhang, Yun; Mazumdar, Abhijit; Hilsenbeck, Susan G; Mills, Gordon B; Brown, Powel H

    2013-06-01

    Triple-negative breast cancers (TNBC) are aggressive with no effective targeted therapies. A combined database analysis identified 32 inflammation-related genes differentially expressed in TNBCs and 10 proved critical for anchorage-independent growth. In TNBC cells, an LPA-LPAR2-EZH2 NF-κB signaling cascade was essential for expression of interleukin (IL)-6, IL-8, and CXCL1. Concurrent inhibition of IL-6 and IL-8 expression dramatically inhibited colony formation and cell survival in vitro and stanched tumor engraftment and growth in vivo. A Cox multivariable analysis of patient specimens revealed that IL-6 and IL-8 expression predicted patient survival times. Together these findings offer a rationale for dual inhibition of IL-6/IL-8 signaling as a therapeutic strategy to improve outcomes for patients with TNBCs.

  12. Pertussis toxin B-oligomer suppresses IL-6 induced HIV-1 and chemokine expression in chronically infected U1 cells via inhibition of activator protein 1.

    Science.gov (United States)

    Rizzi, Chiara; Crippa, Massimo P; Jeeninga, Rienk E; Berkhout, Ben; Blasi, Francesco; Poli, Guido; Alfano, Massimo

    2006-01-15

    Pertussis toxin B-oligomer (PTX-B) inhibits HIV replication in T lymphocytes and monocyte-derived macrophages by interfering with multiple steps of the HIV life cycle. PTX-B prevents CCR5-dependent (R5) virus entry in a noncompetitive manner, and it also exerts suppressive effects on both R5- and CXCR4-dependent HIV expression at a less-characterized postentry level. We demonstrate in this study that PTX-B profoundly inhibits HIV expression in chronically infected promonocytic U1 cells stimulated with several cytokines and, particularly, the IL-6-mediated effect, a cytokine that triggers viral production in these cells independently of NF-kappaB activation. From U1 cells we have subcloned a cell line, named U1-CR1, with increased responsiveness to IL-6. In these cells, PTX-B neither down-regulated the IL-6R nor prevented IL-6 induced signaling in terms of STAT3 phosphorylation and DNA binding. In contrast, PTX-B inhibited AP-1 binding to target DNA and modified its composition with a proportional increases in FosB, Fra2, and ATF2. PTX-B inhibited IL-6-induced HIV-1 long-terminal repeat-driven transcription from A, C, E, and F viral subtypes, which contain functional AP-1 binding sites, but failed to inhibit transcription from subtypes B and D LTR devoid of these sites. In addition, PTX-B inhibited the secretion of IL-6-induced, AP-1-dependent genes, including urokinase-type plasminogen activator, CXCL8/IL-8, and CCL2/monocyte chemotactic protein-1. Thus, PTX-B suppression of IL-6 induced expression of HIV and cellular genes in chronically infected promonocytic cells is strongly correlated to inhibition of AP-1.

  13. Elevated expression of APE1/Ref-1 and its regulation on IL-6 and IL-8 in bone marrow stromal cells of multiple myeloma.

    Science.gov (United States)

    Xie, Jia-Yin; Li, Meng-Xia; Xiang, De-Bing; Mou, Jiang-Hong; Qing, Yi; Zeng, Lin-Li; Yang, Zhen-Zhou; Guan, Wei; Wang, Dong

    2010-10-01

    A number of growth factors secreted by bone marrow stromal cells (BMSCs), including interleukin-6 and -8 (IL-6/8), are important for the initiation and progression of multiple myeloma (MM). However, the mechanisms that regulate the production of IL-6/8 by BMSC have not yet been well characterized. Human dual functional protein apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE1/Ref-1) is essential for cell survival and proliferation. Previous studies showed that APE1/Ref-1 was overexpressed in tumor cells, but few studies showed its expression in supportive cells in the tumor microenvironment. We first detected APE1/Ref-1 expression in BMSCs of normal, initial, and recurrent MM patients, and then explore the correlation between APE1/Ref-1 level and IL-6/8 secretion of BMSCs. A marked increase of APE1/Ref-1 expression and abnormal subcellular distribution were observed in MM BMSCs. APE1/Ref-1 overexpression was related to higher secretary level of IL-6/8 by MM BMSCs and the IL-6/8 secretion was blocked significantly by adenovirus-mediated APE1/Ref-1-specific (small interfering RNA) siRNA. Our results also demonstrated that APE1/Ref-1-specific siRNA significantly inhibited DNA binding activity of AP-1 and nuclear factor-κB (NF-κB), 2 important transcription factors in the regulation IL-6/8 secretion in MM BMSCs. The results provided by the present study indicate APE1/Ref-1, which plays a regulatory role in IL-6/8 production by BMSCs, may be a potential therapeutic target of MM.

  14. IL-6/sIL-6R trans-signalling, but not TNF-alpha induced angiogenesis in a HUVEC and synovial cell co-culture system.

    Science.gov (United States)

    Hashizume, Misato; Hayakawa, Naohiko; Suzuki, Miho; Mihara, Masahiko

    2009-10-01

    Angiogenesis in synovia is a characteristic of RA patients. We examined whether IL-6 or TNF-alpha induce tubule formation in a co-culture system of fibroblast-like synovial cells from RA patients (RA-FLS) and human umbilical vein endothelial cells (HUVEC). The effects of IL-6 and TNF-alpha on the expression of angiogenic factors in RA-FLS and HUVEC, and the proliferation of HUVEC were also studied. IL-6 + sIL-6R induced tubule formation, whereas IL-6 alone did not. IL-6/sIL-6R-induced tubule formation was completely suppressed by the addition of either anti-IL-6R or anti-VEGF antibody. TNF-alpha did not induce tubule formation. On the contrary, it decreased CD31-positive area compared with the control. IL-6 + sIL-6R augmented VEGF production in RA-FLS, whereas IL-6 alone did not. Anti-IL-6R antibody suppressed IL-6/sIL-6R-induced VEGF production, but not spontaneous VEGF production. In contrast, TNF-alpha did not induce VEGF production from RA-FLS and HUVEC. IL-6 + sIL-6R stimulation of RA-FLS strongly induced mRNA expression of VEGF, but not of other angiogenic factors, such as EGF, bFGF, TGF-beta, IL-1, TNF-alpha and IL-8. Neither IL-6 nor IL-6/sIL-6R promoted HUVEC proliferation, whereas TNF-alpha significantly inhibited VEGF-induced HUVEC proliferation. In conclusion, IL-6/sIL-6R complex showed angiogenic activity via the production of VEGF from RA-FLS, but TNF-alpha was anti-angiogenic in our experimental system.

  15. Single administration of recombinant IL-6 restores the gene expression of lipogenic enzymes in liver of fasting IL-6-deficient mice

    DEFF Research Database (Denmark)

    Gavito, A L; Cabello, R; Suarez, J;

    2016-01-01

    BACKGROUND AND PURPOSE: Lipogenesis is intimately controlled by hormones and cytokines as well as nutritional conditions. IL-6 participates in the regulation of fatty acid metabolism in the liver. We investigated the role of IL-6 in mediating fasting/re-feeding changes in the expression of hepatic...... in vivo. The involvement of STAT3 in mediating these IL-6 responses was investigated by using siRNA in human HepG2 cells. KEY RESULTS: During feeding, the up-regulation in the hepatic expression of lipogenic genes presented similar time kinetics in WT and IL-6(-/-) mice. During fasting, expression...... lipogenic enzymes. EXPERIMENTAL APPROACH: Gene and protein expression of lipogenic enzymes were examined in livers of wild-type (WT) and IL-6-deficient (IL-6(-/-) ) mice during fasting and re-feeding conditions. Effects of exogenous IL-6 administration on gene expression of these enzymes were evaluated...

  16. Non-raft adenylyl cyclase 2 defines a cAMP signaling compartment that selectively regulates IL-6 expression in airway smooth muscle cells: differential regulation of gene expression by AC isoforms.

    Science.gov (United States)

    Bogard, Amy S; Birg, Anna V; Ostrom, Rennolds S

    2014-04-01

    Adenylyl cyclase (AC) isoforms differ in their tissue distribution, cellular localization, regulation, and protein interactions. Most cell types express multiple AC isoforms. We hypothesized that cAMP produced by different AC isoforms regulates unique cellular responses in human bronchial smooth muscle cells (BSMC). Overexpression of AC2, AC3, or AC6 had distinct effects on forskolin (Fsk)-induced expression of a number of known cAMP-responsive genes. These data show that different AC isoforms can differentially regulate gene expression. Most notable, overexpression and activation of AC2 enhanced interleukin 6 (IL-6) expression, but overexpression of AC3 or AC6 had no effect. IL-6 production by BSMC was induced by Fsk and select G protein-coupled receptor (GPCR) agonists, though IL-6 levels did not directly correlate with global cAMP levels. Treatment with PKA selective 6-Bnz-cAMP or Epac selective 8-CPT-2Me-cAMP cAMP analogs revealed a predominant role for PKA in cAMP-mediated induction of IL-6. IL-6 promoter mutations demonstrated that AP-1 and CRE transcription sites were required for Fsk to stimulate IL-6 expression. Our present study defines an AC2 cAMP signaling compartment that specifically regulates IL-6 expression in BSMC via Epac and PKA and demonstrates that other AC isoforms are excluded from this pool.

  17. Astrocyte-targeted expression of IL-6 protects the CNS against a focal brain injury

    DEFF Research Database (Denmark)

    Penkowa, Milena; Giralt, Mercedes; Lago, Natalia

    2003-01-01

    The effect of CNS-targeted IL-6 gene expression has been thoroughly investigated in the otherwise nonperturbed brain but not following brain injury. Here we examined the impact of astrocyte-targeted IL-6 production in a traumatic brain injury (cryolesion) model using GFAP-IL6 transgenic mice...... significantly increased up to but not including 20 dpl in the GFAP-IL6 mice. Oxidative stress as well as apoptotic cell death was significantly decreased throughout the time period studied in the GFAP-IL6 mice compared to controls. This could be linked to the altered inflammatory response as well...... as to the transgenic IL-6-induced increase of the antioxidant, neuroprotective proteins metallothionein-I + II. These results indicate that although in the brain the chronic astrocyte-targeted expression of IL-6 spontaneously induces an inflammatory response causing significant damage, during an acute...

  18. Nuclear IL-33 regulates soluble ST2 receptor and IL-6 expression in primary human arterial endothelial cells and is decreased in idiopathic pulmonary arterial hypertension

    Energy Technology Data Exchange (ETDEWEB)

    Shao, Dongmin [Section of Vascular Biology, National Heart and Lung Institute, Imperial College London, London (United Kingdom); Perros, Frédéric [Faculté de Médecine, Université Paris-Sud, Paris, Clamart (France); Caramori, Gaetano [Dipartimento di Scienze Mediche, Sezione di Medicina Interna e Cardiorespiratoria, Centro Interdipartimentale per lo Studio delle Malattie Infiammatorie delle Vie Aeree e Patologie Fumo-Correlate, University of Ferrara, Ferrara (Italy); Meng, Chao [Section of Vascular Biology, National Heart and Lung Institute, Imperial College London, London (United Kingdom); Department of Geriatrics, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai (China); Dormuller, Peter [Faculté de Médecine, Université Paris-Sud, Paris, Clamart (France); Chou, Pai-Chien [Airways Disease, National Heart and Lung Institute (United Kingdom); Church, Colin [Scottish Pulmonary Vascular Unit, University of Glasgow (United Kingdom); Papi, Alberto; Casolari, Paolo [Dipartimento di Scienze Mediche, Sezione di Medicina Interna e Cardiorespiratoria, Centro Interdipartimentale per lo Studio delle Malattie Infiammatorie delle Vie Aeree e Patologie Fumo-Correlate, University of Ferrara, Ferrara (Italy); Welsh, David; Peacock, Andrew [Scottish Pulmonary Vascular Unit, University of Glasgow (United Kingdom); Humbert, Marc [Faculté de Médecine, Université Paris-Sud, Paris, Clamart (France); Adcock, Ian M. [Airways Disease, National Heart and Lung Institute (United Kingdom); Wort, Stephen J., E-mail: s.wort@imperial.ac.uk [Section of Vascular Biology, National Heart and Lung Institute, Imperial College London, London (United Kingdom)

    2014-08-15

    Highlights: • Nuclear IL-33 expression is reduced in vascular endothelial cells from PAH patients. • Knockdown of IL-33 leads to increased IL-6 and sST2 mRNA expression. • IL-33 binds homeobox motifs in target gene promoters and recruits repressor proteins. - Abstract: Idiopathic pulmonary arterial hypertension (IPAH) is an incurable condition leading to right ventricular failure and death and inflammation is postulated to be associated with vascular remodelling. Interleukin (IL)-33, a member of the “alarmin” family can either act on the membrane ST2 receptor or as a nuclear repressor, to regulate inflammation. We show, using immunohistochemistry, that IL-33 expression is nuclear in the vessels of healthy subjects whereas nuclear IL-33 is markedly diminished in the vessels of IPAH patients. This correlates with reduced IL-33 mRNA expression in their lung. In contrast, serum levels of IL-33 are unchanged in IPAH. However, the expression of the soluble form of ST2, sST2, is enhanced in the serum of IPAH patients. Knock-down of IL-33 in human endothelial cells (ECs) using siRNA is associated with selective modulation of inflammatory genes involved in vascular remodelling including IL-6. Additionally, IL-33 knock-down significantly increased sST2 release from ECs. Chromatin immunoprecipitation demonstrated that IL-33 bound multiple putative homeodomain protein binding motifs in the proximal and distal promoters of ST2 genes. IL-33 formed a complex with the histone methyltransferase SUV39H1, a transcriptional repressor. In conclusion, IL-33 regulates the expression of IL-6 and sST2, an endogenous IL-33 inhibitor, in primary human ECs and may play an important role in the pathogenesis of PAH through recruitment of transcriptional repressor proteins.

  19. The bioactivity of teleost IL-6: IL-6 protein in orange-spotted grouper (Epinephelus coioides) induces Th2 cell differentiation pathway and antibody production.

    Science.gov (United States)

    Chen, Hsin-Hung; Lin, Han-Tso; Foung, Yi-Fan; Han-You Lin, John

    2012-10-01

    Interleukin 6 (IL-6) is a protein secreted by T cells and macrophages and plays an important role in immune response. IL-6 regulates the proliferation and differentiation of T cells, and elicits immunoglobulin production in B cells. In this study, the cDNA il-6 (gil-6) sequence of the orange spotted grouper (Epinephelus coioides) was obtained. The deduced IL-6 (gIL-6) protein comprised 223 amino acids, the sequence shared approximately 30% similarity with mammalian IL-6, and between 47% and 69% similarity with other available teleost IL-6. The protein comprises the signal peptide, the IL-6 family signature, and conserved amino acid residues found in IL-6 sequences of other teleost. In order to understand the bioactivity and influence of gIL-6 on humoral immune response, recombinant gIL-6 (rgIL-6) synthesized by prokaryotes was injected into orange spotted groupers, and the immune-related gene expression at various times in various organs was observed. Our results revealed that the Th1 specific transcription factor t-bet was down-regulated and Th2 specific transcription factors gata3, and c-maf were up-regulated in immune organs, following IL-6 stimulation. Additionally, higher levels of igm mRNA and translated protein were detected in rgIL-6 stimulated fish. These results indicate that IL-6 in groupers regulates the differentiation of naїve T helper cells into Th2 cells and elicits the production of antibodies.

  20. EFFECTS OF IFN-a COMBINED WITH IL-6 ON GROWTH AND EXPRESSION OF THE GENES RELATED TO CELL-GROWTH AND APOPTOSIS OF BONE MARROW CELLS FROM PATIENTS WITH CML

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Objective: To investigate the effects of interferon-a (IFN-a ) and IFN-a combined with interleukin-6 (IL-6) on growth and expression of bcr-abl, bcl-2 and c-myc genes in the mononuclear cells (MNCs) from bone marrow (BM) of patients with chronic myelogenous leukemia (CML). Methods: MNCs were collected from BM of the patients with CML in chronic phase by centrifugation in lymphocyte separation medium and cultured in liquid with IFN-a (200U/ml) or IFN-a (200U/ml) plus IL-6 (100 ng/ml). The growing cells were counted every day. The expression levels of b -actin, bcr-abl, bcl-2 and c-myc genes in the MNCs incubated for 24 h were detected by reverse transcriptase-polymerase chain reaction (RT-PCR) and relatively quantitative analysis of the amplified fragments by optical density scanning for the bands on gel. Results: The cell growth was markedly suppressed by IFN-a but the degree of cell-growth inhibition was slightly decreased by IL-6 on the basis of IFN-a effect. The expression of bcr-abl chimeric gene was intensely inhibited by IFN-a or IFN-a plus IL-6. The expression of bcl-2 gene was suppressed by either IFN-a or IFN-a plus IL-6, whereas that of c-myc gene was also inhibited by IFN-a but strongly elevated by IL-6 on the basis of IFN-a action. Conclusions: Both IFN-a and IFN-a plus IL-6 can inhibit the expression of anti-apoptosis gene such as bcr-abl and bcl-2 and regulate the expression of the gene related to cell proliferation and differentiation such as c-myc. Either IFN-a or IFN-a combined with IL-6 will serve as a trustful strategy of clinical treatment for CML.

  1. Nuclear IL-33 regulates soluble ST2 receptor and IL-6 expression in primary human arterial endothelial cells and is decreased in idiopathic pulmonary arterial hypertension.

    Science.gov (United States)

    Shao, Dongmin; Perros, Frédéric; Caramori, Gaetano; Meng, Chao; Dormuller, Peter; Chou, Pai-Chien; Church, Colin; Papi, Alberto; Casolari, Paolo; Welsh, David; Peacock, Andrew; Humbert, Marc; Adcock, Ian M; Wort, Stephen J

    2014-08-15

    Idiopathic pulmonary arterial hypertension (IPAH) is an incurable condition leading to right ventricular failure and death and inflammation is postulated to be associated with vascular remodelling. Interleukin (IL)-33, a member of the "alarmin" family can either act on the membrane ST2 receptor or as a nuclear repressor, to regulate inflammation. We show, using immunohistochemistry, that IL-33 expression is nuclear in the vessels of healthy subjects whereas nuclear IL-33 is markedly diminished in the vessels of IPAH patients. This correlates with reduced IL-33 mRNA expression in their lung. In contrast, serum levels of IL-33 are unchanged in IPAH. However, the expression of the soluble form of ST2, sST2, is enhanced in the serum of IPAH patients. Knock-down of IL-33 in human endothelial cells (ECs) using siRNA is associated with selective modulation of inflammatory genes involved in vascular remodelling including IL-6. Additionally, IL-33 knock-down significantly increased sST2 release from ECs. Chromatin immunoprecipitation demonstrated that IL-33 bound multiple putative homeodomain protein binding motifs in the proximal and distal promoters of ST2 genes. IL-33 formed a complex with the histone methyltransferase SUV39H1, a transcriptional repressor. In conclusion, IL-33 regulates the expression of IL-6 and sST2, an endogenous IL-33 inhibitor, in primary human ECs and may play an important role in the pathogenesis of PAH through recruitment of transcriptional repressor proteins.

  2. Measuring IL-6 and sIL-6R in serum from patients treated with tocilizumab and/or siltuximab following CAR T cell therapy.

    Science.gov (United States)

    Chen, Fang; Teachey, David T; Pequignot, Edward; Frey, Noelle; Porter, David; Maude, Shannon L; Grupp, Stephan A; June, Carl H; Melenhorst, Jan J; Lacey, Simon F

    2016-07-01

    T cells expressing a CD19-specific chimeric antigen receptor (CAR19) are demonstrating remarkable efficacy in hematologic malignancies. Treatment is often associated with life-threatening cytokine release syndrome (CRS) which can be effectively treated with cytokine blockade using the antibodies, Siltuximab or Tocilizumab respectively targeting IL-6 or the IL-6 receptor. As IL-6 blockade is moving into the clinic for the treatment of CRS as well as IL-6-driven rheumatologic and malignant diseases, clinicians are utilizing serum cytokine panels more frequently to assess the effects of IL-6 inhibitors. It is paramount to ascertain whether levels obtained are accurate, especially as certain drugs may, in theory, affect quantification. We report the comparative quantification of IL-6 and sIL-6R using Luminex-based immunoassay kits from two vendors. Our results indicate good agreement of the commercial immunoassays in measurement of IL-6 but disagreement in quantitation of sIL-6R. We found that both Siltuximab and Tocilizumab can interfere with the measurement of their respective ligands using reagents from one vendor but not the second. This has significant implications for the analysis of IL-6 and sIL-6R pharmacokinetics analysis in Siltuximab or Tocilizumab-treated patients. We found that high levels of IL-6 can falsely reduce the measured levels of sIL-6R and high levels of sIL-6R can reduce levels of IL-6 when measured with some commercial assays. These data demonstrate the importance of assessing the impact of cytokine-blocking agents on accuracy of clinical biomarker assays in other diseases, as drugs targeting TNF-alpha, IL1B, and IL5 are being used more frequently in a large number of diseases.

  3. Study on the expression of IL-6/STAT3 in endometrial cancer cells mediated by GPR30%雌激素跨膜受体GPR30介导子宫内膜癌中IL-6/STAT3炎症信号通路的激活

    Institute of Scientific and Technical Information of China (English)

    蔡玲玉; 贺银燕; 席晓薇; 张箴波; 万小平

    2013-01-01

    目的:探讨新型雌激素跨膜受体GPR30对子宫内膜癌中IL-6/STAT3炎症信号通路的调节作用.方法:将子宫内膜癌细胞系Ishikawa、KLE分为5组:对照组、E2组、G1组(GPR30特异性激动剂)、E2+G15组(GPR30特异性抑制剂)、G1 +G15组.应用转染技术下调Ishikawa和KLE细胞中GPR30的表达后,分别给予E2和G1作用.Western blot法检测各组细胞中STAT3的蛋白表达水平;ELISA法检测细胞培养上清中IL-6的含量.结果:Ishikawa、KLE细胞系中E2组和G1组的STAT3蛋白及IL-6表达水平均显著高于对照组、E2+G15组、G1+G15组(P<0.05).GPR30稳定下调后,E2+ RNAi组和G1+RNAi组中STAT3蛋白与IL-6表达上调均被阻断(P<0.05).结论:E2和G1能促进子宫内膜癌细胞中IL-6/STAT3的表达,GPR30的表达下调和阻滞剂能抑制E2和G1诱导的子宫内膜癌细胞IL-6/STAT3的表达.GPR30可通过激活IL-6/STAT3炎症通路而在子宫内膜癌组织中发挥重要作用.%Objective:To study the expression of IL-6/STAT3 in endometrial carcinoma cell lines mediated by G-protein coupled receptor 30 (GPR30).Methods:The endometrial cancer cell lines Ishikawa and KLE were divided into 5 groups:Con,E2,G1,E2+G15 (GPR30 specific antagonist),G1 + G15.The expression of GPR30 was downregulated in endometrial cancer cells by transfection with shGPR30-pGFP-V-RS,a GPR30 antisense expression vector.The protein expression level of STAT3 in each group was determined by Western blot.The expression level of IL-6 was detected by ELISA.Result:The expression of STAT3 and the secretion of IL-6 in E2 and G1 group were significantly higher than those in the control group,E2 +G15 and G1 +G15 group(P<0.05).Inhibition of GPR30 by RNA interference could reduce the expression of STAT3 and the secretion of IL-6 in E2 and G1 group.Conclusions:The E2 and G1 can promote the expression of IL-6/STAT3 in endometrial cancer cells.Downregulation of GPR30 can inhibit the expression of IL-6/STAT3 induced by E2 and G1 in

  4. Chikusetsusaponin IVa Butyl Ester (CS-IVa-Be), a Novel IL6R Antagonist, Inhibits IL6/STAT3 Signaling Pathway and Induces Cancer Cell Apoptosis.

    Science.gov (United States)

    Yang, Jie; Qian, Shihui; Cai, Xueting; Lu, Wuguang; Hu, Chunping; Sun, Xiaoyan; Yang, Yang; Yu, Qiang; Gao, S Paul; Cao, Peng

    2016-06-01

    The activation of IL6/STAT3 signaling is associated with the pathogenesis of many cancers. Agents that suppress IL6/STAT3 signaling have cancer-therapeutic potential. In this study, we found that chikusetsusaponin IVa butyl ester (CS-IVa-Be), a triterpenoid saponin extracted from Acanthopanas gracilistylus W.W.Smith, induced cancer cell apoptosis. CS-IVa-Be inhibited constitutive and IL6-induced STAT3 activation, repressed STAT3 DNA-binding activity, STAT3 nuclear translocation, IL6-induced STAT3 luciferase reporter activity, IL6-induced STAT3-regulated antiapoptosis gene expression in MDA-MB-231 cells, and IL6-induced TF-1 cell proliferation. Surprisingly, CS-IVa-Be inhibited IL6 family cytokines rather than other cytokines induced STAT3 activation. Further studies indicated that CS-IVa-Be is an antagonist of IL6 receptor via directly binding to the IL6Rα with a Kd of 663 ± 74 nmol/L and the GP130 (IL6Rβ) with a Kd of 1,660 ± 243 nmol/L, interfering with the binding of IL6 to IL6R (IL6Rα and GP130) in vitro and in cancer cells. The inhibitory effect of CS-IVa-Be on the IL6-IL6Rα-GP130 interaction was relatively specific as CS-IVa-Be showed higher affinity to IL6Rα than to LIFR (Kd: 4,910 ± 1,240 nmol/L) and LeptinR (Kd: 4,990 ± 915 nmol/L). We next demonstrated that CS-IVa-Be not only directly induced cancer cell apoptosis but also sensitized MDA-MB-231 cells to TRAIL-induced apoptosis via upregulating DR5. Our findings suggest that CS-IVa-Be as a novel IL6R antagonist inhibits IL6/STAT3 signaling pathway and sensitizes the MDA-MB-231 cells to TRAIL-induced cell death. Mol Cancer Ther; 15(6); 1190-200. ©2016 AACR.

  5. Protein kinase CK2 modulates IL-6 expression in inflammatory breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Drygin, Denis, E-mail: ddrygin@cylenepharma.com; Ho, Caroline B.; Omori, Mayuko; Bliesath, Joshua; Proffitt, Chris; Rice, Rachel; Siddiqui-Jain, Adam; O' Brien, Sean; Padgett, Claire; Lim, John K.C.; Anderes, Kenna; Rice, William G.; Ryckman, David

    2011-11-11

    Highlights: Black-Right-Pointing-Pointer We examine the potential cross-talk between CK2 and IL-6. Black-Right-Pointing-Pointer Inhibition of CK2 by siRNA or CX-4945 inhibits expression of IL-6 in models of IBC. Black-Right-Pointing-Pointer Treatment of IBC patient in the clinic with CX-4945 reduces her IL-6 plasma levels. Black-Right-Pointing-Pointer We demonstrate that CK2 is a potential therapeutic target for IL-6 driven diseases. -- Abstract: Inflammatory breast cancer is driven by pro-angiogenic and pro-inflammatory cytokines. One of them Interleukin-6 (IL-6) is implicated in cancer cell proliferation and survival, and promotes angiogenesis, inflammation and metastasis. While IL-6 has been shown to be upregulated by several oncogenes, the mechanism behind this phenomenon is not well characterized. Here we demonstrate that the pleotropic Serine/Threonine kinase CK2 is implicated in the regulation of IL-6 expression in a model of inflammatory breast cancer. We used siRNAs targeted toward CK2 and a selective small molecule inhibitor of CK2, CX-4945, to inhibit the expression and thus suppress the secretion of IL-6 in in vitro as well as in vivo models. Moreover, we report that in a clinical trial, CX-4945 was able to dramatically reduce IL-6 levels in plasma of an inflammatory breast cancer patient. Our data shed a new light on the regulation of IL-6 expression and position CX-4945 and potentially other inhibitors of CK2, for the treatment of IL-6-driven cancers and possibly other diseases where IL-6 is instrumental, including rheumatoid arthritis.

  6. IL-6 promotes growth and epithelial-mesenchymal transition of CD133+ cells of non-small cell lung cancer.

    Science.gov (United States)

    Lee, Soo Ok; Yang, Xiaodong; Duan, Shanzhou; Tsai, Ying; Strojny, Laura R; Keng, Peter; Chen, Yuhchyau

    2016-02-09

    We examined IL-6 effects on growth, epithelial-mesenchymal transition (EMT) process, and metastatic ability of CD133+ and CD133- cell subpopulations isolated from three non-small cell lung cancer (NSCLC) cell lines: A549, H157, and H1299. We developed IL-6 knocked-down and scramble (sc) control cells of A549 and H157 cell lines by lentiviral infection system, isolated CD133+ and CD133- sub-populations, and investigated the IL-6 role in self-renewal/growth of these cells. IL-6 showed either an inhibitory or lack of effect in modulating growth of CD133- cells depending on intracellular IL-6 levels, but there was higher self-renewal ability of IL-6 expressing CD133+ cells than IL-6 knocked down cells, confirming the promoter role of IL-6 in CD133+ cells growth. We then examined tumor growth of xenografts developed from CD133+ cells of A549IL-6si vs. A549sc cell lines. Consistently, there was retarded growth of tumors developed from A549IL-6si, CD133+ cells compared to tumors originating from A549sc, CD133+ cells. The effect of IL-6 in promoting CD133+ self-renewal was due to hedgehog (Hhg) and Erk signaling pathway activation and higher Bcl-2/Bcl-xL expression. We also investigated whether IL-6 regulates the EMT process of CD133- and CD133+ cells differently. Expression of the EMT/metastasis-associated molecules in IL-6 expressing cells was higher than in IL-6 knocked down cells. Together, we demonstrated dual roles of IL-6 in regulating growth of CD133- and CD133+ subpopulations of lung cancer cells and significant regulation of IL-6 on EMT/metastasis increase in CD133+ cells, not in CD133- cells.

  7. Memory B cells from older people express normal levels of cyclooxygenase-2 and produce higher levels of IL-6 and IL-10 upon in vitro activation.

    Science.gov (United States)

    Bancos, Simona; Phipps, Richard P

    2010-01-01

    Worldwide the elderly population is increasing. The elderly show deficiencies in immune function. B lymphocytes are essential elements of the immune system responsible for antibody production. This laboratory previously showed that activated human B cells isolated from young adults express cyclooxygenase-2 (Cox-2) and that Cox-2 is essential for optimal antibody responses. Recent data suggests that Cox-2 expression decreases with age in mouse bone tissue. There is no information regarding Cox-2 expression in B cells from older human subjects. We investigated the expression and activity of Cox-2 in naïve and memory B cells from older people. We show that B cells from older subjects show similar Cox-2 protein expression and activity, antibody production and proliferation compared to younger people. However, we found that activated memory B cells from older people produce higher levels of IL-6 and IL-10 compared to young adults. Therefore, the dysregulated cytokine production could contribute to immune senescence in the elderly.

  8. Arsenite evokes IL-6 secretion, autocrine regulation of STAT3 signaling, and miR-21 expression, processes involved in the EMT and malignant transformation of human bronchial epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Luo, Fei; Xu, Yuan [Institute of Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University (China); The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University (China); Ling, Min [Jiangsu Center for Disease Control and Prevention, Nanjing 211166, Jiangsu (China); Zhao, Yue; Xu, Wenchao [Institute of Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University (China); The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University (China); Liang, Xiao [Mental Health Center of Xuhui-CDC, Shanghai 200232 (China); Jiang, Rongrong; Wang, Bairu [Institute of Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University (China); The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University (China); Bian, Qian [Jiangsu Center for Disease Control and Prevention, Nanjing 211166, Jiangsu (China); Liu, Qizhan, E-mail: drqzliu@hotmail.com [Institute of Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University (China); The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University (China)

    2013-11-15

    Arsenite is an established human carcinogen, and arsenite-induced inflammation contributes to malignant transformation of cells, but the molecular mechanisms by which cancers are produced remain to be established. The present results showed that, evoked by arsenite, secretion of interleukin-6 (IL-6), a pro-inflammatory cytokine, led to the activation of STAT3, a transcription activator, and to increased levels of a microRNA, miR-21. Blocking IL-6 with anti-IL-6 antibody and inhibiting STAT3 activation reduced miR-21 expression. For human bronchial epithelial cells, cultured in the presence of anti-IL-6 antibody for 3 days, the arsenite-induced EMT and malignant transformation were reversed. Thus, IL-6, acting on STAT3 signaling, which up-regulates miR-21in an autocrine manner, contributes to the EMT induced by arsenite. These data define a link from inflammation to EMT in the arsenite-induced malignant transformation of HBE cells. This link, mediated through miRNAs, establishes a mechanism for arsenite-induced lung carcinogenesis. - Highlights: • Arsenite evokes IL-6 secretion. • IL-6 autocrine mediates STAT3 signaling and up-regulates miR-21expression. • Inflammation is involved in arsenite-induced EMT.

  9. The activation of TLR7 regulates the expression of VEGF, TIMP1, MMP2, IL-6, and IL-15 in Hela cells.

    Science.gov (United States)

    Li, Lei; Cheng, Feng-Wei; Wang, Fang; Jia, Bo; Luo, Xin; Zhang, Sheng-Quan

    2014-04-01

    Toll-like receptors (TLRs) play important roles in activation of immunoreaction and tumor development. Toll-like receptor 7 (TLR7), one of the TLRs binding with single-stranded RNA, activates intracellular pathways and stimulates the release of proinflammatory cytokines, chemokines. In this study, we investigated the impact of the TLR7-signaling pathway on the expression of vascular endothelial growth factor (VEGF), matrix metalloproteinase 2 (MMP2), tissue inhibitor of metalloproteinase 1 (TIMP1), interleukin 6 (IL-6), and interleukin 15 (IL-15), which have been testified to refer to the immunomodulating and tumor progression. We confirmed that the TLR7 was expressed by Hela cells, despite the abundance was weak. Gardiquimod, one of the TLR7 ligands, can promote these five genes expression in varying degrees. After stimulating with gardiquimod, the expression of the IL-15V1, 3 increased about 4.5 times on RNA level, the other expression was only up-regulated about 2 times. We also discovered that gardiquimod could activate the MAPK/ERK- and PI3K/AKT-signaling pathways, and the specific inhibitors studies indicate that, the effect of gardiquimod on these genes expression is mainly or partially dependent on the activation of these two signaling pathways. To sum up, the activation of TLR7 signaling pathway may modulate some genes expression in Hela cells and may contribute to the pathogenesis of the cervical cancer.

  10. Effects of Porphyromonas gingivalis on expression of IL-6 and IL-1 β in rabbit vascular smooth muscle cells%牙龈卟啉单胞菌对兔血管平滑肌细胞分泌IL-1β、IL-6的影响

    Institute of Scientific and Technical Information of China (English)

    赵瑜敏; 张明珠; 税艳青; 陈立忠; 崔平平; 雷雅燕

    2012-01-01

    目的:观察牙龈卟啉单胞菌(Porphyromonas gingivalis,Pg)上清液对体外培养的兔血管平滑肌细胞分泌IL-1β、IL-6的影响.方法:组织块法培养兔腹主动脉血管平滑肌细胞,并对其细胞来源进行鉴定.用4.3×106 CFU/mL的Pg上清液刺激细胞12、24、48h后,通过ELISA检测IL-1β、IL -6的水平;同时用RT-PCR检测其mRNA表达的情况.结果:Pg上清液刺激24h和48 h时能促进血管平滑肌细胞分泌IL-6,分别与同一时间点的对照组相比差异均有统计学意义(P<0.05),而且24 h时,IL-6表达最强,而IL-1β的表达最低,明显低于相同时间的对照组和其他时间点的实验组(P<0.05).RT-PCR检测显示,4.3×106 CFU/mL的Pg 上清刺激血管平滑细胞12、24、48 h后细胞内均有IL - 1β、IL-6的基因表达,在24 h时,血管平滑肌细胞的IL-Iβ基因表达减少,而IL-6基因表达增加.结论:Pg上清液可促进细胞合成和分泌IL-6,在动脉粥样硬化的发生发展过程中可能发挥一定作用.%AIM; To investigate the effects of Porphyromonas gingivalis on the expression of IL-6 and IL-1β in rabbit vascular smooth muscle cells (CSMCs). METHODS; Rabbit VSMCs were derived from primary cluture of rabbit abdominal aorta. VSMCs were stimulated with P. gingivalis supernatant. At 12 h, 24 h and 48 h of stimulation, VSMCs cell culture medium was subjected to ELISA for IL-6 and IL-1β protein measurement. RNA was extracted from the cells and RT-PCR was conducted to determine IL-6 and IL-1 β gene expression. RESULTS; Exposure to P. gingivalis supernatant significantly increased gene expression and protein secretion of IL-6 in VSMCs ( P < 0. 05 ) . However, IL-1β expression was significantly decreased at 24 h of P. gingivalis exprosure ( P < 0. 05 ) , although a slight increase was observed at 48 h. CONCLUSION; P. gingivalis supernatant shows different effects on IL-6 and IL-1β expression in VSMCs. P. gingivalis may play an important role in the development of

  11. Mechanism of IL-6 expression in THP-1 cells induced by type ⅣB pili of Salmonella typhi%伤寒杆菌ⅣB型菌毛诱导THP-1细胞IL-6表达的机制探讨

    Institute of Scientific and Technical Information of China (English)

    汪付兵; 涂建成

    2013-01-01

    目的 探讨伤寒杆菌ⅣB型菌毛诱导THP-1细胞IL-6表达的机制.方法 将THP-1细胞或人外周血单个核细胞PBMC分别与有ⅣB型菌毛的A21-6菌、缺失ⅣB型菌毛的pilS菌共同孵育,ELISA法检测IL-6水平,荧光素酶报道基因分析法检测核转录因子(NF)-κB活化水平;用蛋白激酶C(PKC)活化抑制剂DECA预处THP-1细胞,然后以A21-6菌诱导,测定NF-κB活化水平和IL-6水平.结果 THP-1细胞或PBMC经有ⅣB型菌毛的A21-6菌诱导后,IL-6的产生水平以及NF-κB活化水平均显著高于相应对照组.PKC活化抑制剂DECA一定程度上能够抑制ⅣB型菌毛诱导的THP-1细胞NF-κB活化水平和IL-6水平.结论 ⅣB型菌毛作为细菌一种重要致病因素,经由PKC-NF-κB通路促进THP-1细胞的IL-6表达.%Objective To investigate the mechanism of IL-6 expression in THP-1 cells induced by type Ⅳ B pili of Salmonella typhi through activation of PKC-NF-κB pathway.Methods THP-1 cells and peripheral blood mononuclear cell (PBMC) were incubated with the Salmonella typhi strain A21-6 or Salmonella typhi strain pilS-respectively,the level of IL-6 was detected by ELISA,the activity of NF-κB was measured by luciferase reporter gene assay.THP-1 cells pretreated with PKC inhibitor DECA were induced by the Salmonella typhi strain A21-6,the level of IL-6 and the activity of NF-κB were detected as above.Results The type ⅣB piliated Salmonella typhi strain A21-6 could stimulate significantly higher expression of IL-6 and activity of NF-κB than those of typhi nonpiliated strain pilS-.The PKC inhibitor DECA reduced the expression of IL-6 and the activity of NF-κB induced by the piliated Salmonella typhi strain A21-6.Conclusion Type Ⅳ B pili as an important pathogenic bacterium,promotes the expression of IL-6 in THP-1 cells via the PKC-NF-κB pathway.

  12. (-)-Epigallocatechin-3-gallate inhibits VEGF expression induced by IL-6 via Stat3 in gastric cancer

    Institute of Scientific and Technical Information of China (English)

    Bao-He Zhu; Hua-Yun Chen; Wen-Hua Zhan; Cheng-You Wang; Shi-Rong Cai; Zhao Wang; Chang-Hua Zhang; Yu-Long He

    2011-01-01

    AIM: To demonstrate that (-)-Epigallocatechin-3-gallate (EGCG) inhibits vascular endothelial growth factor (VEGF) expression and angiogenesis induced by interleukin-6 (IL-6) via suppressing signal transducer and activator of transcription 3 (Stat3) activity in gastric cancer.METHODS: Human gastric cancer (AGS) cells were treated with IL-6 (50 ng/mL) and EGCG at different concentrations. VEGF, total Stat3 and activated Stat3 protein levels in the cell lyses were examined by Western blotting, VEGF protein level in the conditioned medium was measured by enzyme-linked immunosorbent assay, and the level of VEGF mRNA was evaluated by reverse transcription polymerase chain reaction (RTPCR).Stat3 nuclear translocation was determined by Western blotting with nuclear extract, and Stat3-DNA binding activity was examined with Chromatin immunoprecipitation (ChIP) assay. IL-6 induced endothelial cell proliferation was measured with 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl tetrazoliumbromide assay, in vitro angiogenesis was determined with endothelial cell tube formation assay in Matrigel, and IL-6-induced angiogenesis in vitro was measured with Matrigel plug assay.RESULTS: There was a basal expression and secretion of VEGF in AGS cells. After stimulation with IL-6, VEGF expression was apparently up-regulated and a 2.4-fold increase was observed. VEGF secretion in the conditioned medium was also increased by 2.8 folds. When treated with EGCG, VEGF expression and secretion were dose-dependently decreased. IL-6 also increased VEGF mRNA expression by 3.1 folds. EGCG treatment suppressed VEGF mRNA expression in a dose-dependent manner. EGCG dose-dependently inhibited Stat3 activation induced by IL-6, but did not change the total Stat3 expression. When treated with EGCG or AG490,VEGF expressions were reduced to the level or an even lower level in the tumor cells not stimulated with IL-6. However, PD98059 and LY294002 did not change VEGF expression induced by IL-6. EGCG inhibited

  13. Splenic Stromal Cells from Aged Mice Produce Higher Levels of IL-6 Compared to Young Mice

    Science.gov (United States)

    Park, Jihyun; Miyakawa, Takuya; Shiokawa, Aya; Nakajima-Adachi, Haruyo; Hachimura, Satoshi

    2014-01-01

    Inflamm-aging indicates the chronic inflammatory state resulting from increased secretion of proinflammatory cytokines and mediators such as IL-6 in the elderly. Our principle objective was to identify cell types that were affected with aging concerning IL-6 secretion in the murine model. We compared IL-6 production in spleen cells from both young and aged mice and isolated several types of cells from spleen and investigated IL-6 mRNA expression and protein production. IL-6 protein productions in cultured stromal cells from aged mice spleen were significantly high compared to young mice upon LPS stimulation. IL-6 mRNA expression level of freshly isolated stromal cells from aged mice was high compared to young mice. Furthermore, stromal cells of aged mice highly expressed IL-6 mRNA after LPS injection in vivo. These results suggest that stromal cells play a role in producing IL-6 in aged mice and imply that they contribute to the chronic inflammatory condition in the elderly. PMID:24729663

  14. Correlations of the infiltration of myeloid-derived suppressor cells with IL-6 expression and prognosis in patients with breast cancer%乳腺癌髓系来源抑制细胞浸润与IL-6表达水平及患者预后的相关性研究

    Institute of Scientific and Technical Information of China (English)

    陈洁英; 蒋蒙蒙; 于文文; 魏枫; 任秀宝; 于津浦

    2016-01-01

    目的:探讨乳腺癌髓系来源抑制细胞(myeloid-derived suppressor cells,MDSCs)浸润与肿瘤组织原位白介素-6(interleukin-6,IL-6)表达及患者预后的相关性。方法:收集天津医科大学肿瘤医院2012年10月至2014年10月间经手术切除的113例女性乳腺癌石蜡组织切片、上海芯超生物科技有限公司提供的2001年1月至2004年8月经手术切除的女性乳腺癌患者组织芯片140例,免疫组织化学方法检测肿瘤源性IL-6表达水平和MDSCs浸润情况,分析MDSCs的浸润与IL-6表达的相关性,以及MDSCs浸润与临床病理指标及预后的相关性。结果:MDSCs浸润与肿瘤大小、淋巴结受累、病理分期、组织分级和患者预后相关,MDSCs浸润数与IL-6表达水平相关。结论:乳腺癌细胞分泌的IL-6可能是肿瘤局部MDSCs浸润与募集的原因之一,乳腺癌MDSCs浸润可作为患者预后不良的预测因素。%Objective:To investigate the correlation of the infiltration of myeloid-derived suppressor cells (MDSC) with interleukin-6 (IL-6) expression and prognosis in patients with breast cancer. Methods:Tumor tissue slices were obtained from patients with breast can-cer who underwent surgery. The expression of IL-6 and the number of MDSCs were detected through immunohistochemistry analysis. The correlation of MDSC infiltration with IL-6 expression and prognosis in patients with breast cancer was also analyzed. Results:MD-SC infiltration was correlated with the infiltration of lymph nodes, tumor volume, tumor stage, histology grade, and overall survival of the patients. MDSC infiltration was also significantly correlated with IL-6 expression. Conclusion:IL-6 secreted by breast cancer cells may induce local infiltration and aggregation of MDSCs. Increased number of MDSCs could be the negative prognostic factor of pa-tients with breast cancer.

  15. Interferon Regulatory Factor 7 Promoted Glioblastoma Progression and Stemness by Modulating IL-6 Expression in Microglia

    Science.gov (United States)

    Li, Zongze; Huang, Qiming; Chen, Heping; Lin, Zhiqin; Zhao, Meng; Jiang, Zhongli

    2017-01-01

    Background: Interferon Regulatory Factor 7 (IRF7) is associated with chronic inflammation initiated by the activation of microglia. However it remains poorly defined how IRF7 activates microglia to initiate inflammatory microenvironment, and thus promotes the growth and malignancy of glioblastoma multiforme (GBM). This study investigated the role of IRF7 expression in microglia which increases GBM progression. Methods: We established stable human microglia (HMs) over-expressing IRF-7 or empty vector by lentiviral transduction and stable selection. These HM-IRF-7 cells were co-cultured with U87-MG to examine their influence on GBM, in terms of cell proliferation, apoptosis and stemness of U87-MG. By qRT-PCR and ELISA assays, the expression of key genes and secretion of inflammatory factors were identified in inflammatory signal pathway respectively. We also analyzed whether the expression of IRF7 and its target gene IL-6 correlated with PFS (progression-free survival) and OS (overall survival) in clinical samples by Kaplan-Meier survival curves. Results: HMs can be engineered to stably express high level of IFR7 with IRF7 lentivirus, and was found to promote U87-MG growth and inhibit its apoptosis in co-culture. Meanwhile, U87-MG seemed to show stem cell character with ALDH1 expression. These results may be related to IRF7 initiating IL-6 expression and secretion in both HM and U87-MG cells. The IRF7 and IL-6 were highly expressed in GBM tissues, and IL-6 secretion was high in GBM serums, both of which were significantly correlated with PFS and OS. Conclusions: The immune function of HMs was changed while it expressed IRF7 genes. The results demonstrated for the first time that IRF7 of microglia promoted GBM growth and stemness by mediating IL-6 expression, and revealed that IRF-7 and IL-6 were independent factors affecting the overall survival probability.

  16. 低氧对大鼠大脑皮层细胞表达IL-1β、IL-6和TNF-α mRNA的影响%Effects of hypoxia on the expression of IL-1 β、IL-6 and TNF-α mRNA in cerebral cortex cells of rats

    Institute of Scientific and Technical Information of China (English)

    李华华; 娄淑杰

    2013-01-01

    目的:观察不同氧浓度环境下不同时间处理对大鼠大脑皮层细胞表达IL-1β、IL-6和TNF-α mRNA的影响.方法:原代培养新生SD大鼠大脑皮层细胞,设1%、4%两个低氧浓度和3、6h两个低氧处理时间,处理结束后收集各组细胞,采用实时荧光定量PCR (RT-QPCR)方法检测各组细胞表达IL-1β、IL-6和TNF-α mRNA情况.结果:与相应的常氧对照组相比,1%和4%氧浓度环境处理细胞3h和6h时,IL-1β和TNF-α mRNA表达量均无明显变化(P>0.05);处理细胞3h时,IL-6 mRNA表达量均无明显变化(P>0.05),但有上升的趋势,处理细胞6h时IL-6 mRNA表达量均显著升高(P<0.05).结论:1%和4%氧浓度环境虽均对大脑皮层细胞表达IL-1β和TNF-α mRNA无影响,但可诱导细胞表达IL-6 mRNA,且具有时间依赖性.%Objective: To investigate the effects of different time treatment on levels of IL-1β, IL-6 and TNF-α mRNA expressed by cerebral cortex cells in rat under different oxygen concentration. Methods: Primary cultured cerebral cortex cells were subjected to hypoxia (1% and 4% ) for 3 hours and 6 hours. The production of IL-1β, IL-6 and TNF-α mRNA were analyzed by RT-QPCR. Results: Compared with matched normoxic controls, the production of IL-1β and TNF-a mRNA had no significant difference when cells were subjected to hypoxia (1% and 4% ) for 3 hours or 6 hours; and the production of IL-6 mRNA had no significant difference when cells were subjected to hypoxia (1% and 4% ) for 3h, but had an increased trend; while the levels of IL-6 mRNA were significantly increased when subjected to hypoxia (1 % and 4% ) for 6 hours. Conclusion.- The stimulation of hypoxia (1% and 4% ) on the production of IL-6mRNA had a time-dependent, but hypoxia had no effect on the production of IL-1β and TNF-α mRNA.

  17. Shp2 Plays a Critical Role in IL-6-Induced EMT in Breast Cancer Cells

    Science.gov (United States)

    Sun, Xuan; Zhang, Jie; Wang, Zhiyong; Ji, Wei; Tian, Ran; Zhang, Fei; Niu, Ruifang

    2017-01-01

    Accumulative evidence demonstrates that the protein tyrosine phosphatase Shp2 functions as a powerful tumor promoter in many types of cancers. Abnormal expression of Shp2 has been implicated in many human malignancies. Overexpression of Shp2 in cancer tissues is correlated with cancer metastasis, resistance to targeted therapy, and poor prognosis. The well-known function of Shp2 is its positive role in regulating cellular signaling initiated by growth factors and cytokines, including interleukin-6 (IL-6). Several recent studies have shown that Shp2 is required for epithelial-mesenchymal transition (EMT), triggered by growth factors. However, whether Shp2 is involved in IL-6-signaling-promoted breast cancer EMT and progression, remains undefined. In this study, we showed that exogenous and endogenous IL-6 can enhance breast cancer invasion and migration, through the promotion of EMT. IL-6 also induces the activation of Erk1/2 and the phosphorylation of Shp2. Knockdown of Shp2 attenuated the IL-6-induced downregulation of E-cadherin, as well as IL-6-promoted cell migration and invasion. Moreover, by using Shp2 phosphatase mutants, phosphor-tyrosine mimicking, and deficiency mutants, we provided evidence that the phosphatase activity of Shp2 and its tyrosine phosphorylation, are necessary for the IL-6-induced downregulation of E-cadherin and the phosphorylation of Erk1/2. Our findings uncover an important function that links Shp2 to IL-6-promoted breast cancer progression. PMID:28208810

  18. 八肽胆囊收缩素对TNF-α诱导的大鼠滑膜细胞株RSC-364 IL-6的作用及其可能的分子机制%Effects of cholecystokinin octapeptide on TNF- α- induced IL- 6 expression and its possible molecular mechanismin rat synovial cell strain RSC-364

    Institute of Scientific and Technical Information of China (English)

    赵占胜; 金玉怀; 丛斌; 李淑瑾; 徐锦荣; 姚玉霞; 凌亦凌

    2007-01-01

    AIM: To investigate the effect of sulfated cholecystokinin octapeptide (CCK -8 ) on TNF -α induced IL - 6 mRNA expression, NF - κB activation in the rat fibroblast - like synovial cell strain RSC - 364 and its possible receptor mechanisms. METHODS: RSC -364 cells were stimulated with TNF - α( 10 μg/L) in the presence or absence of sCCK- 8( 10-8 - 10-6 mol/L) or/and CCK receptor antagonist proglumide(2 mg/L). IL -6 and CCK receptor A/B (CCK- AR/CCK/BR) mRNA expression were assayed by reverse transcription polymerase chain reaction (RT- PCR) at 3 h after stimulation, and nuclear factor - κB (NF - κB) binding activity was analyzed by electrophoretic mobility shift assay (EMSA) at lh after stimulation. At 30 min of stimulation the IκB protein level in cytoplasma was measured by Western blotting. RESULTS: Both CCK - AR and CCK - BR were constitutively expressed on RSC - 364. sCCK - 8, at concentrations from 10-8 mol/L to 10 -6 mol/L, significantly increased IL - 6 mRNA expression, CCK - AR and CCK - BR mRNA expression, NF - κB binding activity and IκB protein degradation. The effects of sCCK - 8 on NF - κB activity and IκB degradation level were attenuated by CCK receptor antagonist proglumide. CONCLUSION: sCCK - 8 upregulats TNF - α- induced IL - 6 mRNA expression by NF - κB pathway through its receptor on rat synoviocytes, suggesting its possible regulatory role in the pathogenesis of rheumatoid arthritis.%目的:观察硫酸化八肽胆囊收缩素(sCCK-8)对TNF-α诱导大鼠滑膜细胞株RSC-364IL-6mRNA表达及核因子NF-κB的影响及其可能的受体机制.方法:大鼠滑膜细胞株RSC-364经TNF-α(10μg/L)、sCCK-8(10-8-10-6 mol/L)、CCK受体拮抗剂丙谷胺(2 mg/L)及溶剂单独或联合孵育3 h,用RT-PCR检测细胞IL-6、CCK-AR及CCK-BR mRNA的表达,孵育1 h,用电泳迁移率检测NF-κB活性,孵育30 min,用Western blotting检测胞浆IκB蛋白表达.结果:RSC-364细胞固有表达CCK-A/B受体,sCCK-8(10-8-10-6 mol/L)使IL-6

  19. The Akt1/IL-6/STAT3 pathway regulates growth of lung tumor initiating cells.

    Science.gov (United States)

    Malanga, Donatella; De Marco, Carmela; Guerriero, Ilaria; Colelli, Fabiana; Rinaldo, Nicola; Scrima, Marianna; Mirante, Teresa; De Vitis, Claudia; Zoppoli, Pietro; Ceccarelli, Michele; Riccardi, Miriam; Ravo, Maria; Weisz, Alessandro; Federico, Antonella; Franco, Renato; Rocco, Gaetano; Mancini, Rita; Rizzuto, Antonia; Gulletta, Elio; Ciliberto, Gennaro; Viglietto, Giuseppe

    2015-12-15

    Here we report that the PI3K/Akt1/IL-6/STAT3 signalling pathway regulates generation and stem cell-like properties of Non-Small Cell Lung Cancer (NSCLC) tumor initiating cells (TICs). Mutant Akt1, mutant PIK3CA or PTEN loss enhances formation of lung cancer spheroids (LCS), self-renewal, expression of stemness markers and tumorigenic potential of human immortalized bronchial cells (BEAS-2B) whereas Akt inhibition suppresses these activities in established (NCI-H460) and primary NSCLC cells. Matched microarray analysis of Akt1-interfered cells and LCSs identified IL-6 as a critical target of Akt signalling in NSCLC TICs. Accordingly, suppression of Akt in NSCLC cells decreases IL-6 levels, phosphorylation of IkK and IkB, NF-kB transcriptional activity, phosphorylation and transcriptional activity of STAT3 whereas active Akt1 up-regulates them. Exposure of LCSs isolated from NSCLC cells to blocking anti-IL-6 mAbs, shRNA to IL-6 receptor or to STAT3 markedly reduces the capability to generate LCSs, to self-renew and to form tumors, whereas administration of IL-6 to Akt-interfered cells restores the capability to generate LCSs. Finally, immunohistochemical studies in NSCLC patients demonstrated a positive correlative trend between activated Akt, IL-6 expression and STAT3 phosphorylation (n = 94; p < 0.05). In conclusion, our data indicate that aberrant Akt signalling contributes to maintaining stemness in lung cancer TICs through a NF-kB/IL-6/STAT3 pathway and provide novel potential therapeutic targets for eliminating these malignant cells in NSCLC.

  20. The Akt1/IL-6/STAT3 pathway regulates growth of lung tumor initiating cells

    Science.gov (United States)

    Malanga, Donatella; De Marco, Carmela; Guerriero, Ilaria; Colelli, Fabiana; Rinaldo, Nicola; Scrima, Marianna; Mirante, Teresa; De Vitis, Claudia; Zoppoli, Pietro; Ceccarelli, Michele; Riccardi, Miriam; Ravo, Maria; Weisz, Alessandro; Federico, Antonella; Franco, Renato; Rocco, Gaetano; Mancini, Rita; Rizzuto, Antonia; Gulletta, Elio; Ciliberto, Gennaro; Viglietto, Giuseppe

    2015-01-01

    Here we report that the PI3K/Akt1/IL-6/STAT3 signalling pathway regulates generation and stem cell-like properties of Non-Small Cell Lung Cancer (NSCLC) tumor initiating cells (TICs). Mutant Akt1, mutant PIK3CA or PTEN loss enhances formation of lung cancer spheroids (LCS), self-renewal, expression of stemness markers and tumorigenic potential of human immortalized bronchial cells (BEAS-2B) whereas Akt inhibition suppresses these activities in established (NCI-H460) and primary NSCLC cells. Matched microarray analysis of Akt1-interfered cells and LCSs identified IL-6 as a critical target of Akt signalling in NSCLC TICs. Accordingly, suppression of Akt in NSCLC cells decreases IL-6 levels, phosphorylation of IkK and IkB, NF-kB transcriptional activity, phosphorylation and transcriptional activity of STAT3 whereas active Akt1 up-regulates them. Exposure of LCSs isolated from NSCLC cells to blocking anti-IL-6 mAbs, shRNA to IL-6 receptor or to STAT3 markedly reduces the capability to generate LCSs, to self-renew and to form tumors, whereas administration of IL-6 to Akt-interfered cells restores the capability to generate LCSs. Finally, immunohistochemical studies in NSCLC patients demonstrated a positive correlative trend between activated Akt, IL-6 expression and STAT3 phosphorylation (n = 94; p < 0.05). In conclusion, our data indicate that aberrant Akt signalling contributes to maintaining stemness in lung cancer TICs through a NF-kB/IL-6/STAT3 pathway and provide novel potential therapeutic targets for eliminating these malignant cells in NSCLC. PMID:26486080

  1. Photodynamic therapy affects the expression of IL-6 and IL-10 in vivo

    Science.gov (United States)

    Gollnick, Sandra O.; Musser, David A.; Henderson, Barbara W.

    1998-05-01

    Photodynamic therapy (PDT), which can effectively destroy malignant tissue, also induces a complex immune response which potentiates anti-tumor immunity, but also inhibits skin contact hypersensitivity (CHS) and prolongs skin graft survival. The underlying mechanisms responsible for these effects are poorly understood, but are likely to involve meditation by cytokines. We demonstrate in a BALB/c mouse model that PDT delivered to normal and tumor tissue in vivo causes marked changes in the expression of cytokines interleukin (IL)-6 and IL-10. IL-6 mRNA and protein are rapidly and strongly enhanced in the PDT treated EMT6 tumor. Previous studies have shown that intratumoral injection of IL- 6 or transduction of the IL-6 gene into tumor cells can enhance tumor immunogenicity and inhibit tumor growth in experimental murine tumor systems. Thus, PDT may enhance local anti-tumor immunity by up-regulating IL-6. PDT also results in an increase in IL-10 mRNA and protein in the skin. The same PDT regime which enhances IL-10 production in the skin has been shown to strongly inhibit the CHS response. The kinetics of IL-10 expression coincide with the known kinetics of PDT induced CHS suppression and we propose that the enhanced IL-10 expression plays a role in the observed suppression of cell mediated responses seen following PDT.

  2. Corticosteroids reduce IL-6 in ASM cells via up-regulation of MKP-1.

    Science.gov (United States)

    Quante, Timo; Ng, Yee Ching; Ramsay, Emma E; Henness, Sheridan; Allen, Jodi C; Parmentier, Johannes; Ge, Qi; Ammit, Alaina J

    2008-08-01

    The mechanisms by which corticosteroids reduce airway inflammation are not completely understood. Traditionally, corticosteroids were thought to inhibit cytokines exclusively at the transcriptional level. Our recent evidence, obtained in airway smooth muscle (ASM), no longer supports this view. We have found that corticosteroids do not act at the transcriptional level to reduce TNF-alpha-induced IL-6 gene expression. Rather, corticosteroids inhibit TNF-alpha-induced IL-6 secretion by reducing the stability of the IL-6 mRNA transcript. TNF-alpha-induced IL-6 mRNA decays at a significantly faster rate in ASM cells pretreated with the corticosteroid dexamethasone (t(1/2) = 2.4 h), compared to vehicle (t(1/2) = 9.0 h; P ASM cells.

  3. Kinetics of IL-6 production defines T effector cell responsiveness to regulatory T cells in multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Bettina Trinschek

    Full Text Available In multiple sclerosis (MS autoaggressive T effector cells (Teff are not efficiently controlled by regulatory T cells (Treg but the underlying mechanisms are incompletely understood. Proinflammatory cytokines are key factors facilitating Teff activity in chronic inflammation. Here we investigated the influence of IL-6 on Treg sensitivity of Teff from therapy-naïve MS patients with or without active disease. Compared to healthy volunteers and independent of disease course CD4(+ and especially CD8(+ MS-Teff were insensitive against functional active Treg from healthy controls. This unresponsiveness was caused by accelerated production of IL-6, elevated IL-6 receptor expression and phosphorylation of protein kinase B (PKB/c-Akt in MS-Teff. In a positive feedback loop, IL-6 itself induced its accelerated synthesis and enhanced phosphorylation of PKB/c-Akt that finally mediated Treg resistance. Furthermore, accelerated IL-6 release especially by CD8(+ Teff prevented control of surrounding Teff, described here as "bystander resistance". Blockade of IL-6 receptor signaling or direct inhibition of PKB/c-Akt phosphorylation restored Treg responsiveness of Teff and prevented bystander resistance. In Teff of healthy controls (HC exogenous IL-6 also changed the kinetics of IL-6 production and induced Treg unresponsiveness. This modulation was only transient in Teff from healthy volunteers, whereas accelerated IL-6 production in MS-Teff maintained also in absence of IL-6. Hence, we showed that the kinetics of IL-6 production instead of elevated IL-6 levels defines the Teff responsiveness in early Treg-T cell communication in MS independent of their disease course and propose IL-6 and associated PKB/c-Akt activation as effective therapeutic targets for modulation of Teff activity in MS.

  4. 天麻素对高糖诱导的神经小胶质细胞IL-1β,IL-6表达的影响%Gastrodine represses expression of IL-lβ,IL-6 induced by hyperglycemia in gitter cells

    Institute of Scientific and Technical Information of China (English)

    杜晓红; 毛瑞阳; 刘毅; 李颖; 单亦升

    2009-01-01

    目的:研究天麻素对高糖诱导的神经小胶质细胞白介素-lβ(IL-1β)、白介素-6(IL-6)表达的影响.方法:将体外培养的小鼠小胶质瘤细胞(BV-2细胞)分成对照组、高糖组、天麻素低、中、高(25,50,100 mg·L~(-1))剂量组,培养24 h,观察细胞形态.应用酶联免疫吸附法(ELISA)测定培养上清中IL-1β,IL-6蛋白浓度,应用逆转录聚合酶链反应(RT-PCR)方法评价IL-1β,IL-6 mRNA表达.结果:与对照组相比,高糖组培养24 h后,细胞出现聚集,胞体、胞核变大,枝状突起明显,胞浆内颗粒物增多现象,天麻素各剂量组上述改变较轻.与对照组相比,高糖组细胞培养上清液中IL-1β,IL-6浓度,以及细胞内IL-1β,IL-6 mRNA表达明显增加,具有显著统计学差异(P<0.05);而与高糖组相比,天麻素各组细胞培养上清液中IL-1β,IL-6浓度,以及细胞IL-1β,IL-6 mRNA表达均降低,均具有显著统计学差异(P<0.05),其中以中浓度天麻素组最为显著,与高、低浓度组相比,均具有显著统计学差异(P<0.05).结论:天麻素能抑制高糖诱导的神经小胶质细胞IL-1β,IL-6表达.%Objective:To Inflammatory factors have been known to induce nerve cells apoptosis and decrease learning capacity of diabetics.The aim of this study is to evaluate the inhibitory effect of Gastrodine on the expression of interleukin-1β(IL-1β),interleu-kin-6 (IL-6) in culturing for gitter cells (BV-2 cells) induced by high concentration of glucose.Method:The BV-2 cells incubated in vitro with different concentrations of glucose and gastrodine were divided into five groups; control group (glucose: 25 mmol·L~(-1)),high concetration of glucose (glucose: 45 mmol·L~(-1) HCG) group and Gastrodine groups (glucose 45 mmol·L~(-1) with gastrodine 25mg·L~(-1)(LG),50 mg·L~(-1)(MG),100 mg·L~(-1)(HG).After culturing for 24h,morphological changes of cells were observed by inverted phase contrast microscope.The supernatant protein of IL-1β and IL-6 was

  5. IL-6 is increased in the cerebellum of autistic brain and alters neural cell adhesion, migration and synaptic formation

    Directory of Open Access Journals (Sweden)

    Dobkin Carl

    2011-05-01

    Full Text Available Abstract Background Although the cellular mechanisms responsible for the pathogenesis of autism are not understood, a growing number of studies have suggested that localized inflammation of the central nervous system (CNS may contribute to the development of autism. Recent evidence shows that IL-6 has a crucial role in the development and plasticity of CNS. Methods Immunohistochemistry studies were employed to detect the IL-6 expression in the cerebellum of study subjects. In vitro adenoviral gene delivery approach was used to over-express IL-6 in cultured cerebellar granule cells. Cell adhesion and migration assays, DiI labeling, TO-PRO-3 staining and immunofluorescence were used to examine cell adhesion and migration, dendritic spine morphology, cell apoptosis and synaptic protein expression respectively. Results In this study, we found that IL-6 was significantly increased in the cerebellum of autistic subjects. We investigated how IL-6 affects neural cell development and function by transfecting cultured mouse cerebellar granule cells with an IL-6 viral expression vector. We demonstrated that IL-6 over-expression in granule cells caused impairments in granule cell adhesion and migration but had little effect on the formation of dendritic spines or granule cell apoptosis. However, IL-6 over-expression stimulated the formation of granule cell excitatory synapses, without affecting inhibitory synapses. Conclusions Our results provide further evidence that aberrant IL-6 may be associated with autism. In addition, our results suggest that the elevated IL-6 in the autistic brain could alter neural cell adhesion, migration and also cause an imbalance of excitatory and inhibitory circuits. Thus, increased IL-6 expression may be partially responsible for the pathogenesis of autism.

  6. IL-6 acts on endothelial cells to preferentially increase their adherence for lymphocytes.

    Science.gov (United States)

    Watson, C; Whittaker, S; Smith, N; Vora, A J; Dumonde, D C; Brown, K A

    1996-07-01

    Using a quantitative monolayer adhesion assay, the current report shows that treatment of human umbilical vein endothelial cells (HUVEC) with IL-6 increases their adhesiveness for blood lymphocytes, particularly CD4+ cells, but not for polymorphonuclear cells and monocytes. This effect, which was most pronounced when using low concentrations of the cytokine (0.1-1.0 U/ml) and a short incubation period (4h), was also apparent with microvascular endothelial cells and a hybrid endothelial cell line. Skin lesions from patients with mycosis fungoides contain high levels of IL-6, and blood lymphocytes from patients with this disorder also exhibited an enhanced adhesion to IL-6-treated HUVEC. The cytokine enhanced intercellular adhesion molecule-1 (ICAM-1) expression and induced the expression of vascular cell adhesion molecule-1 (VCAM-1) and E-selectin on endothelial cells. Antibody blocking studies demonstrated that the vascular adhesion molecules ICAM-1, VCAM-1 and E-selectin and the leucocyte integrin LFA-1 all contributed to lymphocyte binding to endothelium activated by IL-6. It is proposed that IL-6 may be involved in the recruitment of lymphocytes into non-lymphoid tissue.

  7. Chronic administration of recombinant IL-6 upregulates lipogenic enzyme expression and aggravates high-fat-diet-induced steatosis in IL-6-deficient mice

    Directory of Open Access Journals (Sweden)

    Margarita Vida

    2015-07-01

    Full Text Available Interleukin-6 (IL-6 has emerged as an important mediator of fatty acid metabolism with paradoxical effects in the liver. Administration of IL-6 has been reported to confer protection against steatosis, but plasma and tissue IL-6 concentrations are elevated in chronic liver diseases, including fatty liver diseases associated with obesity and alcoholic ingestion. In this study, we further investigated the role of IL-6 on steatosis induced through a high-fat diet (HFD in wild-type (WT and IL-6-deficient (IL-6−/− mice. Additionally, HFD-fed IL-6−/− mice were also chronically treated with recombinant IL-6 (rIL-6. Obesity in WT mice fed a HFD associated with elevated serum IL-6 levels, fatty liver, upregulation of carnitine palmitoyltransferase 1 (CPT1 and signal transducer and activator of transcription-3 (STAT3, increased AMP kinase phosphorylation (p-AMPK, and downregulation of the hepatic lipogenic enzymes fatty acid synthase (FAS and stearoyl-CoA desaturase 1 (SCD1. The HFD-fed IL-6−/− mice showed severe steatosis, no changes in CPT1 levels or AMPK activity, no increase in STAT3 amounts, inactivated STAT3, and marked downregulation of the expression of acetyl-CoA carboxylase (ACCα/β, FAS and SCD1. The IL-6 chronic replacement in HFD-fed IL-6−/− mice restored hepatic STAT3 and AMPK activation but also increased the expression of the lipogenic enzymes ACCα/β, FAS and SCD1. Furthermore, rIL-6 administration was associated with aggravated steatosis and elevated fat content in the liver. We conclude that, in the context of HFD-induced obesity, the administration of rIL-6 might contribute to the aggravation of fatty liver disease through increasing lipogenesis.

  8. Quercetin abrogates IL-6/STAT3 signaling and inhibits glioblastoma cell line growth and migration

    Energy Technology Data Exchange (ETDEWEB)

    Michaud-Levesque, Jonathan; Bousquet-Gagnon, Nathalie; Beliveau, Richard, E-mail: oncomol@nobel.si.uqam.ca

    2012-05-01

    Evidence has suggested that STAT3 functions as an oncogene in gliomagenesis. As a consequence, changes in the inflammatory microenvironment are thought to promote tumor development. Regardless of its origin, cancer-related inflammation has many tumor-promoting effects, such as the promotion of cell cycle progression, cell proliferation, cell migration and cell survival. Given that IL-6, a major cancer-related inflammatory cytokine, regulates STAT3 activation and is upregulated in glioblastoma, we sought to investigate the inhibitory effects of the chemopreventive flavonoid quercetin on glioblastoma cell proliferation and migration triggered by IL-6, and to determine the underlying mechanisms of action. In this study, we show that quercetin is a potent inhibitor of the IL-6-induced STAT3 signaling pathway in T98G and U87 glioblastoma cells. Exposure to quercetin resulted in the reduction of GP130, JAK1 and STAT3 activation by IL-6, as well as a marked decrease of the proliferative and migratory properties of glioblastoma cells induced by IL-6. Interestingly, quercetin also modulated the expression of two target genes regulated by STAT3, i.e. cyclin D1 and matrix metalloproteinase-2 (MMP-2). Moreover, quercetin reduced the recruitment of STAT3 at the cyclin D1 promoter and inhibited Rb phosphorylation in the presence of IL-6. Overall, these results provide new insight into the role of quercetin as a blocker of the STAT3 activation pathway stimulated by IL-6, with a potential role in the prevention and treatment of glioblastoma.

  9. IL-6/STAT3 signaling pathway is activated in plasma cell mastitis.

    Science.gov (United States)

    Liu, Yang; Zhang, Jian; Zhou, Yu-Hui; Jiang, Yi-Na; Zhang, Wei; Tang, Xiao-Jiang; Ren, Yu; Han, Shui-Ping; Liu, Pei-Jun; Xu, Jing; He, Jian-Jun

    2015-01-01

    Plasma cell mastitis (PCM), a particular type of mastitis, mainly occurs in females at nonpregnant and nonlactating stages. The infiltration of abundant plasma cells and lymphocytes is the hallmark of the disease. The incidence rate of PCM increased gradually and its pathogenesis remained unclear. In this study, we investigated the expression of IL-6/STAT3 signaling pathway, which is vital not only for the differentiation of plasma cells but also for survival of plasma cells and T lymphocytes, in 30 PCM cases, 10 acute mastitis cases and 10 normal breast tissues by immunohistochemical analysis. IL-6 level was significantly higher in PCM patients than in acute mastitis patients or normal group. The positive rate of IL-6 and p-STAT3 staining in PCM samples was 93.3% (28/30) and 70% (21/30), respectively, and there was a significant positive association between IL-6 and p-STAT3 staining (r=0.408, P=0.025). In PCM group, the rate of nipple retraction was 40% (12/30). Significantly higher IL-6 expression was found in PCM patients with nipple retraction than in other PCM patients. However, no significant difference in IL-6 or p-STAT3 staining was detected between PCM patients experiencing recurrence and other PCM patients. In addition, Bcl-2 level was higher in PCM patients than in acute mastitis patients or normal group, but there was no difference in Bcl-2 immunostaining between PCM patients experiencing recurrence and other PCM patients. These indicate that IL-6/STAT3 signaling is activated in PCM and may play an important role in the pathogenesis of PCM.

  10. IL-6 contributes to an immune tolerance checkpoint in post germinal center B cells.

    Science.gov (United States)

    Yan, Yi; Wang, Ying-Hua; Diamond, Betty

    2012-02-01

    The generation of a B cell repertoire involves producing and subsequently purging autoreactive B cells. Receptor editing, clonal deletion and anergy are key mechanisms of central B cell tolerance. Somatic mutation of antigen-activated B cells within the germinal center produces a second wave of autoreactivity; but the regulatory mechanisms that operate at this phase of B cell activation are poorly understood. We recently identified a post germinal center tolerance checkpoint, where receptor editing is re-induced to extinguish autoreactivity that is generated by somatic hypermutation. Re-induction of the recombinase genes RAG1 and RAG2 in antigen-activated B cells requires antigen to engage the B cell receptor and IL-7 to signal through the IL-7 receptor. We demonstrate that this process requires IL-6 to upregulate IL-7 receptor expression on post germinal center B cells. Diminishing IL-6 by blocking antibody or haplo-insufficiency leads to reduced expression of the IL-7 receptor and RAG and increased titers of anti-DNA antibodies following immunization with a peptide mimetope of DNA. The dependence on IL-6 to initiate receptor editing is B cell intrinsic. Interestingly, estradiol decreases IL-6 expression thereby increasing the anti-DNA response. Our data reveal a novel regulatory cascade to control post germinal center B cell autoreactivity.

  11. Murine hematopoietic progenitor cells produce IL-6 in response to IgE.

    Science.gov (United States)

    Schneider, E; Salachas, F; Lemoine, F M; Arnould, A; Machavoine, F; Ploemacher, R E; Dy, M

    1995-04-01

    Similarly to interleukin-3 (IL-3), IgE is capable of inducing IL-6 production by murine bone marrow cells (BMC). IgE responder cells do not belong to the mature bone marrow compartment but coenrich with hematopoietic progenitors in the low-density fraction of a discontinuous Ficoll gradient. A significant enhancement of IL-6 production is observed after a 4-hour stimulation, reaching a maximum between 24 and 48 hours and is preceded by increased mRNA expression. The effect of IgE on IL-6 production is not mediated by IL-3 since it is not modified by anti-IL-3 antibodies. Upon a 4-hour exposure to IgE or IL-3, a similar percentage of progenitor-enriched BMC expresses IL-6 mRNA (3.9 and 5.4%, respectively, as determined by in situ hybridization), which is not further increased by a combination of both stimuli. IgE and IL-3 responder cells also cannot be distinguished on the basis of size, internal structure, and rhodamine (Rh) retention. The BMC sorted in the most fluorescent Rhbright subset (approximately 0.2% of total BMC) produce 30- to 40-fold more IL-6 than unfractionated cells and are similarly enriched for CFU-cells (CFU-C). The most primitive cells concentrated in the Rhdull fraction do not express this biological activity. The sorted Rhbright population does not contain mature mast cells/basophils or monocytes, and IL-6 is not produced in response to Fc epsilon RI cross-linkage after presensitization with IgE.

  12. Hypoxia-induced aggressiveness of pancreatic cancer cells is due to increased expression of VEGF, IL-6 and miR-21, which can be attenuated by CDF treatment.

    Directory of Open Access Journals (Sweden)

    Bin Bao

    Full Text Available Hypoxia is known to play critical roles in cell survival, angiogenesis, tumor invasion, and metastasis. Hypoxia mediated over-expression of hypoxia-inducible factor (HIF has been shown to be associated with therapeutic resistance, and contributes to poor prognosis of cancer patients. Emerging evidence suggest that hypoxia and HIF pathways contributes to the acquisition of epithelial-to-mesenchymal transition (EMT, maintenance of cancer stem cell (CSC functions, and also maintains the vicious cycle of inflammation-all which lead to therapeutic resistance. However, the precise molecular mechanism(s by which hypoxia/HIF drives these events are not fully understood. Here, we show, for the first time, that hypoxia leads to increased expression of VEGF, IL-6, and CSC signature genes Nanog, Oct4 and EZH2 consistent with increased cell migration/invasion and angiogenesis, and the formation of pancreatospheres, concomitant with increased expression of miR-21 and miR-210 in human pancreatic cancer (PC cells. The treatment of PC cells with CDF, a novel synthetic compound inhibited the production of VEGF and IL-6, and down-regulated the expression of Nanog, Oct4, EZH2 mRNAs, as well as miR-21 and miR-210 under hypoxia. CDF also led to decreased cell migration/invasion, angiogenesis, and formation of pancreatospheres under hypoxia. Moreover, CDF decreased gene expression of miR-21, miR-210, IL-6, HIF-1α, VEGF, and CSC signatures in vivo in a mouse orthotopic model of human PC. Collectively, these results suggest that the anti-tumor activity of CDF is in part mediated through deregulation of tumor hypoxic pathways, and thus CDF could become a novel, and effective anti-tumor agent for PC therapy.

  13. B cells produce less IL-10, IL-6 and TNF-α in myasthenia gravis.

    Science.gov (United States)

    Yilmaz, Vuslat; Oflazer, Piraye; Aysal, Fikret; Parman, Yeşim G; Direskeneli, Haner; Deymeer, Feza; Saruhan-Direskeneli, Güher

    2015-06-01

    B cells from myasthenia gravis (MG) patients with autoantibodies (Aab) against acetylcholine receptor (AChR), muscle-specific kinase (MuSK) or with no detectable Aab were investigated as cytokine producing cells in this study. B cells were evaluated for memory phenotypes and expressions of IL-10, IL-6 and IL-12A. Induced productions of IL-10, IL-6, IL-12p40, TNF-α and LT from isolated B cells in vitro were measured by immunoassays. MG patients receiving immunosuppressive treatment had higher proportions of memory B cells compared with healthy controls and untreated patients. With CD40 stimulation MG patients produced significantly lower levels of IL-10, IL-6. With CD40 and B cell receptor stimulation of B cells, TNF-α production also decreased in addition to these cytokines. The lower levels of these cytokine productions were not related to treatment. Our results confirm a disturbance of B cell subpopulations in MG subgroups on immunosuppressive treatment. B cell derived IL-10, IL-6 and TNF-α are down-regulated in MG, irrespective of different antibody productions. Ineffective cytokine production by B cells may be a susceptibility factor in dysregulation of autoimmune Aab production.

  14. Expression and interaction of secretory immunoglobulin A, interleukin 6, and dendritic cells in oral cancers%SIgA IL-6和树突状细胞在口腔癌中的表达及相互作用

    Institute of Scientific and Technical Information of China (English)

    张素欣; 尹克; 段玉芹; 陈彦平; 郭兰涛; 李天客; 陈中

    2013-01-01

      目的:探讨分泌型免疫球蛋白A(secretory immunoglobulin A,SIgA)、白细胞介素-6(interleukin-6,IL-6)和树突状细胞(dendritic cell,DC)在口腔癌中的表达和相互作用.方法:选取60例原发口腔癌患者为研究对象,20例健康志愿者唾液为正常对照,用ELISA法检测唾液中的SIgA、IL-6含量.用免疫组织化学法和流式细胞仪检测癌组织中CD1a、CD83、CD80及CD86的表达情况.经病理证实的20例良性肿瘤患者正常口腔黏膜组织为对照.结果:口腔癌患者唾液SIgA的含量明显低于对照组,IL-6的含量明显高于对照组,差异有统计学意义(P0.05),与临床分期及淋巴结转移呈负相关(P0.05). Correlation analysis showed that the CD80 and CD86 levels were negatively correlated with the clinical stage and lymph node metastases (P<0.05). Conclusion:The SIgA and IL-6 content can be used as auxiliary indicators for oral cancer diagnosis. The increasing IL-6 level could account for the decreased SIgA production. Immune deficiency occurs in the DCs of oral cancer patients, and the expression levels of CD80 and CD86 reflect this prognostic evaluation. IL-6 may inhibit the formation of SIgA and cause the immune tolerance of DC. Thus, the effective immune response is lost, thereby promoting carcinogenesis and the progress of oral cancer.

  15. Avian leukosis virus subgroup J induces VEGF expression via NF-κB/PI3K-dependent IL-6 production.

    Science.gov (United States)

    Gao, Yanni; Zhang, Yao; Yao, Yongxiu; Guan, Xiaolu; Liu, Yongzhen; Qi, Xiaole; Wang, Yongqiang; Liu, Changjun; Zhang, Yanping; Gao, Honglei; Nair, Venugopal; Wang, Xiaomei; Gao, Yulong

    2016-12-06

    Avian leukosis virus subgroup J (ALV-J) is an oncogenic virus causing hemangiomas and myeloid tumors in chickens. Interleukin-6 (IL-6) is a multifunctional pro-inflammatory interleukin involved in many types of cancer. We previously demonstrated that IL-6 expression was induced following ALV-J infection in chickens. The aim of this study is to characterize the mechanism by which ALV-J induces IL-6 expression, and the role of IL-6 in tumor development. Our results demonstrate that ALV-J infection increases IL-6 expression in chicken splenocytes, peripheral blood lymphocytes, and vascular endothelial cells. IL-6 production is induced by the ALV-J envelope protein gp85 and capsid protein p27 via PI3K- and NF-κB-mediated signaling. IL-6 in turn induced expression of vascular endothelial growth factor (VEGF)-A and its receptor, VEGFR-2, in vascular endothelial cells and embryonic vascular tissues. Suppression of IL-6 using siRNA inhibited the ALV-J induced VEGF-A and VEGFR-2 expression in vascular endothelial cells, indicating that the ALV-J-induced VEGF-A/VEGFR-2 expression is mediated by IL-6. As VEGF-A and VEGFR-2 are important factors in oncogenesis, our findings suggest that ALV-J hijacks IL-6 to promote tumorigenesis, and indicate that IL-6 could potentially serve as a therapeutic target in ALV-J infections.

  16. IL-6/STAT3/TFF3 signaling regulates human biliary epithelial cell migration and wound healing in vitro.

    Science.gov (United States)

    Jiang, Gui-xing; Zhong, Xiang-yu; Cui, Yun-fu; Liu, Wei; Tai, Sheng; Wang, Zhi-dong; Shi, Yu-guang; Zhao, Shi-yong; Li, Chun-long

    2010-12-01

    Interleukin-6 (IL-6), through activation of the signal transducer and activator of transcription 3 (STAT3) and trefoil factor family 3 (TFF3), has been implicated in the promotion of mouse biliary epithelial cell (BEC) proliferation and migration. However, it is still unclear whether the IL-6/STAT3/TFF3 signaling had similar effects on human BECs. Here, we showed that exposure of human BECs to recombinant IL-6 resulted in STAT3 phosphorylation and increased the expression of TFF3 at both mRNA and protein levels. Moreover, inhibition of STAT3 using RNA interference significantly abrogated IL-6-induced TFF3 expression. In an in-vitro wound healing model, IL-6 facilitated human BEC migration. This promotion of cell migration by IL-6 was blocked when STAT3 was knocked down. Interestingly, the addition of exogenous TFF3 could rescue the cell migration defects caused by STAT3 silencing. In conclusion, our data indicate that STAT3 plays a critical role in IL-6-induced TFF3 expression in human BECs and the IL-6/STAT3/TFF3 signaling is involved in human BEC migration and wound healing.

  17. Hormonal-receptor positive breast cancer: IL-6 augments invasion and lymph node metastasis via stimulating cathepsin B expression

    Directory of Open Access Journals (Sweden)

    Sherif A. Ibrahim

    2016-09-01

    Full Text Available Hormonal-receptor positive (HRP breast cancer patients with positive metastatic axillary lymph nodes are characterized by poor prognosis and increased mortality rate. The mechanisms by which cancer cells invade lymph nodes have not yet been fully explored. Several studies have shown that expression of IL-6 and the proteolytic enzyme cathepsin B (CTSB was associated with breast cancer poor prognosis. In the present study, the effect of different concentrations of recombinant human IL-6 on the invasiveness capacity of HRP breast cancer cell line MCF-7 was tested using an in vitro invasion chamber assay. The impact of IL-6 on expression and activity of CTSB was also investigated. IL-6 treatment promoted the invasiveness potential of MCF-7 cells in a dose-dependent manner. Furthermore, MCF-7 cells displayed elevated CTSB expression and activity associated with loss of E-cadherin and upregulation of vimentin protein levels upon IL-6 stimulation. To validate these results in vivo, the level of expression of IL-6 and CTSB in the carcinoma tissues of HRP-breast cancer patients with positive and negative axillary metastatic lymph nodes (pLNs and nLNs was assessed. Western blot and immunohistochemical staining data showed that expression of IL-6 and CTSB was higher in carcinoma tissues in HRP-breast cancer with pLNs than those with nLNs patients. ELISA results showed carcinoma tissues of HRP-breast cancer with pLNs exhibited significantly elevated IL-6 protein levels by approximately 2.8-fold compared with those with nLNs patients (P < 0.05. Interestingly, a significantly positive correlation between IL-6 and CTSB expression was detected in clinical samples of HRP-breast cancer patients with pLNs (r = 0.78, P < 0.01. Collectively, this study suggests that IL-6-induced CTSB may play a role in lymph node metastasis, and that may possess future therapeutic implications for HRP-breast cancer patients with pLNs. Further studies are necessary to fully

  18. Association Between IL-4 and IL-6 Expression Variants and Gastric Cancer Among Portuguese Population

    Directory of Open Access Journals (Sweden)

    Ana Maria Sampaio

    2015-07-01

    Conclusion: IL-6 and IL-4 expression variants seem to have an important role in GC risk mechanisms. This study provides preliminary evidence that IL-4 and IL-6 polymorphisms, although not directly linked to the disease, may be useful tools in the study of this multifactorial disease.

  19. In humans IL-6 is released from the brain during and after exercise and paralleled by enhanced IL-6 mRNA expression in the hippocampus of mice

    DEFF Research Database (Denmark)

    Rasmussen, Per; Vedel, J-C; Olesen, J

    2011-01-01

    Aim: Plasma interleukin-6 (IL-6) increases during exercise by release from active muscles and during prolonged exercise also from the brain. The IL-6 release from muscles continues into recovery and we tested whether the brain also releases IL-6 in recovery from prolonged exercise in humans....... Additionally, it was evaluated in mice whether brain release of IL-6 reflected enhanced IL-6 mRNA expression in the brain as modulated by brain glycogen levels. Methods: Nine healthy male subjects completed 4 h of ergometer rowing while the arterio-jugular venous difference (a-v diff) for IL-6 was determined....... The IL-6 mRNA and the glycogen content were determined in mouse hippocampus, cerebellum and cortex before and after 2 h treadmill running (N = 8). Results: At rest, the IL-6 a-v diff was negligible but decreased to -2.2 ± 1.9 pg ml(-1) at the end of exercise and remained low (-2.1 ± 2.1 pg ml(-1) ) 1 h...

  20. D-dopachrome tautomerase promotes IL-6 expression and inhibits adipogenesis in preadipocytes

    OpenAIRE

    2012-01-01

    We previously identified D-dopachrome tautomerase (DDT) as a novel adipokine whose mRNA levels in adipocytes are negatively correlated with obesity-related clinical parameters, and which acts on adipocytes to regulate lipid metabolism. Here we investigated functions of DDT on preadipocytes. Recombinant DDT (rDDT) enhanced both the expression and secretion of interleukin-6 (IL-6) in SGBS cells, a human preadipocyte cell line. Treatment with rDDT increased levels of phosphorylated ERK1/2, but n...

  1. Effect of orthodontic force on inflammatory periodontal tissue remodeling and expression of IL-6 and IL-8 in rats

    Institute of Scientific and Technical Information of China (English)

    Jian-Hao Yang; Zheng-Chen Li; Wei-Dong Kong; Wu Zhang; Ying-Ping Jia; Yue-Lan Zhang; Lin-Bo Liu; Xue-Ping Han

    2013-01-01

    ABSTRACT Objective:To investigate effect of orthodontic force on inflammatory periodontal tissue remodeling and expression ofIL-6 andIL-8 in rats.Methods:EightySD rats were randomly divided into4 groups, blank control group(groupA) with5 rats, treatment normal group(group B) with25 rats, inflammation control group(group(groupC) with25 rats, inflammation treatment group(groupD) with25 rats.Immunohistochemistry and histomorphometric analysis was performed to measure the expression ofIL-6,IL-8 and the first molar to the recent movement in the distance.Results:The expression ofIL-8 reached a maximum on day5 and declined thereafter in groupB; the expression ofIL-6 reached a maximum on day5 in groupB.The expression ofIL-6 andIL-8 was gradually weakened with time in groupC.The expression of IL-6 andIL-8 were high, and reached a maximum on day5 and declined thereafter in groupD. AD of positive cells in groupD were higher than groupB at each time point(P<0.05).The time which0.49N orthodontic force was loaded was longer, orthodontic tooth movement distance was greater.Movement distance in groupD were longer than groupB(P<0.05).Conclusions:Orthodontic force as well as inflammatory stimulus can evoke the expression ofIL-6 andIL-8. Under the combined effects of inflammation and orthodontic force, the expression ofIL-6,IL-8 will increase.

  2. Differential T Cell Cytokine Receptivity and Not Signal Quality Distinguishes IL-6 and IL-10 Signaling during Th17 Differentiation.

    Science.gov (United States)

    Jones, Lindsay L; Alli, Rajshekhar; Li, Bofeng; Geiger, Terrence L

    2016-04-01

    How a large number of cytokines differentially signal through a small number of signal transduction pathways is not well resolved. This is particularly true for IL-6 and IL-10, which act primarily through STAT3 yet induce dissimilar transcriptional programs leading alternatively to pro- and anti-inflammatory effects. Kinetic differences in signaling, sustained to IL-10 and transient to IL-6, are critical to this in macrophages. T cells are also key targets of IL-6 and IL-10, yet how differential signaling in these cells leads to divergent cellular fates is unclear. We show that, unlike for macrophages, signal duration cannot explain the distinct effects of these cytokines in T cells. Rather, naive, activated, activated-rested, and memory CD4(+) T cells differentially express IL-6 and IL-10 receptors in an activation state-dependent manner, and this impacts downstream cytokine effects. We show a dominant role for STAT3 in IL-6-mediated Th17 subset maturation. IL-10 cannot support Th17 differentiation because of insufficient cytokine receptivity rather than signal quality. Enforced expression of IL-10Rα on naive T cells permits an IL-10-generated STAT3 signal equivalent to that of IL-6 and equally capable of promoting Th17 formation. Similarly, naive T cell IL-10Rα expression also allows IL-10 to mimic the effects of IL-6 on both Th1/Th2 skewing and Tfh cell differentiation. Our results demonstrate a key role for the regulation of receptor expression rather than signal quality or duration in differentiating the functional outcomes of IL-6 and IL-10 signaling, and identify distinct signaling properties of these cytokines in T cells compared with myeloid cells.

  3. Human intestinal mucosa-associated Lactobacillus and Bifidobacterium strains with probiotic properties modulate IL-10, IL-6 and IL-12 gene expression in THP-1 cells.

    Science.gov (United States)

    Čitar, M; Hacin, B; Tompa, G; Štempelj, M; Rogelj, I; Dolinšek, J; Narat, M; Matijašić, B Bogovič

    2015-01-01

    Lactobacilli and bifidobacteria are considered one of the permanent genera of the physiological human intestinal microbiota and represent an enormous pool of potential probiotic candidates. Approximately 450 isolates of presumptive Lactobacillus or Bifidobacterium strains were obtained from bioptic samples of colonic and ileal mucosa from 15 adolescents aged 12 to 18 years. On the basis of randomly amplified polymorphic DNA (RAPD)-PCR analysis, 20 strains were selected for further taxonomic classification and characterisation, as well as assessment of probiotic properties and safety. Importantly, selected strains showed the capability of colonising different parts of the intestine. The most frequently isolated species was Lactobacillus paracasei followed by Lactobacillus fermentum. The majority of isolates were susceptible to antimicrobials of human and veterinary importance, however, tetracycline and/or erythromycin resistance was observed in Lactobacillus plantarum and L. fermentum strains. Thirteen strains were able to ferment more than 19 different carbon sources and three out of five tested strains exerted antagonistic activity against several different indicator strains. Two Lactobacillus isolates (L. paracasei L350 and L. fermentum L930 bb) and one Bifidobacterium isolate (Bifidobacterium animalis subsp. animalis IM386) fulfilled in vitro selection criteria for probiotic strains and exhibited strong downregulation of pro-inflammatory cytokines IL-6 and IL-12 and upregulation of anti-inflammatory IL-10. The selected strains represent suitable candidates for further studies regarding their positive influence on host health and could play an important role in ameliorating the symptoms of inflammatory bowel diseases.

  4. Pseuderanthemum palatiferum leaf extract inhibits the proinflammatory cytokines, TNF-α and IL-6 expression in LPS-activated macrophages.

    Science.gov (United States)

    Sittisart, Patcharawan; Chitsomboon, Benjamart; Kaminski, Norbert E

    2016-11-01

    The anti-inflammatory potential and underlying mechanisms of an ethanol extract of Pseuderanthemum palatiferum (EEP) leaves was investigated using LPS-activated macrophages. Our results show EEP produced a concentration-dependent suppression of TNF-α and IL-6 secretion by LPS-activated mouse peritoneal macrophages. EEP also suppressed LPS-induced TNF-α and IL-6 protein and mRNA levels in mouse-derived myeloid cell line RAW264.7. To further elucidate the molecular mechanisms responsible for impaired TNF-α and IL-6 regulation by EEP, the activation of transcription factors, NF-κB, C/EBP, and AP-1, was monitored using electrophoretic mobility shift assays. EEP suppressed LPS-induced NF-κB DNA binding activity within both the TNF-α and IL-6 promoters in RAW264.7 cells with impairment being more pronounced in the IL-6 promoter. In addition, EEP exhibited a concentration-dependent suppression of C/EBP and AP-1 DNA binding activity within the IL-6 promoter. Concordantly, IL-6 luciferase promoter reporter activity was also suppressed by EEP in transiently transfected RAW264.7 cells, upon LPS activation. EEP analysis by GC-MS and HPLC DAD-MSD revealed the presence of β-sitosterol and various polyphenols, respectively, which are known to possess anti-inflammatory activity. Collectively, these results suggest that the anti-inflammatory effects of EEP are mediated, at least in part, by modulating TNF-α and IL-6 expression through impairment of NF-κB, C/EBP, and AP-1 activity.

  5. Basophil-derived IL-6 regulates TH17 cell differentiation and CD4 T cell immunity

    Science.gov (United States)

    Yuk, Chae Min; Park, Hyeung Ju; Kwon, Bo-In; Lah, Sang Joon; Chang, Jun; Kim, Ji-Young; Lee, Kyung-Mi; Park, Su-Hyung; Hong, Seokchan; Lee, Seung-Hyo

    2017-01-01

    Basophils are rare, circulating granulocytes proposed to be involved in T helper (TH) type 2 immunity, mainly through secretion of interleukin (IL)-4. In addition to IL-4, basophils produce IL-6 and tumor necrosis factor (TNF)-α in response to immunoglobulin E (IgE) crosslinking. Differentiation of TH17 cells requires IL-6 and transforming growth factor (TGF)-β, but whether basophils play a significant role in TH17 induction is unknown. Here we show a role for basophils in TH17 cell development by using in vitro T cell differentiation and in vivo TH17-mediated inflammation models. Bone marrow derived-basophils (BMBs) and splenic basophils produce significant amounts of IL-6 as well as IL-4 following stimulation with IgE crosslink or cholera toxin (CT). In addition, through IL-6 secretion, BMBs cooperate with dendritic cells to promote TH17 cell differentiation. In the TH17 lung inflammation model, basophils are recruited to the inflamed lungs following CT challenge, and TH17 responses are significantly reduced in the absence of basophils or IL-6. Furthermore, reconstitution with wild-type, but not IL-6-deficient, basophils restored CT-mediated lung inflammation. Lastly, basophil-deficient mice showed reduced phenotypes of TH17-dependent experimental autoimmune encephalomyelitis. Therefore, our results indicate that basophils are an important inducer of TH17 cell differentiation, which is dependent on IL-6 secretion. PMID:28134325

  6. The Expression of Human Cytomegalovirus MicroRNA MiR-UL148D during Latent Infection in Primary Myeloid Cells Inhibits Activin A-triggered Secretion of IL-6.

    Science.gov (United States)

    Lau, Betty; Poole, Emma; Krishna, Benjamin; Sellart, Immaculada; Wills, Mark R; Murphy, Eain; Sinclair, John

    2016-08-05

    The successful establishment and maintenance of human cytomegalovirus (HCMV) latency is dependent on the expression of a subset of viral genes. Whilst the exact spectrum and functions of these genes are far from clear, inroads have been made for protein-coding genes. In contrast, little is known about the expression of non-coding RNAs. Here we show that HCMV encoded miRNAs are expressed de novo during latent infection of primary myeloid cells. Furthermore, we demonstrate that miR-UL148D, one of the most highly expressed viral miRNAs during latent infection, directly targets the cellular receptor ACVR1B of the activin signalling axis. Consistent with this, we observed upregulation of ACVR1B expression during latent infection with a miR-UL148D deletion virus (ΔmiR-UL148D). Importantly, we observed that monocytes latently infected with ΔmiR-UL148D are more responsive to activin A stimulation, as demonstrated by their increased secretion of IL-6. Collectively, our data indicates miR-UL148D inhibits ACVR1B expression in latently infected cells to limit proinflammatory cytokine secretion, perhaps as an immune evasion strategy or to postpone cytokine-induced reactivation until conditions are more favourable. This is the first demonstration of an HCMV miRNA function during latency in primary myeloid cells, implicating that small RNA species may contribute significantly to latent infection.

  7. Effects of ulinastatin and docataxel on breast tumor growth and expression of IL-6, IL-8, and TNF-α

    Directory of Open Access Journals (Sweden)

    Luo Jie

    2011-02-01

    Full Text Available Abstract Objective This study investigated the effects of Ulinastatin (UTI and docataxel (Taxotere, TAX on tumor growth and expression of interleukin-6 (IL-6, interleukin-8 (IL-8, and tumor necrosis factor-α (TNF-α in breast cancer. Methods MDA-MB-231 human breast carcinoma cells were cultured in vitro and injected into nude mice to establish breast tumor xenografts in vivo. Cultured cells and mice with tumors were randomly divided into four groups for treatment with TAX, UTI, and TAX+UTI. The effects of these drug treatments on cell proliferation and apoptosis was measured using the MTT assay and the Annexin V/propidium iodide (PI double-staining method, respectively. IL-6, IL-8, and TNF-α expression levels were determined by measuring mRNA transcripts in cultured cells by RT-PCR and cytokine proteins in solid tumors using immunohistochemistry. Results UTI, TAX, and UTI+TAX inhibited the growth of MDA-MB-231 cells in vitro and tumors in vivo. These two drugs, particularly when used in combination, promote tumor cell apoptosis and down-regulate the expression IL-6, IL-8, and TNF-α cytokines. Conclusion Both UTI and TAX inhibited the growth of MDA-MB-231 breast carcinoma cells. UTI enhanced the inhibitory effect of TAX by a mechanism consistent with the down-regulated expression of IL-6, IL-8, and TNF-α.

  8. Direct crosstalk between cancer and osteoblast lineage cells fuels metastatic growth in bone via auto-amplification of IL-6 and RANKL signaling pathways.

    Science.gov (United States)

    Zheng, Yu; Chow, Shu-Oi; Boernert, Katja; Basel, Dennis; Mikuscheva, Anastasia; Kim, Sarah; Fong-Yee, Colette; Trivedi, Trupti; Buttgereit, Frank; Sutherland, Robert L; Dunstan, Colin R; Zhou, Hong; Seibel, Markus J

    2014-09-01

    The bone microenvironment and its modification by cancer and host cell interactions is a key driver of skeletal metastatic growth. Interleukin-6 (IL-6) stimulates receptor activator of NF-κB ligand (RANKL) expression in bone cells, and serum IL-6 levels are associated with poor clinical outcomes in cancer patients. We investigated the effects of RANKL on cancer cells and the role of tumor-derived IL-6 within the bone microenvironment. Using human breast cancer cell lines to induce tumors in the bone of immune-deficient mice, we first determined whether RANKL released by cells of the osteoblast lineage directly promotes IL-6 expression by cancer cells in vitro and in vivo. We then disrupted of IL-6 signaling in vivo either via knockdown of IL-6 in tumor cells or through treatment with specific anti-human or anti-mouse IL-6 receptor antibodies to investigate the tumor effect. Finally, we tested the effect of RANK knockdown in cancer cells on cancer growth. We demonstrate that osteoblast lineage-derived RANKL upregulates secretion of IL-6 by breast cancers in vivo and in vitro. IL-6, in turn, induces expression of RANK by cancer cells, which sensitizes the tumor to RANKL and significantly enhances cancer IL-6 release. Disruption in vivo of this auto-amplifying crosstalk by knockdown of IL-6 or RANK in cancer cells, or via treatment with anti-IL-6 receptor antibodies, significantly reduces tumor growth in bone but not in soft tissues. RANKL and IL-6 mediate direct paracrine-autocrine signaling between cells of the osteoblast lineage and cancer cells, significantly enhancing the growth of metastatic breast cancers within bone.

  9. Expression of NF-κB and IL-6 in oral precancerous and cancerous lesions: An immunohistochemical study

    Science.gov (United States)

    Nikitakis, Nikolaos; Sfakianou, Aikaterini; Avgoustidis, Dimitrios; Sklavounou-Andrikopoulou, Alexandra

    2016-01-01

    Background The purpose of this study was to evaluate the immunohistochemical expression of NF-κB and IL-6 in oral premalignant and malignant lesions and to investigate their possible correlation with the presence of subepithelial inflammation. Material and Methods Thirty two oral premalignant lesions, clinically compatible with leukoplakia or erythroplakia, were investigated. Microscopically, 11 of them showed hyperkeratosis and acanthosis (epithelial hyperplasia) and 21 showed dysplasia of varying degrees. Nine cases of OSCC and four control cases of normal oral mucosa were also included in the study. Immunohistochemical staining with NF-κB (p65) and IL-6 was performed. IL-6 and nuclear NF-κB staining were assessed as positive or negative. For cytoplasmic localization of NF-κB, a total score combining intensity and percentage of positive epithelial cells was additionally calculated. The presence of inflammation was also recorded. Results Intensity and total scores for NF-κΒ cytoplasmic immunostaining showed a statistically significant gradual increase from normal mucosa to OSCC (p=0.012 and p=0.026 respectively). Non-statistically significant increased NF-κΒ nuclear localization was detected in dysplasias and OSCCs. Positive statistical correlation was detected between the presence of inflammation and IL-6 expression (p=0.015). No correlation between NF-κΒ and IL-6 was detected. Conclusions NF-κΒ is activated in the early stages of oral carcinogenesis. IL-6 may have an NF-κΒ-independent role, possibly through regulation of the inflammatory response. Key words:NF-κB, IL-6, immunohistochemistry, oral squamous cell carcinoma, oral precancerous lesion. PMID:26595830

  10. IL-6 trans-Signaling-Dependent Rapid Development of Cytotoxic CD8+ T Cell Function

    Directory of Open Access Journals (Sweden)

    Jan P. Böttcher

    2014-09-01

    Full Text Available Immune control of infections with viruses or intracellular bacteria relies on cytotoxic CD8+ T cells that use granzyme B (GzmB for elimination of infected cells. During inflammation, mature antigen-presenting dendritic cells instruct naive T cells within lymphoid organs to develop into effector T cells. Here, we report a mechanistically distinct and more rapid process of effector T cell development occurring within 18 hr. Such rapid acquisition of effector T cell function occurred through cross-presenting liver sinusoidal endothelial cells (LSECs in the absence of innate immune stimulation and known costimulatory signaling. Rather, interleukin-6 (IL-6 trans-signaling was required and sufficient for rapid induction of GzmB expression in CD8+ T cells. Such LSEC-stimulated GzmB-expressing CD8+ T cells further responded to inflammatory cytokines, eliciting increased and protracted effector functions. Our findings identify a role for IL-6 trans-signaling in rapid generation of effector function in CD8+ T cells that may be beneficial for vaccination strategies.

  11. Serum Levels of IL-6 Type Cytokines and Soluble IL-6 Receptors in Active B-Cell Chronic Lymphocytic Leukemia and in Cladribine Induced Remission

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    T. Robak

    1999-01-01

    Full Text Available We have investigated the serum concentrations of interleukin-6 (IL-6 and two IL-6 family cytokines-oncostatin M (OSM and leukemia inhibitory factor (LIF-in 63 patients with B-cell chronic lymphocytic leukemia (B-CLL and 17 healthy controls using the enzyme-linked immunosorbent assay (ELISA method. Simultaneously, we measured the serum levels of the soluble forms of two subunits of the IL-6 receptor complex-ligand binding glycoprotein 80 (sIL-6R and glycoprotein 130 (sgp130. The cytokines and receptors were evaluated in 25 untreated patients and 38 patients treated with cladribine (2-CdA, as well as in 17 healthy controls. We have correlated the serum levels of these proteins with Rai's clinical stage of the disease, the response to 2-CdA treatment and some hematological parameters. We have also evaluated the correlation of the IL-6 serum level with the concentration of OSM and IL-6 soluble receptors. IL-6 was measurable in 62/63 (98.4%, OSM in 20/25 (80% of untreated and 14/38 (37.8% of the treated patients. sIL-6R and sgp130 were detectable in all 63 patients and LIF in none of the CLL patients. IL-6 serum level in untreated patients was not significantly different as compared to its concentration in the control group (P>0.05. However, in the patients treated with 2-CdA the IL-6 level was significantly lower (P0.05. We have found significant positive correlation between the levels of sIL6R and the lymphocytes count in CLL patients (Ρ=0.423; P<0.001. In addition, sIL-6R and OSM serum concentrations correlated also with CLL Rai stage. In conclusion, the serum level of IL-6, OSM and sIL-6R, but not LIF and sgp130, are useful indicators of CLL activity.

  12. Regulatory Effect of E2, IL-6 and IL-8 on the Growth of Epithelial Ovarian Cancer Cells

    Institute of Scientific and Technical Information of China (English)

    Yue Wang; Jie Yang; Yan Gao; Yongrui Du; Leyuan Bao; Wenyan Niu; Zhi Yao

    2005-01-01

    To determine the regulatory effects of estrogen and cytokine IL-6 and IL-8 on the growth of epithelial ovarian cancer (OVCA), we first examined the status of estrogen receptors (ERα and ERβ), IL-6 receptor (IL-6Rα and gp130), and IL-8 receptor (IL-8RA and IL-8RB) on five epithelial OVCA cell lines by semiquantitative RT-PCR and Western blot analysis. Results showed that the expressions of these receptors were variable on the five cells.Those OVCA cells expressing the receptors were selected to study related molecular mechanism. MTT assay was performed to observe the effects of 17β-estradiol (E2), IL-6 and IL-8 on cell proliferation. We discovered that E2 markedly promoted the proliferation of CAOV-3 and OVCAR-3 cell in a time- and dose-dependent manner.Tamoxifen (Txf), an ER inhibitor, completely blocked the proliferation of the E2-induced cells, and IL-6- or/and IL-8-neutralizing antibody only showed partially blocking activity. IL-6 and IL-8 were able to significantly stimulate CAOV-3 and OVCAR-3 cell proliferation in a time- and dose-dependent manner, which had a potential synergistic effect on CAOV-3 cells but not on OVCAR-3 cells. The cell proliferation induced by these two cytokines was abolished completely by their specific neutralizing antibodies, partially by Txf, but not by unrelated goat IgG.Taken together, our results suggested that estrogen, IL-6 and IL-8 could modulate OVCA growth by forming a reciprocal cascade with amplifying effect. Cellular & Molecular Immunology.

  13. IL-6 Receptor Is a Possible Target against Growth of Metastasized Lung Tumor Cells in the Brain

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    Mami Noda

    2012-12-01

    Full Text Available In the animal model of brain metastasis using human lung squamous cell carcinoma-derived cells (HARA-B inoculated into the left ventricle of the heart of nude mice, metastasized tumor cells and brain resident cells interact with each other. Among them, tumor cells and astrocytes have been reported to stimulate each other, releasing soluble factors from both sides, subsequently promoting tumor growth significantly. Among the receptors for soluble factors released from astrocytes, only IL-6 receptor (IL-6R on tumor cells was up-regulated during the activation with astrocytes. Application of monoclonal antibody against human IL-6R (tocilizumab to the activated HARA-B cells, the growth of HARA-B cells stimulated by the conditioned medium of HARA-B/astrocytes was significantly inhibited. Injecting tocilizumab to animal models of brain metastasis starting at three weeks of inoculation of HARA-B cells, two times a week for three weeks, significantly inhibited the size of the metastasized tumor foci. The up-regulated expression of IL-6R on metastasized lung tumor cells was also observed in the tissue from postmortem patients. These results suggest that IL-6R on metastasized lung tumor cells would be a therapeutic target to inhibit the growth of the metastasized lung tumor cells in the brain.

  14. IL-6调节MPP+处理的SH-SY5Y细胞的ERK分泌%IL-6 modulates pERK secretion of SH-SY5Y cells treated by MPP+

    Institute of Scientific and Technical Information of China (English)

    李学忠; 陈强; 沈卉君; 庄原苏; 周小平

    2012-01-01

    Objective To observe the effects of IL-6 on the survival and the expression of extracellular regulated protein kinases ( pERK) of SH-SY5Y cells treated by l-methyl-4-phenylpyridinium(MPP+ ). Methods The SH-SY5Y cells treated by MPP+ were intervened with IL-6 and mophological changes and the expression and location of pERK were observed. Results After treated by MPP+ , the viability of SH-SY5Y cells decreased and the expression of pERK elevated, which peaked in 24 h and mainly located in the cytoplasm. After adminstration of IL-6, the expression of pERK was increased and peaked in 6 h and mainly located in the nucleus. IL-6 reduced the apoptosis of MPP+-treated SH-SY5Y cells and promoted the secretion of pERK, which was downregulated by EPK inhibitor U0126 in vitro. Conclusions IL-6 can regulate the exprsssion of pERK, decrease MPP+-induced cell injury and promote SH-SY5Y cell survival.%目的 观察IL-6对1-甲基-4-苯基吡啶(MPP+)处理的SH-SY5Y细胞的生长和pERK的影响.方法 对MPP+处理的SH-SY5Y细胞进行IL-6干预,观察细胞结构形态的改变以及pERK的含量变化和定位.结果 MPP+处理的SH-SY5Y细胞系细胞活力下降;细胞系pERK上升,高峰在24 h,主要定位于胞浆;IL-6干预的SH-SY5Y细胞系pERK上升,高峰在6h,多定位于胞核.IL-6可以降低MPP+处理的SH-SY5Y细胞系的凋亡,使pERK分泌高峰提前;加用ERK抑制剂U0126可以下调IL-6对Mpp+处理的SH-SY5Y细胞系的影响.结论 IL-6可以通过调节pERK,减少MPP+诱导的细胞损伤,促进SH-SY5Y细胞的存活.

  15. Foxp3⁺ Treg cells in the inflamed CNS are insensitive to IL-6-driven IL-17 production.

    Science.gov (United States)

    O'Connor, Richard A; Floess, Stefan; Huehn, Jochen; Jones, Simon A; Anderton, Stephen M

    2012-05-01

    Foxp3(+) T regulatory (Treg) cells can be induced to produce interleukin (IL)-17 by in vitro exposure to proinflammatory cytokines, drawing into question their functional stability at sites of inflammation. Unlike their splenic counterparts, Treg cells from the inflamed central nervous system (CNS-Treg cells) during EAE resisted conversion to IL-17 production when exposed to IL-6. We show that the highly activated phenotype of CNS-Treg cells includes elevated expression of the Th1-associated molecules CXCR3 and T-bet, but reduced expression of the IL-6 receptor α chain (CD126) and the signaling chain gp130. We found a lack of IL-6 receptor on all CNS CD4(+) T cells, which was reflected by an absence of both classical and trans-IL-6 signaling in CNS CD4(+) cells, compared with their splenic counterparts. We propose that extinguished responsiveness to IL-6 (via down-regulation of CD126 and gp130) stabilizes the regulatory phenotype of activated Treg cells at sites of autoimmune inflammation.

  16. Enhanced chemosensitization in multidrug-resistant human breast cancer cells by inhibition of IL-6 and IL-8 production.

    Science.gov (United States)

    Shi, Zhi; Yang, Wei-Min; Chen, Li-Pai; Yang, Dong-Hua; Zhou, Qi; Zhu, Jin; Chen, Jun-Jiang; Huang, Ruo-Chun; Chen, Zhe-Sheng; Huang, Ruo-Pan

    2012-10-01

    Drug resistance remains a major hurdle to successful cancer treatment. Many mechanisms such as overexpression of multidrug-resistance related proteins, increased drug metabolism, decreased apoptosis, and impairment of signal transduction pathway can contribute multidrug resistance (MDR). Recent studies strongly suggest a close link between cytokines and drug resistance. To identify new targets involved in drug resistance, we established a multidrug-resistant human breast cancer cell line MCF-7/R and examined the cytokine profile using cytokine antibody array technology. Among 120 cytokines/chemokines screened, IL-6, IL-8, and 13 other proteins were found to be markedly increased in drug-resistant MCF-7/R cell line as compared to sensitive MCF-7/S cell line, while 7 proteins were specifically reduced in drug-resistant MCF-7/R cells. Neutralizing antibodies against IL-6 and IL-8 partially reversed the drug resistance of MCF-7/R to paclitaxel and doxorubicin, while a neutralizing antibody against MCP-1 had no significant effect. Inhibition of endogenous IL-6 or IL-8 by siRNA technology significantly enhanced drug sensitivity of MCF-7/R cells. Furthermore, overexpression of IL-6 or IL-8 expression by transfection increased the ADM resistance in MCF-7/S cells. Our data suggest that increased expression levels of IL-6 and IL-8 may contribute to MDR in human breast cancer cells.

  17. Thyrotropin regulates IL-6 expression in CD34+ fibrocytes: clear delineation of its cAMP-independent actions.

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    Nupur Raychaudhuri

    Full Text Available IL-6 plays diverse roles in normal and disease-associated immunity such as that associated with Graves' disease (GD. In that syndrome, the orbit undergoes remodeling during a process known as thyroid-associated ophthalmopathy (TAO. Recently, CD34(+ fibrocytes were found to infiltrate the orbit in TAO where they transition into CD34(+ orbital fibroblasts. Surprisingly, fibrocytes display high levels of functional thyrotropin receptor (TSHR, the central antigen in GD. We report here that TSH and the pathogenic anti-TSHR antibodies that drive hyperthyroidism in GD induce IL-6 expression in fibrocytes and orbital fibroblasts. Unlike TSHR signaling in thyroid epithelium, that occurring in fibrocytes is completely independent of adenylate cyclase activation and cAMP generation. Instead TSH activates PDK1 and both AKT/PKB and PKC pathways. Expression and use of PKCβII switches to that of PKCµ as fibrocytes transition to TAO orbital fibroblasts. This shift is imposed by CD34(- orbital fibroblasts but reverts when CD34(+ fibroblasts are isolated. The up-regulation of IL-6 by TSH results from coordinately enhanced IL-6 gene promoter activity and increased IL-6 mRNA stability. TSH-dependent IL-6 expression requires activity at both CREB (-213 to -208 nt and NF-κB (-78 to -62 nt binding sites. These results provide novel insights into the molecular action of TSH and signaling downstream for TSHR in non-thyroid cells. Fibrocytes neither express adenylate cyclase nor generate cAMP and thus these findings are free from any influence of cAMP-related signaling. They identify potential therapeutic targets for TAO.

  18. A microRNA network dysregulated in asthma controls IL-6 production in bronchial epithelial cells.

    Science.gov (United States)

    Martinez-Nunez, Rocio T; Bondanese, Victor P; Louafi, Fethi; Francisco-Garcia, Ana S; Rupani, Hitasha; Bedke, Nicole; Holgate, Stephen; Howarth, Peter H; Davies, Donna E; Sanchez-Elsner, Tilman

    2014-01-01

    MicroRNAs are short non-coding single stranded RNAs that regulate gene expression. While much is known about the effects of individual microRNAs, there is now growing evidence that they can work in co-operative networks. MicroRNAs are known to be dysregulated in many diseases and affect pathways involved in the pathology. We investigated dysregulation of microRNA networks using asthma as the disease model. Asthma is a chronic inflammatory disease of the airways characterized by bronchial hyperresponsiveness and airway remodelling. The airway epithelium is a major contributor to asthma pathology and has been shown to produce an excess of inflammatory and pro-remodelling cytokines such as TGF-β, IL-6 and IL-8 as well as deficient amounts of anti-viral interferons. After performing microRNA arrays, we found that microRNAs -18a, -27a, -128 and -155 are down-regulated in asthmatic bronchial epithelial cells, compared to cells from healthy donors. Interestingly, these microRNAs are predicted in silico to target several components of the TGF-β, IL-6, IL-8 and interferons pathways. Manipulation of the levels of individual microRNAs in bronchial epithelial cells did not have an effect on any of these pathways. Importantly, knock-down of the network of microRNAs miR-18a, -27a, -128 and -155 led to a significant increase of IL-8 and IL-6 expression. Interestingly, despite strong in silico predictions, down-regulation of the pool of microRNAs did not have an effect on the TGF-β and Interferon pathways. In conclusion, using both bioinformatics and experimental tools we found a highly relevant potential role for microRNA dysregulation in the control of IL-6 and IL-8 expression in asthma. Our results suggest that microRNAs may have different roles depending on the presence of other microRNAs. Thus, interpretation of in silico analysis of microRNA function should be confirmed experimentally in the relevant cellular context taking into account interactions with other micro

  19. A microRNA network dysregulated in asthma controls IL-6 production in bronchial epithelial cells.

    Directory of Open Access Journals (Sweden)

    Rocio T Martinez-Nunez

    Full Text Available MicroRNAs are short non-coding single stranded RNAs that regulate gene expression. While much is known about the effects of individual microRNAs, there is now growing evidence that they can work in co-operative networks. MicroRNAs are known to be dysregulated in many diseases and affect pathways involved in the pathology. We investigated dysregulation of microRNA networks using asthma as the disease model. Asthma is a chronic inflammatory disease of the airways characterized by bronchial hyperresponsiveness and airway remodelling. The airway epithelium is a major contributor to asthma pathology and has been shown to produce an excess of inflammatory and pro-remodelling cytokines such as TGF-β, IL-6 and IL-8 as well as deficient amounts of anti-viral interferons. After performing microRNA arrays, we found that microRNAs -18a, -27a, -128 and -155 are down-regulated in asthmatic bronchial epithelial cells, compared to cells from healthy donors. Interestingly, these microRNAs are predicted in silico to target several components of the TGF-β, IL-6, IL-8 and interferons pathways. Manipulation of the levels of individual microRNAs in bronchial epithelial cells did not have an effect on any of these pathways. Importantly, knock-down of the network of microRNAs miR-18a, -27a, -128 and -155 led to a significant increase of IL-8 and IL-6 expression. Interestingly, despite strong in silico predictions, down-regulation of the pool of microRNAs did not have an effect on the TGF-β and Interferon pathways. In conclusion, using both bioinformatics and experimental tools we found a highly relevant potential role for microRNA dysregulation in the control of IL-6 and IL-8 expression in asthma. Our results suggest that microRNAs may have different roles depending on the presence of other microRNAs. Thus, interpretation of in silico analysis of microRNA function should be confirmed experimentally in the relevant cellular context taking into account interactions

  20. The phosphatase of regenerating liver-3 (PRL-3) is important for IL-6-mediated survival of myeloma cells.

    Science.gov (United States)

    Slørdahl, Tobias S; Abdollahi, Pegah; Vandsemb, Esten N; Rampa, Christoph; Misund, Kristine; Baranowska, Katarzyna A; Westhrin, Marita; Waage, Anders; Rø, Torstein B; Børset, Magne

    2016-05-10

    Multiple myeloma (MM) is a neoplastic proliferation of bone marrow plasma cells. PRL-3 is a phosphatase induced by interleukin (IL)-6 and other growth factors in MM cells and promotes MM-cell migration. PRL-3 has also been identified as a marker gene for a subgroup of patients with MM. In this study we found that forced expression of PRL-3 in the MM cell line INA-6 led to increased survival of cells that were depleted of IL-6. It also caused redistribution of cells in cell cycle, with an increased number of cells in G2M-phase. Furthermore, forced PRL-3 expression significantly increased phosphorylation of Signal transducer and activator of transcription (STAT) 3 both in the presence and the absence of IL-6. Knockdown of PRL-3 with shRNA reduced survival in MM cell line INA-6. A pharmacological inhibitor of PRL-3 reduced survival in the MM cell lines INA-6, ANBL-6, IH-1, OH-2 and RPMI8226. The inhibitor also reduced survival in 9 of 9 consecutive samples of purified primary myeloma cells. Treatment with the inhibitor down-regulated the anti-apoptotic protein Mcl-1 and led to activation of the intrinsic apoptotic pathway. Inhibition of PRL-3 also reduced IL-6-induced phosphorylation of STAT3. In conclusion, our study shows that PRL-3 is an important mediator of growth factor signaling in MM cells and hence possibly a good target for treatment of MM.

  1. Cloning,expression and purification of the ligand-binding region of human IL-6R in E.coli and its preliminary functional identification

    Institute of Scientific and Technical Information of China (English)

    段聚宝; 王嘉玺; 韩家淮; 彭善云; 邹民吉; 苗继红; 赵春文; 马贤凯

    1995-01-01

    The ligand-binding region of human IL-6R is taken as the target gene fragment to be clonedand expressed.With pET-3b as expressing vector,two recombinants pET-6R(B)and pET-6R(B)4 have beenconstructed encoding the ligand-binding region(28 kD)of hIL-6R and its dimmer(53 kD),respectively.Afterinduction with IPTG,they produced two proteins rIL6R-28 of 28 kD and rIL6R-53 of 53 kD amounting to 50%and 30% of total bacteria proteins,respectively.The expressed products were mainly recovered as inclusionbodies.After purification and renaturation,both of them were capable of augmenting the growth-stimulatingeffect of IL-6 on 7TD1 cells,an IL-6 dependent cell line.The result of ELISA also revealed that bothrIL6R-28 and rIL6R-53 had the obvious ligand-binding activity.

  2. IL-6 Signaling in Myelomonocytic Cells Is Not Crucial for the Development of IMQ-Induced Psoriasis.

    Science.gov (United States)

    Klebow, Sabrina; Hahn, Matthias; Nikoalev, Alexei; Wunderlich, F Thomas; Hövelmeyer, Nadine; Karbach, Susanne H; Waisman, Ari

    2016-01-01

    Psoriasis is an autoimmune skin disease that is associated with aberrant activity of immune cells and keratinocytes. In mice, topical application of TLR7/8 agonist IMQ leads to a skin disorder resembling human psoriasis. Recently, it was shown that the IL-23/ IL-17 axis plays a deciding role in the pathogenesis of human psoriasis, as well as in the mouse model of IMQ-induced psoriasis-like skin disease. A consequence of IL-17A production in the skin includes increased expression and production of IL-6, resulting in the recruitment of neutrophils and other myelomonocytic cells to the site of inflammation. To further investigate and characterize the exact role of IL-6 signaling in myelomonocytic cells during experimental psoriasis, we generated mice lacking the IL-6 receptor alpha specifically in myelomonocytic cells (IL-6RαΔmyel). Surprisingly, disease susceptibility of these mice was not affected in this model. Our study shows that classical IL-6 signaling in myelomonocytic cells does not play an essential role for disease development of IMQ-induced psoriasis-like skin disease.

  3. Expression and cytotoxicity of a human interleukin-6 tumor necrosis factor derivative fusion protein (5'IL6-TNF△) in vitro

    Institute of Scientific and Technical Information of China (English)

    1999-01-01

    Objective :To develop an agent that is more active against receptor-bearing target cells without increasing the toxic effect on non-target cells. Methods :By the use of molecular biology techniques,we designed and constructed a fusion protein 5'IL6-TNF△ by connecting the human interleukin-6 (hIL-6) gene and a human tumor necrosis factor α derivative (TNF△) gene througha synthetic linker sequence followed by subsequent expression in E. Coli. Results: In cytotoxicity assay with myeloma cell line U266, the normal type of 5' IL6-TNF△ showed an antitumor activity 3 times higher than that of TNF△;and the antitumor activity of 5'IL6-TNF△ blocked by IL-6Rwas only 1/30 of that of normal type of 5' IL6-TNF△. Meanwhile,the 5'IL6-TNF△ blocked by an ti-TNF antibody did not show any cytotoxicity to U266 cells. In activity assay with L929 cells ,the toxic effect of the fusion protein was found 1/22 of that of TNF△. Conclusion: The 5'IL6-TNF△fusion protein might be a useful cytotoxic agent in cancer treatment.

  4. Do baseline Cereblon gene expression and IL-6 receptor expression determine the response to thalidomide-dexamethasone treatment in multiple myeloma patients?

    Science.gov (United States)

    Bedewy, Ahmed M L; El-Maghraby, Shereen M

    2014-01-01

    Immunomodulatory drugs (IMiDs) are key components of treatment for hematologic malignancies, especially multiple myeloma (MM). Cereblon (CRBN) expression was described to be essential for the activity of thalidomide. Furthermore, IMiD binding to CRBN is cytotoxic to multiple myeloma cells and absence of CRBN confers IMiDs resistance. Interleukin-6 (IL-6) is a potent pleiotropic cytokine that regulates plasma cell (PC) growth via the IL-6 receptor (IL-6R). IL-6/IL-6R autocrine activity is implicated in the development and progression of cancers including cervical cancer, prostate cancer, and multiple myeloma. The aim of the study was to evaluate CRBN and IL-6R expressions and their impact on clinical efficacy of dexamethasone-thalidomide therapy in multiple myeloma (MM) patients, in addition to their association with other clinical and prognostic parameters. Forty-six newly diagnosed MM patients were enrolled in the study. We measured CRBN expression prior to therapy initiation by real-time polymerase chain reaction in 46 bone marrow (BM) aspiration samples of patients and controls. In addition, IL-6R expression was evaluated on BM biopsies of patients and controls by immunohistochemistry (IHC). Twenty-eight males (60.9%) and 18 females (39.1%) were enrolled. The mean age was 65.11 ± 7.3 yr (range 39-77 yr). Median CRBN expression in 46 BM samples of MM patients was significantly higher than in controls (P CRBN expression. IL-6R expression was significantly higher in patients than in controls. IL-6R expression was significantly associated with response to treatment (P CRBN expression (P = 0.001).In conclusion, CRBN expression may provide a biomarker to predict response to IMiD in patients with MM and its high expression can serve as a marker of good prognosis. Strong IL-6R expression is associated with poor response to therapy in multiple myeloma patients and may be used as a prognostic marker.

  5. Radon Exposure, IL-6 Promoter Variants, and Lung Squamous Cell Carcinoma in Former Uranium Miners

    OpenAIRE

    2015-01-01

    Background: High radon exposure is a risk factor for squamous cell carcinoma, a major lung cancer histology observed in former uranium miners. Radon exposure can cause oxidative stress, leading to pulmonary inflammation. Interleukin-6 (IL-6) is a pro-carcinogenic inflammatory cytokine that plays a pivotal role in lung cancer development. Objectives: We assessed whether single nucleotide polymorphisms (SNPs) in the IL6 promoter are associated with lung cancer in former uranium miners with high...

  6. NK-CD11c+ Cell Crosstalk in Diabetes Enhances IL-6-Mediated Inflammation during Mycobacterium tuberculosis Infection

    Science.gov (United States)

    Cheekatla, Satyanarayana Swamy; Tripathi, Deepak; Venkatasubramanian, Sambasivan; Nathella, Pavan Kumar; Paidipally, Padmaja; Ishibashi, Munenori; Welch, Elwyn; Tvinnereim, Amy R.; Ikebe, Mitsuo; Valluri, Vijaya Lakshmi; Babu, Subash; Kornfeld, Hardy; Vankayalapati, Ramakrishna

    2016-01-01

    In this study, we developed a mouse model of type 2 diabetes mellitus (T2DM) using streptozotocin and nicotinamide and identified factors that increase susceptibility of T2DM mice to infection by Mycobacterium tuberculosis (Mtb). All Mtb-infected T2DM mice and 40% of uninfected T2DM mice died within 10 months, whereas all control mice survived. In Mtb-infected mice, T2DM increased the bacterial burden and pro- and anti-inflammatory cytokine and chemokine production in the lungs relative to those in uninfected T2DM mice and infected control mice. Levels of IL-6 also increased. Anti-IL-6 monoclonal antibody treatment of Mtb-infected acute- and chronic-T2DM mice increased survival (to 100%) and reduced pro- and anti-inflammatory cytokine expression. CD11c+ cells were the major source of IL-6 in Mtb-infected T2DM mice. Pulmonary natural killer (NK) cells in Mtb-infected T2DM mice further increased IL-6 production by autologous CD11c+ cells through their activating receptors. Anti-NK1.1 antibody treatment of Mtb-infected acute-T2DM mice increased survival and reduced pro- and anti-inflammatory cytokine expression. Furthermore, IL-6 increased inflammatory cytokine production by T lymphocytes in pulmonary tuberculosis patients with T2DM. Overall, the results suggest that NK-CD11c+ cell interactions increase IL-6 production, which in turn drives the pathological immune response and mortality associated with Mtb infection in diabetic mice. PMID:27783671

  7. Encephalitozoon intestinalis Inhibits Dendritic Cell Differentiation through an IL-6-Dependent Mechanism

    Science.gov (United States)

    Bernal, Carmen E.; Zorro, Maria M.; Sierra, Jelver; Gilchrist, Katherine; Botero, Jorge H.; Baena, Andres; Ramirez-Pineda, Jose R.

    2016-01-01

    Microsporidia are a group of intracellular pathogens causing self-limited and severe diseases in immunocompetent and immunocompromised individuals, respectively. A cellular type 1 adaptive response, mediated by IL-12, IFNγ, CD4+, and CD8+ T cells has been shown to be essential for host resistance, and dendritic cells (DC) play a key role at eliciting anti-microsporidial immunity. We investigated the in vitro response of DC and DC precursors/progenitors to infection with Encephalitozoon intestinalis (Ei), a common agent of human microsporidosis. Ei-exposed DC cultures up-regulated the surface expression of MHC class II and the costimulatory molecules CD86 and CD40, only when high loads of spores were used. A vigorous secretion of IL-6 but not of IL-1β or IL-12p70 was also observed in these cultures. Ei-exposed DC cultures consisted of immature infected and mature bystander DC, as assessed by MHC class II and costimulatory molecules expression, suggesting that intracellular Ei spores deliver inhibitory signals in DC. Moreover, Ei selectively inhibited the secretion of IL-12p70 in LPS-stimulated DC. Whereas Ei-exposed DC promoted allogeneic naïve T cell proliferation and IL-2 and IFNγ secretion in DC-CD4+ T cell co-cultures, separated co-cultures with bystander or infected DCs showed stimulation or inhibition of IFNγ secretion, respectively. When DC precursors/progenitors were exposed to Ei spores, a significant inhibition of DC differentiation was observed without shifting the development toward cells phenotypically or functionally compatible with myeloid-derived suppressor cells. Neutralization experiments demonstrated that this inhibitory effect is IL-6-dependent. Altogether this investigation reveals a novel potential mechanism of immune escape of microsporidian parasites through the modulation of DC differentiation and maturation. PMID:26870700

  8. Encephalitozoon intestinalis Inhibits Dendritic Cell Differentiation through an IL-6-Dependent Mechanism.

    Science.gov (United States)

    Bernal, Carmen E; Zorro, Maria M; Sierra, Jelver; Gilchrist, Katherine; Botero, Jorge H; Baena, Andres; Ramirez-Pineda, Jose R

    2016-01-01

    Microsporidia are a group of intracellular pathogens causing self-limited and severe diseases in immunocompetent and immunocompromised individuals, respectively. A cellular type 1 adaptive response, mediated by IL-12, IFNγ, CD4+, and CD8+ T cells has been shown to be essential for host resistance, and dendritic cells (DC) play a key role at eliciting anti-microsporidial immunity. We investigated the in vitro response of DC and DC precursors/progenitors to infection with Encephalitozoon intestinalis (Ei), a common agent of human microsporidosis. Ei-exposed DC cultures up-regulated the surface expression of MHC class II and the costimulatory molecules CD86 and CD40, only when high loads of spores were used. A vigorous secretion of IL-6 but not of IL-1β or IL-12p70 was also observed in these cultures. Ei-exposed DC cultures consisted of immature infected and mature bystander DC, as assessed by MHC class II and costimulatory molecules expression, suggesting that intracellular Ei spores deliver inhibitory signals in DC. Moreover, Ei selectively inhibited the secretion of IL-12p70 in LPS-stimulated DC. Whereas Ei-exposed DC promoted allogeneic naïve T cell proliferation and IL-2 and IFNγ secretion in DC-CD4+ T cell co-cultures, separated co-cultures with bystander or infected DCs showed stimulation or inhibition of IFNγ secretion, respectively. When DC precursors/progenitors were exposed to Ei spores, a significant inhibition of DC differentiation was observed without shifting the development toward cells phenotypically or functionally compatible with myeloid-derived suppressor cells. Neutralization experiments demonstrated that this inhibitory effect is IL-6-dependent. Altogether this investigation reveals a novel potential mechanism of immune escape of microsporidian parasites through the modulation of DC differentiation and maturation.

  9. The effect of IL-6 on the trophoblast cell line HTR-8/SVneo

    Directory of Open Access Journals (Sweden)

    Jovanović Milica

    2010-01-01

    Full Text Available Embryonic development up to the blastocyst stage, implantation into the uterine wall and the development of the functional placenta are steps crucial for the establishment of normal pregnancy. Specific cells of the placenta, the trophoblast cells, invade the uterine stroma and spiral arteries, adapting them to pregnancy. Interleukin-6 is present in the human endometrium during the receptive phase and early pregnancy. Trophoblasts also produce IL-6, which was found to stimulate trophoblast invasion and migration in vitro. Here we show that the activity of MMP-9 may contribute to the observed increased invasion. In addition, in the HTR-8/SVneo trophoblast cell line IL-6 increases cell proliferation. .

  10. Satellite cells derived from obese humans with type 2 diabetes and differentiated into myocytes in vitro exhibit abnormal response to IL-6.

    Directory of Open Access Journals (Sweden)

    Camilla Scheele

    Full Text Available Obesity and type 2 diabetes are associated with chronically elevated systemic levels of IL-6, a pro-inflammatory cytokine with a role in skeletal muscle metabolism that signals through the IL-6 receptor (IL-6Rα. We hypothesized that skeletal muscle in obesity-associated type 2 diabetes develops a resistance to IL-6. By utilizing western blot analysis, we demonstrate that IL-6Rα protein was down regulated in skeletal muscle biopsies from obese persons with and without type 2 diabetes. To further investigate the status of IL-6 signaling in skeletal muscle in obesity-associated type 2 diabetes, we isolated satellite cells from skeletal muscle of people that were healthy (He, obese (Ob or were obese and had type 2 diabetes (DM, and differentiated them in vitro into myocytes. Down-regulation of IL-6Rα was conserved in Ob myocytes. In addition, acute IL-6 administration for 30, 60 and 120 minutes, resulted in a down-regulation of IL-6Rα protein in Ob myocytes compared to both He myocytes (P<0.05 and DM myocytes (P<0.05. Interestingly, there was a strong time-dependent regulation of IL-6Rα protein in response to IL-6 (P<0.001 in He myocytes, not present in the other groups. Assessing downstream signaling, DM, but not Ob myocytes demonstrated a trend towards an increased protein phosphorylation of STAT3 in DM myocytes (P = 0.067 accompanied by a reduced SOCS3 protein induction (P<0.05, in response to IL-6 administration. Despite this loss of negative control, IL-6 failed to increase AMPKα2 activity and IL-6 mRNA expression in DM myocytes. There was no difference in fusion capacity of myocytes between cell groups. Our data suggest that negative control of IL-6 signaling is increased in myocytes in obesity, whereas a dysfunctional IL-6 signaling is established further downstream of IL-6Rα in DM myocytes, possibly representing a novel mechanism by which skeletal muscle function is compromised in type 2 diabetes.

  11. IL-27 Activates Human Trophoblasts to Express IP-10 and IL-6: Implications in the Immunopathophysiology of Preeclampsia

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    Nanlin Yin

    2014-01-01

    Full Text Available Purpose. To investigate the effects of IL-27 on human trophoblasts and the underlying regulatory signaling mechanisms in preeclampsia. Methods. The expression of IL-27 and IL-27 receptor (WSX-1 was studied in the placenta or sera from patients with preeclampsia. In vitro, we investigated the effects of IL-27 alone or in combination with inflammatory cytokine tumor necrosis factor (TNF-α on the proinflammatory activation of human trophoblast cells (HTR-8/SVneo and the underlying intracellular signaling molecules. Results. The expression of IL-27 and IL-27 receptor α (WSX-1 was significantly elevated in the trophoblastic cells from the placenta of patients with preeclampsia compared with control specimens. In vitro, IL-27 could induce the expression of inflammatory factors IFN-γ-inducible protein 10 (CXCL10/IP-10 and IL-6 in trophoblasts, and a synergistic effect was observed in the combined treatment of IL-27 and TNF-α on the release of IP-10 and IL-6. Furthermore, the production of IP-10 and IL-6 stimulated by IL-27 was differentially regulated by intracellular activation of phosphatidylinositol 3-OH kinase-AKT, p38MAPK, and JAK/STAT pathways. Conclusions. These results provide a new insight into the IL-27-activated immunopathological effects mediated by distinct intracellular signal transduction molecules in preeclampsia.

  12. Deleted in malignant brain tumors 1 (DMBT1) elicits increased VEGF and decreased IL-6 production in type II lung epithelial cells

    DEFF Research Database (Denmark)

    Müller, Hanna; Nagel, Christian; Weiss, Christel

    2015-01-01

    between VEGF and IL-6 levels to DMBT1 expression in the lungs of preterm and term infants and in lung epithelial cells in vitro. METHODS: We examined by ELISA VEGF levels in 120 tracheal aspirates of 57 preterm and term infants and tested for correlation with different perinatal factors as well...... as with DMBT1 levels. To examine the effect of DMBT1 on VEGF and IL-6 expression we compared type II lung epithelial A549 cells stably transfected with a DMBT1 expression plasmid (DMBT1+ cells) to A549 cells stably transfected with an empty expression plasmid (DMBT1- cells). The concentrations of VEGF and IL-6...... that DMBT1 promotes VEGF and suppresses IL-6 production in alveolar tissues, which could point to DMBT1 having a possible role in the transition from inflammation to regeneration and being a potentially useful clinical marker....

  13. Acrolein stimulates the synthesis of IL-6 and C-reactive protein (CRP) in thrombosis model mice and cultured cells.

    Science.gov (United States)

    Saiki, Ryotaro; Hayashi, Daisuke; Ikuo, Yukiko; Nishimura, Kazuhiro; Ishii, Itsuko; Kobayashi, Kaoru; Chiba, Kan; Toida, Toshihiko; Kashiwagi, Keiko; Igarashi, Kazuei

    2013-12-01

    Measurements of protein-conjugated acrolein (PC-Acro), IL-6, and C-reactive protein (CRP) in plasma were useful for identifying silent brain infarction with high sensitivity and specificity. The aim of this study was to determine whether acrolein causes increased production of IL-6 and CRP in thrombosis model mice and cultured cells. In mice with photochemically induced thrombosis, acrolein produced at the locus of infarction increased the level of IL-6 and then CRP in plasma. This was confirmed in cell culture systems - acrolein stimulated the production of IL-6 in mouse neuroblastoma Neuro-2a cells, mouse macrophage-like J774.1 cells, and human umbilical vein endothelial cells (HUVEC), and IL-6 in turn stimulated the production of CRP in human hepatocarcinoma cells. The level of IL-6 mRNA was increased by acrolein through an increase in phosphorylation of the transcription factors, c-Jun, and NF-κB p65. Furthermore, CRP stimulated IL-6 production in mouse macrophage-like J774.1 cells and HUVEC. IL-6 functioned as a protective factor against acrolein toxicity in Neuro-2a cells and HUVEC. These results show that acrolein stimulates the synthesis of IL-6 and CRP, which function as protecting factors against acrolein toxicity, and that the combined measurement of PC-Acro, IL-6, and CRP is effective for identification of silent brain infarction. The combined measurements of protein-conjugated acrolein (PC-Acro), IL-6, and C-reactive protein (CRP) in plasma were useful for identifying silent brain infarction. The aim of this study was to determine whether acrolein causes increased production of IL-6 and CRP, and indeed acrolein increased IL-6 synthesis and IL-6 in turn increased CRP synthesis. Furthermore, IL-6 decreased acrolein toxicity in several cell lines.

  14. Role of IL-6 in exercise training- and cold-induced UCP1 expression in subcutaneous white adipose tissue.

    Directory of Open Access Journals (Sweden)

    Jakob G Knudsen

    Full Text Available Expression of brown adipose tissue (BAT associated proteins like uncoupling protein 1 (UCP1 in inguinal WAT (iWAT has been suggested to alter iWAT metabolism. The aim of this study was to investigate the role of interleukin-6 (IL-6 in exercise training and cold exposure-induced iWAT UCP1 expression. The effect of daily intraperitoneal injections of IL-6 (3 ng/g in C57BL/6 mice for 7 days on iWAT UCP1 expression was examined. In addition, the expression of UCP1 in iWAT was determined in response to 3 days of cold exposure (4°C and 5 weeks of exercise training in wild type (WT and whole body IL-6 knockout (KO mice. Repeated injections of IL-6 in C57BL/6 mice increased UCP1 mRNA but not UCP1 protein content in iWAT. Cold exposure increased iWAT UCP1 mRNA content similarly in IL-6 KO and WT mice, while exercise training increased iWAT UCP1 mRNA in WT mice but not in IL-6 KO mice. Additionally, a cold exposure-induced increase in iWAT UCP1 protein content was blunted in IL-6 KO mice, while UCP1 protein content in iWAT was lower in both untrained and exercise trained IL-6 KO mice than in WT mice. In conclusion, repeated daily increases in plasma IL-6 can increase iWAT UCP1 mRNA content and IL-6 is required for an exercise training-induced increase in iWAT UCP1 mRNA content. In addition IL-6 is required for a full induction of UCP1 protein expression in response to cold exposure and influences the UCP1 protein content iWAT of both untrained and exercise trained animals.

  15. Effects of RNA interference-induced tryptase down-regulation in P815 cells on IL-6 and TNF-α release of endothelial cells

    Institute of Scientific and Technical Information of China (English)

    Yi-feng JIANG; Feng-di ZHAO; Xiao-bo LI; Yan-xia NING; Xiu-ling ZHI; Rui-zhe QIAN; Lian-hua YIN

    2008-01-01

    Objective:To explore the effects of down-regulated tryptase expression in mast cells on the synthesis and release of interleukin-6(IL-6)and tumor necrosis factor-alpha(TNF-α) of vascular endothelial cells.Methods:Tryptase-siRNA (small-interfering RNA)vector was constructed to inhibit tryptase expression in P815 cells.The medium of P815 cells treated by the tryptase-siRNA(RNAi-P815 group)or pure vector(P815 group)was collected and used to culture bEnd.3 cells.The messenger RNAs (mRNAs)of IL-6 and TNF-a in bEnd.3 cells and their protein levels in the medium were measured by reverse transcription polymerase chain reaction(RT-PCR)and enzyme-linked immunosorbent assay(ELISA),respectively.Results:IL-6 and TNF-α mRNAs in bEnd.3 cells cultured in RNAi-P815-conditioned medium decreased significantly compared to those in P815-conditioned medium.Consistently.IL-6 and TNF-α protein levels in the medium of bEnd.3 of RNAi-P815 group were lower than those of P815 group.Conclusion:Reduced tryptase expression significantly inhibited the synthesis and release of IL-6 and TNF-α in vascular endothelial cells.RNA interference targeting tryptasc expression may be a new anti-inflammatory strategy for vascular diseases.

  16. Treg/Th17 Cell Imbalance and IL-6 Profile in Patients With Unexplained Recurrent Spontaneous Abortion.

    Science.gov (United States)

    Zhu, Liqiong; Chen, Hui; Liu, Meilan; Yuan, Yu; Wang, Zhaohua; Chen, Ying; Wei, Jing; Su, Fang; Zhang, Jianping

    2016-10-02

    Regulatory T cells (Treg) and T helper 17 cells (Th17) are 2 distinct subsets of CD4(+) T cells, which are mutually antagonistic in the immune response. Recently, dysregulation of these 2 cell subsets have been described in the pathogenesis of unexplained recurrent spontaneous abortion (URSA). The purpose of this study was to investigate whether the Treg/Th17 balance was perturbed in URSA patients and to explore contributing factors. We found that the proportion of Treg cells and expression of forkhead box P3 (Foxp3) messenger RNA (mRNA) were significantly lower in URSA patients than in healthy controls. However, the proportion of Th17 cells and expression of retinoid-related orphan nuclear receptor-γt (ROR-γt) mRNA were higher in URSA patients than in controls, revealing inverse correlation with Treg. The ratio of Treg/Th17 and Foxp3/ROR-γt decreased in patients with URSA compared to healthy controls. The serum levels of interleukin (IL)-6 and IL-17A were significantly higher, whereas IL-10 was lower in URSA patients compared with controls, and the level of IL-6 showed a positive correlation with Th17, ROR-γt and inverse correlation with Treg, Foxp3. The present study indicated that an imbalance between Treg and Th17 cells might be implicated in the pathogenesis of URSA and this seems to relate to elevation in serum IL-6 level.

  17. Interleukin-6 receptor expression in contracting human skeletal muscle: regulating role of IL-6

    DEFF Research Database (Denmark)

    Keller, Pernille; Penkowa, Milena; Keller, Charlotte

    2005-01-01

    and rest (n=6+5), or recombinant human IL-6 infusion (rhIL-6) or saline infusion (n=6+6). We further obtained skeletal muscle samples from IL-6 knockout (KO) mice and wild-type C57/BL-6 mice in response to a 1-h bout of exercise. In exercising human skeletal muscle, IL-6 receptor mRNA increased sixfold...

  18. Effects of MAPK pathways on ET-induced IL-6 expression in periodontal ligament cells%MAPK信号通路抑制剂对内皮素-1诱导牙周膜细胞分泌白介素-6的影响

    Institute of Scientific and Technical Information of China (English)

    梁莉; 刘洪臣; 王东胜; 鄂玲玲

    2012-01-01

    目的:研究丝裂原激活蛋白激酶(Mitogen-activated protein kinases,MAPKs)信号途径对内皮素-1(endothelin-1,ET-1)诱导牙周膜细胞分泌白介素-6(interleukin-6,IL-6)的调控作用,为探讨ET-1在牙周炎发病机制中的作用奠定基础.方法:体外培养牙周膜细胞,于加ET-1处理前30min分别向培养基中加入ERK通路抑制剂PD98059(10μM),JNK通路抑制剂SP600125(10μM),p38α通路抑制剂SB203580(10μM).再加入100nM ET-1,以未作任何处理的牙周膜细胞为空白对照.刺激12h后提取细胞培养上清液和细胞裂解物,采用实时定量PCR及ELISA检测各组牙周膜细胞IL-6基因及蛋白表达的改变.结果:与对照组相比,ET-1对牙周膜细胞IL-6 mRNA(1.3615±0.0137)及蛋白(352.1252±6.7851 ng/ml)分泌具有显著促进作用,PD98059和SB203580可抑制ET-1对牙周膜细胞IL-6 mRNA及蛋白表达的促进效应,但SP600125的抑制作用不明显.结论:ET-1可激活多条MAPKs信号通路调控牙周膜细胞IL-6的表达.%Objective: To determine whether endothelin-1 modulate the expression of interleukin-6(IL-6) via multiple mitogen-activated protein kinase pathways in periodontal ligament (PDL) cells.Methods: The PDL cells were stimulated with endothelin-1 (100nM) and PD98059(10μM), a biochemical inhibitors of ERK, SP600125(10μM), a biochemical inhibitors of JNK; SB203580(10μM), a biochemical inhibitors of p38 MAPK for 12 hours, respectively.The untreated PDL cells served as normal control.The effects of biochemical inhibitors of ERK, JNK and p38 MAPK on IL-6 mRNA and protein levels were detected by Real time PCR and ELISA.Results: The IL-6 mRNA and protein levels were enhanced by ET-1 stimulation.Both PD98059 and SB203580 may suppress induction of IL-6 by ET-1, whereas SP600125 had little effect on ET-stimulated IL-6 biosynthesis.Conclusion: ET-1 may modulate IL-6 expression through multiple mitogen-activated protein kinase pathways in periodontal ligament cells.

  19. Tumor growth inhibition effect of hIL-6 on colon cancer cells transfected with the target gene by retroviral vector

    Institute of Scientific and Technical Information of China (English)

    Bing Xiao; Bo Jing; Ya Li Zhang; Dian Yuan Zhou; Wan Dai Zhang

    2000-01-01

    AIM To observe the tumor inhibitory effects by transfecting IL-6 cDNA into colon cancer cell line HT-29 with retroviral vector pZIP cDNA.METHODS Human IL-6 gene was reconstructed in retrovirus vector and transfected into incasing cells PA317 by lipofectamine mediated method,the clones of the cells transferred with hIL-6 were selected by G418, and targeted HT-29 cells were infected with the virus granules secreted from PA317 and also selected by G418. Test gene transcription and expression level by hybridization, ELISA and MTT assay, etc.Analyze tumor inhibitory effects according to the cell growth curve, plating forming rate and tumorigenicity in nude mice.RESULT Successfully constructed and transfected recombinant expressing vectors pZIPIL-6 cDNA and got positive transfected cell lines. The colon cancer cell line (HT-29 IL-6)transfected with the hIL-6 gene by retroviral vector was established. The log proliferation period and the doubling time of this cell line was between 4 to 7 days and 2.5 days according to the direct cell count, the cell proliferation was obviously inhibited with MTT assay, the plating inhibitory rate was 50% by plating efficiency test. When HT-29 IL-6 cells were inoculated into the nude mice subcutaneously, carcinogenic activity of the solid tumor was found superior to the control group and the size of tumor was not significantly enlarged. Injection of combination virus fluid containing IL-6 gene into transplantation tumors could inhibit the growth and development of the tumor.CONCLUSION IL-6 could inhibit the growth and proliferation of colon cancer cells by retroviral vector-mediated transduction.

  20. Voluntary Running Suppresses Tumor Growth through Epinephrine- and IL-6-Dependent NK Cell Mobilization and Redistribution

    DEFF Research Database (Denmark)

    2016-01-01

    Regular exercise reduces the risk of cancer and disease recurrence. Yet the mechanisms behind this protection remain to be elucidated. In this study, tumor-bearing mice randomized to voluntary wheel running showed over 60% reduction in tumor incidence and growth across five different tumor models....... Microarray analysis revealed training-induced upregulation of pathways associated with immune function. NK cell infiltration was significantly increased in tumors from running mice, whereas depletion of NK cells enhanced tumor growth and blunted the beneficial effects of exercise. Mechanistic analyses showed...... that NK cells were mobilized by epinephrine, and blockade of β-adrenergic signaling blunted training-dependent tumor inhibition. Moreover, epinephrine induced a selective mobilization of IL-6-sensitive NK cells, and IL-6-blocking antibodies blunted training-induced tumor suppression, intratumoral NK cell...

  1. Regulation of IL-6 and IL-8 production by reciprocal cell-to-cell interactions between tumor cells and stromal fibroblasts through IL-1α in ameloblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Fuchigami, Takao [Department of Biochemistry and Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Department of Oral and Maxillofacial Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Kibe, Toshiro [Department of Oral and Maxillofacial Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Koyama, Hirofumi; Kishida, Shosei; Iijima, Mikio [Department of Biochemistry and Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Nishizawa, Yoshiaki [Kagoshima University Faculty of Medicine, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Hijioka, Hiroshi; Fujii, Tomomi [Department of Oral and Maxillofacial Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Ueda, Masahiro [Natural Science Centre for Research and Education, Kagoshima University, 1-21-24 Koorimoto, Kagoshima 890-8580 (Japan); Nakamura, Norifumi [Department of Oral and Maxillofacial Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Kiyono, Tohru [Department of Virology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuouku, Tokyo 104-0045 (Japan); Kishida, Michiko, E-mail: kmichiko@m2.kufm.kagoshima-u.ac.jp [Department of Biochemistry and Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan)

    2014-09-05

    Highlights: • We studied the interaction between tumor cells and fibroblasts in ameloblastoma. • AM-3 ameloblastoma cells secreted significantly high IL-1α levels. • IL-1α derived from AM-3 cells promoted IL-6 and IL-8 secretion of fibroblasts. • IL-6 and IL-8 activated the cellular motility and proliferation of AM-3 cells. - Abstract: Ameloblastoma is an odontogenic benign tumor that occurs in the jawbone, which invades bone and reoccurs locally. This tumor is treated by wide surgical excision and causes various problems, including changes in facial countenance and mastication disorders. Ameloblastomas have abundant tumor stroma, including fibroblasts and immune cells. Although cell-to-cell interactions are considered to be involved in the pathogenesis of many diseases, intercellular communications in ameloblastoma have not been fully investigated. In this study, we examined interactions between tumor cells and stromal fibroblasts via soluble factors in ameloblastoma. We used a human ameloblastoma cell line (AM-3 ameloblastoma cells), human fibroblasts (HFF-2 fibroblasts), and primary-cultured fibroblasts from human ameloblastoma tissues, and analyzed the effect of ameloblastoma-associated cell-to-cell communications on gene expression, cytokine secretion, cellular motility and proliferation. AM-3 ameloblastoma cells secreted higher levels of interleukin (IL)-1α than HFF-2 fibroblasts. Treatment with conditioned medium from AM-3 ameloblastoma cells upregulated gene expression and secretion of IL-6 and IL-8 of HFF-2 fibroblasts and primary-cultured fibroblast cells from ameloblastoma tissues. The AM3-stimulated production of IL-6 and IL-8 in fibroblasts was neutralized by pretreatment of AM-3 cells with anti-IL-1α antibody and IL-1 receptor antagonist. Reciprocally, cellular motility of AM-3 ameloblastoma cells was stimulated by HFF-2 fibroblasts in IL-6 and IL-8 dependent manner. In conclusion, ameloblastoma cells and stromal fibroblasts behave

  2. Expression ofVEGF,IL-6,IL-8 in serum and peritoneal fluid of patients with endometriosis

    Institute of Scientific and Technical Information of China (English)

    Yu-Xiang Fan

    2015-01-01

    Objective:To explore the expression of VEGF, IL-6, and IL-8 in serum and peritoneal fluid of patients with endometriosis (EMT) and their clinical significances.Methods:EMT patients who were pathologically diagnosed after laparoscopy from February, 2014 to February, 2015 were included in the study and served as the observation group. Moreover, patients with benign ovarian tumor and healthy women who came for physical examination at the same period were selected and served as the disease control group and normal control group, respectively for correlation analysis. The levels of VEGF, IL-6, and IL-8 in serum and peritoneal fluid of subjects in the three groups were compared.Results:The levels of serum VEGF, IL-6, and IL-8 in the observation group were significantly higher than those in the disease control group and the normal control group (P0.05). The levels of VEGF, IL-6, and IL-8 in peritoneal fluid in the observation group were significantly higher than those in the disease control group (P<0.05). With the increasing of EMT staging, the levels of VEGF, IL-6, and IL-8 in serum and peritoneal fluid were correspondingly elevated. The levels of VEGF, IL-6, and IL-8 in serum and peritoneal fluid at stageⅢ-Ⅳ were significantly higher than those at stageⅠ-Ⅱ(P<0.05).Conclusions:VEGF, IL-6 and IL-8 are highly expressed in serum and peritoneal fluid of patients with EMT. With the progression of the disease, the expression of VEGF, IL-6 and IL-8 shows an increasing trend. Clinical detection of the changes of VEGF, IL-6, and IL-8 levels in serum and peritoneal fluid can monitor the progression of EMT condition.

  3. Interaction of vascular smooth muscle cells and monocytes by soluble factors synergistically enhances IL-6 and MCP-1 production.

    Science.gov (United States)

    Chen, Li; Frister, Adrian; Wang, Song; Ludwig, Andreas; Behr, Hagen; Pippig, Susanna; Li, Beibei; Simm, Andreas; Hofmann, Britt; Pilowski, Claudia; Koch, Susanne; Buerke, Michael; Rose-John, Stefan; Werdan, Karl; Loppnow, Harald

    2009-04-01

    Inflammatory mechanisms contribute to atherogenesis. Monocyte chemoattractant protein (MCP)-1 and IL-6 are potent mediators of inflammation. Both contribute to early atherogenesis by luring monocytes and regulating cell functions in the vessel wall. MCP-1 and IL-6 production resulting from the interaction of invading monocytes with local vessel wall cells may accelerate atherosclerosis. We investigated the influence of the interaction of human vascular smooth muscle cells (SMCs) with human mononuclear cells (MNCs) or monocytes on IL-6 and MCP-1 production in a coculture model. Interaction synergistically enhanced IL-6 and MCP-1 production (up to 30- and 10-fold, respectively) compared with separately cultured cells. This enhancement was mediated by CD14-positive monocytes. It was dependent on the SMC-to-MNC/monocyte ratio, and as few as 0.2 monocytes/SMC induced the synergism. Synergistic IL-6 production was observed at the protein, mRNA, and functional level. It was mediated by soluble factors, and simultaneous inhibition of IL-1, TNF-alpha, and IL-6 completely blocked the synergism. IL-1, TNF-alpha, and IL-6 were present in the cultures. Blockade of the synergism by soluble glycoprotein 130Fc/soluble IL-6 receptor, as well as the induction of synergistic IL-6 production by costimulation of SMCs with IL-1, TNF-alpha, and hyper-IL-6, suggested the involvement of IL-6 trans-signaling. The contribution of IL-6 was consistent with enhanced STAT3 phosphorylation. The present data suggest that SMC/monocyte interactions may augment the proinflammatory status in the tissue, contributing to the acceleration of early atherogenesis.

  4. Inflammatory responses in epithelia: endotoxin-induced IL-6 secretion and iNOS/NO production are differentially regulated in mouse mammary epithelial cells

    Directory of Open Access Journals (Sweden)

    Talhouk Rabih S

    2010-11-01

    Full Text Available Abstract Background IL-6 is a pro-inflammatory cytokine that signals via binding to a soluble or membrane bound receptor, while nitric oxide (NO, an oxidative stress molecule, diffuses through the cell membrane without a receptor. Both mediators signal through different mechanisms, yet they are dependent on NFκB. We proposed that both mediators are co-induced and co-regulated in inflamed mammary epithelial cells. Methods SCp2 mammary epithelial cells were treated with bacterial endotoxin (ET for different time periods and analyzed for induction of IL-6 secretion and NO production by ELISA and Griess reaction, respectively. The expression of IL-6 and induced NO synthase (iNOS was assayed by real time PCR and/or western immunoblots, and the activation of NFκB was assayed by immunobinding assay. To investigate the role of mammary cell microenvironment (cell-substratum or interaction of mammary epithelial cell types; critical to mammary development, function, and disease in modulation of the inflammatory response, SCp2 cells were cultured with or without extracellular matrix (EHS or in coculture with their myoepithelial counterpart (SCg6, and assayed for ET-induced IL-6 and NO. Results Endotoxin induced NFκB activation at 1 h after ET application. IL-6 secretion and NO production were induced, but with unexpected delay in expression of mRNA for iNOS compared to IL-6. NFκB/p65 activation was transient but NFκB/p50 activation persisted longer. Selective inhibition of NFκB activation by Wedelolactone reduced ET-induced expression of IL-6 mRNA and protein but not iNOS mRNA or NO production, suggesting differences in IL-6 and iNOS regulation via NFκB. SCp2 cells in coculture with SCg6 but not in presence of EHS dramatically induced IL-6 secretion even in the absence of ET. ET-induced NO production was blunted in SCp2/SCg6 cocultures compared to that in SCp2 alone. Conclusions The differential regulation of IL-6 and iNOS together with the

  5. Exercise-induced increase in IL-6 level enhances GLUT4 expression and insulin sensitivity in mouse skeletal muscle.

    Science.gov (United States)

    Ikeda, Shin-Ichi; Tamura, Yoshifumi; Kakehi, Saori; Sanada, Hiromi; Kawamori, Ryuzo; Watada, Hirotaka

    2016-05-13

    A single bout of exercise is known to increase the insulin sensitivity of skeletal muscle; however, the underlying mechanism of this phenomenon is not fully understood. Because a single bout of exercise induces a transient increase in blood interleukin-6 (IL-6) level, we hypothesized that the enhancement of insulin sensitivity after a single bout of exercise in skeletal muscle is mediated at least in part through IL-6-dependent mechanisms. To test this hypothesis, C57BL6J mice were intravenously injected with normal IgG or an IL-6 neutralizing antibody before exercise. Twenty-four hours after a single bout of exercise, the plantaris muscle was harvested to measure insulin sensitivity and glucose transporter (GLUT)-4 expression levels by ex-vivo insulin-stimulated 2-deoxyglucose (2-DG) uptake and Western blotting, respectively. Compared with sedentary mice, mice that performed exercise showed enhanced IL-6 concentration, insulin-stimulated 2-DG uptake, and GLUT-4 expression in the plantaris muscle. The enhanced insulin sensitivity and GLUT4 expression were canceled by injection of the IL-6 neutralizing antibody before exercise. In addition, IL-6 injection increased GLUT4 expression, both in the plantaris muscle and the soleus muscle in C57BL6J mice. Furthermore, a short period of incubation with IL-6 increased GLUT4 expression in differentiated C2C12 myotubes. In summary, these results suggested that IL-6 increased GLUT4 expression in muscle and that this phenomenon may play a role in the post-exercise enhancement of insulin sensitivity in skeletal muscle.

  6. Clinical Relevance of VPAC1 Receptor Expression in Early Arthritis: Association with IL-6 and Disease Activity.

    Directory of Open Access Journals (Sweden)

    Iria V Seoane

    Full Text Available The vasoactive intestinal peptide (VIP receptors VPAC1 and VPAC2 mediate anti-inflammatory and immunoregulatory responses in rheumatoid arthritis (RA. Data on the expression of these receptors could complement clinical assessment in the management of RA. Our goal was to investigate the correlation between expression of both receptors and the 28-Joint Disease Activity Score (DAS28 in peripheral blood mononuclear cells (PBMCs from patients with early arthritis (EA. We also measured expression of IL-6 to evaluate the association between VIP receptors and systemic inflammation.We analyzed 250 blood samples collected at any of the 5 scheduled follow-up visits from 125 patients enrolled in the Princesa Early Arthritis Register Longitudinal study. Samples from 22 healthy donors were also analyzed. Sociodemographic, clinical, and therapeutic data were systematically recorded. mRNA expression levels were determined using real-time PCR. Then, longitudinal multivariate analyses were performed.PBMCs from EA patients showed significantly higher expression of VPAC2 receptors at baseline compared to healthy donors (p<0.001. With time, however, VPAC2 expression tended to be significantly lower while VPAC1 receptor expression increased in correlation with a reduction in DAS28 index. Our results reveal that more severe inflammation, based on high levels of IL-6, is associated with lower expression of VPAC1 (p<0.001 and conversely with increased expression of VPAC2 (p<0.001. A major finding of this study is that expression of VPAC1 is lower in patients with increased disease activity (p = 0.001, thus making it possible to differentiate between patients with various degrees of clinical disease activity.Patients with more severe inflammation and higher disease activity show lower levels of VPAC1 expression, which is associated with patient-reported impairment. Therefore, VPAC1 is a biological marker in EA.

  7. Clinical Relevance of VPAC1 Receptor Expression in Early Arthritis: Association with IL-6 and Disease Activity

    Science.gov (United States)

    Seoane, Iria V.; Ortiz, Ana M.; Piris, Lorena; Lamana, Amalia; Juarranz, Yasmina; García-Vicuña, Rosario; González-Álvaro, Isidoro; Gomariz, Rosa P.; Martínez, Carmen

    2016-01-01

    Background The vasoactive intestinal peptide (VIP) receptors VPAC1 and VPAC2 mediate anti-inflammatory and immunoregulatory responses in rheumatoid arthritis (RA). Data on the expression of these receptors could complement clinical assessment in the management of RA. Our goal was to investigate the correlation between expression of both receptors and the 28-Joint Disease Activity Score (DAS28) in peripheral blood mononuclear cells (PBMCs) from patients with early arthritis (EA). We also measured expression of IL-6 to evaluate the association between VIP receptors and systemic inflammation. Methods We analyzed 250 blood samples collected at any of the 5 scheduled follow-up visits from 125 patients enrolled in the Princesa Early Arthritis Register Longitudinal study. Samples from 22 healthy donors were also analyzed. Sociodemographic, clinical, and therapeutic data were systematically recorded. mRNA expression levels were determined using real-time PCR. Then, longitudinal multivariate analyses were performed. Results PBMCs from EA patients showed significantly higher expression of VPAC2 receptors at baseline compared to healthy donors (p<0.001). With time, however, VPAC2 expression tended to be significantly lower while VPAC1 receptor expression increased in correlation with a reduction in DAS28 index. Our results reveal that more severe inflammation, based on high levels of IL-6, is associated with lower expression of VPAC1 (p<0.001) and conversely with increased expression of VPAC2 (p<0.001). A major finding of this study is that expression of VPAC1 is lower in patients with increased disease activity (p = 0.001), thus making it possible to differentiate between patients with various degrees of clinical disease activity. Conclusion Patients with more severe inflammation and higher disease activity show lower levels of VPAC1 expression, which is associated with patient-reported impairment. Therefore, VPAC1 is a biological marker in EA. PMID:26881970

  8. IL-6 Compared to Young Mice

    Directory of Open Access Journals (Sweden)

    Jihyun Park

    2014-01-01

    Full Text Available Inflamm-aging indicates the chronic inflammatory state resulting from increased secretion of proinflammatory cytokines and mediators such as IL-6 in the elderly. Our principle objective was to identify cell types that were affected with aging concerning IL-6 secretion in the murine model. We compared IL-6 production in spleen cells from both young and aged mice and isolated several types of cells from spleen and investigated IL-6 mRNA expression and protein production. IL-6 protein productions in cultured stromal cells from aged mice spleen were significantly high compared to young mice upon LPS stimulation. IL-6 mRNA expression level of freshly isolated stromal cells from aged mice was high compared to young mice. Furthermore, stromal cells of aged mice highly expressed IL-6 mRNA after LPS injection in vivo. These results suggest that stromal cells play a role in producing IL-6 in aged mice and imply that they contribute to the chronic inflammatory condition in the elderly.

  9. Measles virus nucleocapsid protein, a key contributor to Paget’s disease, increases IL-6 expression via down-regulation of FoxO3/Sirt1signaling

    Science.gov (United States)

    Wang, Feng-Ming; Sarmasik, Aliye; Hiruma, Yuko; Sun, Quanhong; Sammut, Benedicte; Windle, Jolene J.; Roodman, G. David; Galson, Deborah L.

    2012-01-01

    Measles virus plays an important role as an environmental factor in the pathogenesis of Paget’s disease (PD). Previous studies have shown that IL-6 is increased in the bone marrow of Paget’s patients and that measles virus nucleocapsid protein (MVNP) induces IL-6 secretion by pagetic osteoclasts. Further, IL-6 plays a critical role in the development of pagetic osteoclasts and bone lesions induced by PD, but the mechanisms regulating IL-6 production by MVNP remain unclear. Our current studies revealed that MVNP expression in osteoclast precursors down-regulated Sirt1 mRNA and protein, a negative regulator of NF-κB activity, which is a key factor for IL-6 expression. MVNP expression in NIH3T3 cells also elevated Il-6 transcription and impaired the expression of Sirt1 mRNA both under basal conditions and upon activation of the Sirt1 upstream regulator FoxO3 by LY294002 (a PI3K/AKT inhibitor). Luciferase activity assays showed that constitutively active FoxO3 abolished the repressive effect of MVNP on reporters driven by either FoxO3 response elements or the Sirt1 promoter. Further, protein stability assays revealed that FoxO3 was degraded more rapidly in MVNP-expressing cells than in control cells following the addition of cycloheximide. Similarly, co-transfection of MVNP and FoxO3 into HEK293 cells demonstrated that MVNP decreased the protein levels of over-expressed FoxO3 in a dose-dependent manner. Treatment with the proteasome inhibitor, MG132, blocked the MVNP-triggered decrease of FoxO3, and the treatment with the serine/threonine phosphatase inhibitor, Calyculin A, revealed that MVNP increased phosphorylation of FoxO3. Further, over-expression of Sirt1 or treatment with the Sirt1 activator resveratrol blocked the increase in Il-6 transcription by MVNP. Finally, resveratrol reduced the numbers of TRAP positive multi-nuclear cells in bone marrow cultures from TRAP-MVNP transgenic mice to wild type levels. These results indicate that MVNP decreases FoxO3

  10. Self-renewal of CD133hi cells by IL6/Notch3 signalling regulates endocrine resistance in metastatic breast cancer

    Science.gov (United States)

    Sansone, Pasquale; Ceccarelli, Claudio; Berishaj, Marjan; Chang, Qing; Rajasekhar, Vinagolu K.; Perna, Fabiana; Bowman, Robert L.; Vidone, Michele; Daly, Laura; Nnoli, Jennifer; Santini, Donatella; Taffurelli, Mario; Shih, Natalie N. C.; Feldman, Michael; Mao, Jun J.; Colameco , Christopher; Chen, Jinbo; DeMichele, Angela; Fabbri, Nicola; Healey, John H.; Cricca, Monica; Gasparre, Giuseppe; Lyden, David; Bonafé, Massimiliano; Bromberg, Jacqueline

    2016-01-01

    The mechanisms of metastatic progression from hormonal therapy (HT) are largely unknown in luminal breast cancer. Here we demonstrate the enrichment of CD133hi/ERlo cancer cells in clinical specimens following neoadjuvant endocrine therapy and in HT refractory metastatic disease. We develop experimental models of metastatic luminal breast cancer and demonstrate that HT can promote the generation of HT-resistant, self-renewing CD133hi/ERlo/IL6hi cancer stem cells (CSCs). HT initially abrogates oxidative phosphorylation (OXPHOS) generating self-renewal-deficient cancer cells, CD133hi/ERlo/OXPHOSlo. These cells exit metabolic dormancy via an IL6-driven feed-forward ERlo-IL6hi-Notchhi loop, activating OXPHOS, in the absence of ER activity. The inhibition of IL6R/IL6-Notch pathways switches the self-renewal of CD133hi CSCs, from an IL6/Notch-dependent one to an ER-dependent one, through the re-expression of ER. Thus, HT induces an OXPHOS metabolic editing of luminal breast cancers, paradoxically establishing HT-driven self-renewal of dormant CD133hi/ERlo cells mediating metastatic progression, which is sensitive to dual targeted therapy. PMID:26858125

  11. Self-renewal of CD133(hi) cells by IL6/Notch3 signalling regulates endocrine resistance in metastatic breast cancer.

    Science.gov (United States)

    Sansone, Pasquale; Ceccarelli, Claudio; Berishaj, Marjan; Chang, Qing; Rajasekhar, Vinagolu K; Perna, Fabiana; Bowman, Robert L; Vidone, Michele; Daly, Laura; Nnoli, Jennifer; Santini, Donatella; Taffurelli, Mario; Shih, Natalie N C; Feldman, Michael; Mao, Jun J; Colameco, Christopher; Chen, Jinbo; DeMichele, Angela; Fabbri, Nicola; Healey, John H; Cricca, Monica; Gasparre, Giuseppe; Lyden, David; Bonafé, Massimiliano; Bromberg, Jacqueline

    2016-02-09

    The mechanisms of metastatic progression from hormonal therapy (HT) are largely unknown in luminal breast cancer. Here we demonstrate the enrichment of CD133(hi)/ER(lo) cancer cells in clinical specimens following neoadjuvant endocrine therapy and in HT refractory metastatic disease. We develop experimental models of metastatic luminal breast cancer and demonstrate that HT can promote the generation of HT-resistant, self-renewing CD133(hi)/ER(lo)/IL6(hi) cancer stem cells (CSCs). HT initially abrogates oxidative phosphorylation (OXPHOS) generating self-renewal-deficient cancer cells, CD133(hi)/ER(lo)/OXPHOS(lo). These cells exit metabolic dormancy via an IL6-driven feed-forward ER(lo)-IL6(hi)-Notch(hi) loop, activating OXPHOS, in the absence of ER activity. The inhibition of IL6R/IL6-Notch pathways switches the self-renewal of CD133(hi) CSCs, from an IL6/Notch-dependent one to an ER-dependent one, through the re-expression of ER. Thus, HT induces an OXPHOS metabolic editing of luminal breast cancers, paradoxically establishing HT-driven self-renewal of dormant CD133(hi)/ER(lo) cells mediating metastatic progression, which is sensitive to dual targeted therapy.

  12. Inhibition of NF-IL6 activity by manassantin B, a dilignan isolated from Saururus chinensis, in phorbol myristate acetate-stimulated U937 promonocytic cells.

    Science.gov (United States)

    Son, Kyung-No; Song, In-sung; Shin, Yong-Hyun; Pai, Tong-Kun; Chung, Dae-Kyun; Baek, Nam-In; Lee, Jung Joon; Kim, Jiyoung

    2005-08-31

    Mannasantin B, a dilignan structurally related to manssantin A, is an inhibitor of NF-kappaB transactivation. In the present study, we found that it inhibited PMA-induced expression of IL-1beta, IL-1beta mRNA, and IL-1beta promoter activity in U937 cells with IC50 values of about 50 nM. It also inhibited NF-IL6- and NF-kappaB-induced activation of IL-1beta, with IC50 values of 78 nM and 1.6 microM, respectively, revealing a potent inhibitory effect on NF-IL6. Electrophoretic mobility shift assays showed that manassantin B had an inhibitory effect on DNA binding by NF-IL6, but not by NF-kappaB. Further analysis revealed that transactivation by NF-IL6 was also inhibited. Our results indicate that manassantin B suppresses expression of IL-1beta in promonocytic cells by inhibiting not only NF-kappaB but also NF-IL6 activity. Furthermore, our observations suggest that manassantin B may be clinically useful as a potent inhibitor of NF-IL6 activity.

  13. MicroRNA-181b regulates endotoxin tolerance by targeting IL-6 in macrophage RAW264.7 cells.

    Science.gov (United States)

    Zhang, Wenjun; Shen, Xiaojun; Xie, Luyang; Chu, Maoping; Ma, Yanmei

    2015-01-01

    Interleukin 6 (IL-6) is a major pro-inflammatory cytokine and dysregulation of IL-6 is relevant to many inflammatory diseases. Endotoxin induced tolerance of IL-6 is an important mechanism to avoid the excessive immune reaction. But to date, the molecular mechanisms of endotoxin tolerance of IL-6 remain unclear. Here we reported that IL-6 secretion and microRNA-181b (miR-181b) expression were inversely correlated following LPS stimulation. We also demonstrated that miR-181b targeting the 3'-UTR of IL-6 transcripts and up-regulation of miR-181b was associated with NF-kB. We further demonstrated that up-regulation of miR-181b in response to LPS was required for inducing IL-6 tolerance in macrophage. Our results suggested that the post-transcriptional control mediated by miR-181b could be involved in fine tuning the critical level of IL-6 expression in endotoxin tolerance.

  14. The influence of radiotherapy on IL-2 and IL-6 secretions of mucous membrane epithelial cells of wistar small intestine.

    Science.gov (United States)

    Liu, Bin; Li, Xiaoling; Ai, Fulu; Wang, Tianlu; Chen, Yun; Zhang, Hao

    2015-01-01

    The aim of the study was to investigate the influence of radiotherapy on IL-2 and IL-6 secretions of mucous epithelial cells of small intestine and the inhibition effect of deproteinized calf blood extractive (DCBE, also known as Actovegin in trade name) on apoptosis of mucous epithelial cells of small intestine. 50 wistars were randomly divided into 5 groups with 10 in each including normal group (NG), radiation group (RG), low-dose Actovegin group (L-AG), middle-dose Actovegin group (M-AG), and high-dose Actovegin (H-AG). High-energy X-ray linear accelerator was used for abdominal irradiation of RG, L-AG, M-AG, and H-AG at the exposure dose of 9.0 Gy to establish the wistar radiation damage model. Modeling wistars were injected with medicine for successive 4 days, and their small intestinal mucosas were extracted as pathological sections; then fully automated analyzer was employed to detect their IL-2 and IL-6 levels. Immunohistochemical analysis was carried out to explore the effect of Actovegin on apoptosis of mucous membrane epithelial cells of small intestine. The IL-2 and IL-6 levels of RG are significantly higher than other groups and differences are statistically significant (P 0.05). Compared with RG, the villus height, membrane thickness, crypt depth, and whole layer thickness significantly improved (P < 0.05). However, the expression levels of apoptosis-related protein bax of M-AG and H-AG are significantly lower than RG, and their bcl-2 levels are higher than RG with significant difference between them (P < 0.05). Actovegin is capable of effectively inhibiting the expression of apoptosis-related protein bax and facilitating the expression of anti-apoptosis protein bcl-2, having preferable remediation effect on mucous membrane epithelial cells of radioactive enteritis.

  15. The clinical analysis of expression levels of IL-6, BNP and CRP in patients with brain injury

    Institute of Scientific and Technical Information of China (English)

    Jun-Feng Zhang

    2015-01-01

    Objective: To investigate the clinical analysis of expression levels of brain natriuretic peptide (BNP), interleukin -6 (IL-6), C-reactive protein (CRP) in patients with traumatic brain injury and its clinical significance. Methods: The levels of IL-6, BNP, CRP of 80 cases of traumatic brain injury and 80 cases of healthy people group were determined with radioimmunoassay and immunoassays. Results: The levels of IL-6 and CRP of patients with traumatic brain injury were higher than healthy people group (P<0.05), while the levels of BNP of patients with traumatic brain injury were lower than healthy people group (P<0.05). The levels of CRP and IL-6 of patients with severe were higher than light and moderate traumatic brain injury patients (P<0.05) .Compared with the time of admission, the serum BNP, IL-6 and -CRP levels of the patient admitted to hospital within 24 h reached a peak and gradually decreased in 3d after admission, compared with the previous admission, the difference was statistically significant (P<0.05). The levels of BNP of the severe were lower than light and moderate traumatic brain injury patients (P<0.05). Conclusions: The measurement of serum BNP, IL-6 and CRP levels will help to evaluate the extent of disease in elderly patients with traumatic brain injury and prognosis.

  16. Expression and significance of TNF-α, IL-6, and IL-10 in the serum in patients with mycoplasma pneumonia

    Institute of Scientific and Technical Information of China (English)

    Dong-Hai Zhang

    2016-01-01

    Objective:To explore the expression and clinical significance of TNF-α, IL-6, and IL-10 in the serum in patients with mycoplasma pneumonia (MPP).Methods:A total of 120 patients with MPP who were admitted in our hospital from August, 2014 to June, 2015 were included in the study and served as the observation group, while 60 healthy children who came for physical examinations were served as the control group. The serum levels of IL-6, IL-10, and TNF-α in the observation group at the acute phase and recovery phase were detected and compared with the control group. The serum levels of IL-6, IL-10, and TNF-α in mild and severe MPP patients were compared. The levels of IL-6, IL-10, and TNF-α in the serum and pleural fluid in MPP patients with or with no fibrosis change were compared and analyzed. Results:When compared with the control group, the serum TNF-α and IL-6 levels in the observation group at the acute phase and recovery phase were significantly elevated, while IL-10 level was significantly reduced. The serum TNF-α and IL-6 levels in MPP patients at the acute phase were significantly lower than those at the recovery phase, while IL-10 level was significantly higher than that at the recovery phase. The serum TNF-α and IL-6 levels in the severe group were significantly higher than those in the mild group, while IL-10 level was significantly lower than that in the mild group. TNF-α level in the pleural fluid in MPP patients with fibrosis change was significantly higher than that in MPP patients with no fibrosis change, while the comparison of IL-6 and IL-10 was not statistically significant. TNF-α level in MPP patients with fibrosis change in the pleural fluid was significantly higher than that in the serum, while the comparison of IL-6 and IL-10 was not statistically significant. IL-6, IL-10, and TNF-α levels in MPP patients with no fibrosis change in the pleural fluid were not statistically different from those in the serum.Conclusions:TNF-α, IL-6, and

  17. Acquisition of resistance to trastuzumab in gastric cancer cells is associated with activation of IL-6/STAT3/Jagged-1/Notch positive feedback loop.

    Science.gov (United States)

    Yang, Zhengyan; Guo, Liang; Liu, Dan; Sun, Limin; Chen, Hongyu; Deng, Que; Liu, Yanjun; Yu, Ming; Ma, Yuanfang; Guo, Ning; Shi, Ming

    2015-03-10

    In the present study, we demonstrate that prolonged treatment by trastuzumab induced resistance of NCI-N87 gastric cancer cells to trastuzumab. The resistant cells possessed typical characteristics of epithelial to mesenchymal transition (EMT)/cancer stem cells and acquired more invasive and metastatic potentials both in vitro and in vivo. Long term treatment with trastuzumab dramatically inhibited the phosphorylation of Akt, but triggered the activation of STAT3. The level of IL-6 was remarkably increased, implicating that the release of IL-6 that drives the STAT3 activation initiates the survival signaling transition. Furthermore, the Notch activities were significantly enhanced in the resistant cells, companied by upregulation of the Notch ligand Jagged-1 and the Notch responsive genes Hey1 and Hey2. Inhibiting the endogenous Notch pathway reduced the IL-6 expression and restored the sensitivities of the resistant cells to trastuzumab. Blocking of the STAT3 signaling abrogated IL-6-induced Jagged-1 expression, effectively inhibited the growth of the trastuzumab resistant cells, and enhanced the anti-tumor activities of trastuzumab in the resistant cells. These findings implicate that the IL-6/STAT3/Jagged-1/Notch axis may be a useful target and that combination of the Notch or STAT3 inhibitors with trastuzumab may prevent or delay clinical resistance and improve the efficacy of trastuzumab in gastric cancer.

  18. Increased IL-6 expression in osteoclasts is necessary but not sufficient for the development of Paget's disease of bone.

    Science.gov (United States)

    Teramachi, Jumpei; Zhou, Hua; Subler, Mark A; Kitagawa, Yukiko; Galson, Deborah L; Dempster, David W; Windle, Jolene J; Kurihara, Noriyoshi; Roodman, G David

    2014-06-01

    Measles virus nucleocapsid protein (MVNP) expression in osteoclasts (OCLs) and mutation of the SQSTM1 (p62) gene contribute to the increased OCL activity in Paget's disease (PD). OCLs expressing MVNP display many of the features of PD OCLs. Interleukin-6 (IL-6) production is essential for the pagetic phenotype, because transgenic mice with MVNP targeted to OCLs develop pagetic OCLs and lesions, but this phenotype is absent when MVNP mice are bred to IL-6(-/-) mice. In contrast, mutant p62 expression in OCL precursors promotes receptor activator of NF-κB ligand (RANKL) hyperresponsivity and increased OCL production, but OCLs that form have normal morphology, are not hyperresponsive to 1,25-dihydroxyvitamin D3 (1,25-(OH)2 D3 ), nor produce elevated levels of IL-6. We previously generated p62(P394L) knock-in mice (p62KI) and found that although OCL numbers were increased, the mice did not develop pagetic lesions. However, mice expressing both MVNP and p62KI developed more exuberant pagetic lesions than mice expressing MVNP alone. To examine the role of elevated IL-6 in PD and determine if MVNP mediates its effects primarily through elevation of IL-6, we generated transgenic mice that overexpress IL-6 driven by the tartrate-resistant acid phosphatase (TRAP) promoter (TIL-6 mice) and produce IL-6 at levels comparable to MVNP mice. These were crossed with p62KI mice to determine whether IL-6 overexpression cooperates with mutant p62 to produce pagetic lesions. OCL precursors from p62KI/TIL-6 mice formed greater numbers of OCLs than either p62KI or TIL-6 OCL precursors in response to 1,25-(OH)2 D3 . Histomorphometric analysis of bones from p62KI/TIL-6 mice revealed increased OCL numbers per bone surface area compared to wild-type (WT) mice. However, micro-quantitative CT (µQCT) analysis did not reveal significant differences between p62KI/TIL-6 and WT mice, and no pagetic OCLs or lesions were detected in vivo. Thus, increased IL-6 expression in OCLs from p62KI mice

  19. Selective Inhibitors of Kv11.1 Regulate IL-6 Expression by Macrophages in Response to TLR/IL-1R Ligands

    Directory of Open Access Journals (Sweden)

    Cheryl Hunter

    2010-01-01

    Full Text Available The mechanism by which the platelet-endothelial cell adhesion molecule PECAM-1 regulates leukodiapedesis, vascular endothelial integrity, and proinflammatory cytokine expression in vivo is not known. We recently identified PECAM-1 as a negative regulator of Kv11.1, a specific voltage-gated potassium channel that functioned in human macrophages to reset a resting membrane potential following depolarization. We demonstrate here that dofetilide (DOF, a selective inhibitor of the Kv11.1 current, had a profound inhibitory effect on neutrophil recruitment in mice following TLR/IL-1R–elicited peritonitis or intrascrotal injection of IL-1β, but had no effect on responses seen with TNFα. Furthermore, inhibitors of Kv11.1 (DOF, E4031, and astemizole, but not Kv1.3 (margatoxin, suppressed the expression of IL-6 and MCP-1 cytokines by murine resident peritoneal macrophages, while again having no effect on TNFα. In contrast, IL-6 expression by peritoneal mesothelial cells was unaffected. Using murine P388 cells, which lack endogenous C/EBPβexpression and are unresponsive to LPS for the expression of both IL-6 and MCP-1, we observed that DOF inhibited LPS-induced expression of IL-6 mRNA following ectopic expression of wild-type C/EBPβ, but not a serine-64 point mutant. Finally, DOF inhibited the constitutive activation of cdk2 in murine peritoneal macrophages; cdk2 is known to phosphorylate C/EBPβ at serine-64. Taken together, our results implicate a potential role for Kv11.1 in regulating cdk2 and C/EBPβ activity, where robust transactivation of both IL-6 and MCP-1 transcription is known to be dependent on serine-64 of C/EBPβ. Our data might also explain the altered phenotypes displayed by PECAM-1 knockout mice in several disease models.

  20. TNFα Promotes Th17 Cell Differentiation through IL-6 and IL-1β Produced by Monocytes in Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Yingxia Zheng

    2014-01-01

    Full Text Available TNFα plays an important role in autoimmune pathogenesis and is the main therapeutic target of rheumatoid arthritis. However, its underlying mechanism is not completely understood. In this study, we described that Th17 cells were accumulated in synovial fluid, which was attributable to TNFα aberrantly produced in rheumatoid synovium. Interestingly, TNFα cannot induce IL-17 production of CD4+ T cells directly, but through the monocytes high levels of IL-1β and IL-6 in a TNFRI and TNFRII dependent manner from the active RA patients are produced. TNFα was shown to enhance the phosphorylation level of STAT3 and the expression level of transcription factor RORC of CD4+ T cells when cultured with CD14+ monocytes. Treatment with an approved TNFα blocking antibody showed marked reduction in the levels of IL-6, IL-1β, and IL-17 and the expression level of STAT3 phosphorylation in relation to Th17 cell differentiation in patients with rheumatoid arthritis. The study provides new evidence supporting the critical role of TNFα in the pathogenic Th17 cell differentiation in rheumatoid arthritis.

  1. AGEs-Induced IL-6 Synthesis Precedes RAGE Up-Regulation in HEK 293 Cells: An Alternative Inflammatory Mechanism?

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    Andreea Iren Serban

    2015-08-01

    Full Text Available Advanced glycation end products (AGEs can activate the inflammatory pathways involved in diabetic nephropathy. Understanding these molecular pathways could contribute to therapeutic strategies for diabetes complications. We evaluated the modulation of inflammatory and oxidative markers, as well as the protective mechanisms employed by human embryonic kidney cells (HEK 293 upon exposure to 200 μg/mL bovine serum albumine (BSA or AGEs–BSA for 12, 24 and 48 h. The mRNA and protein expression levels of AGEs receptor (RAGE and heat shock proteins (HSPs 27, 60 and 70, the activity of antioxidant enzymes and the expression levels of eight cytokines were analysed. Cell damage via oxidative mechanisms was evaluated by glutathione and malondialdehyde levels. The data revealed two different time scale responses. First, the up-regulation of interleukin-6 (IL-6, HSP 27 and high catalase activity were detected as early as 12 h after exposure to AGEs–BSA, while the second response, after 24 h, consisted of NF-κB p65, RAGE, HSP 70 and inflammatory cytokine up-regulation, glutathione depletion, malondialdehyde increase and the activation of antioxidant enzymes. IL-6 might be important in the early ignition of inflammatory responses, while the cellular redox imbalance, RAGE activation and NF-κB p65 increased expression further enhance inflammatory signals in HEK 293 cells.

  2. IL-1β and IL-6 Are Highly Expressed in RF+IgE+ Systemic Lupus Erythematous Subtype

    Science.gov (United States)

    Zhang, Junlong; Shen, Beilei; Huang, Zhuochun; Tan, Chunyu; Baan, Carla C.

    2017-01-01

    Background. Systemic lupus erythematosus (SLE) is an autoimmune disease with great heterogeneity in pathogenesis and clinical symptoms. Rheumatoid factor (RF) is one key indicator for rheumatoid arthritis (RA) while immunoglobulin E (IgE) is associated with type I hypersensitivity. To better categorize SLE subtypes, we determined the dominant cytokines based on familial SLE patients. Methods. RF, IgE, and multiple cytokines (i.e., IL-1β, IL-6, IL-8, IL-10, IL-17, IFN-γ, IP-10, MCP-1, and MIP-1β) were measured in sera of familial SLE patients (n = 3), noninherited SLE patients (n = 108), and healthy controls (n = 80). Results. Three familial SLE patients and 5 noninherited SLE cases are with features of RF+IgE+. These RF+IgE+ SLE patients expressed significantly higher levels of IL-1β and IL-6 than the other SLE patients (P < 0.05). IL-6 correlated with both IgE and IL-1β levels in RF+IgE+ SLE patients (r2 = 0.583, P = 0.027; r2 = 0.847, P = 0.001), and IgE also correlated with IL-1β (r2 = 0.567, P = 0.031). Conclusion. Both IL-1β and IL-6 are highly expressed cytokines in RF+IgE+ SLE subtype which may be related to the pathogenesis of this special SLE subtype and provide accurate treatment strategy by neutralizing IL-1β and IL-6. PMID:28286780

  3. The effectiveness of an anti-human IL-6 receptor monoclonal antibody combined with chemotherapy to target colon cancer stem-like cells.

    Science.gov (United States)

    Ying, Jin; Tsujii, Masahiko; Kondo, Jumpei; Hayashi, Yoshito; Kato, Motohiko; Akasaka, Tomofumi; Inoue, Takuta; Shiraishi, Eri; Inoue, Tahahiro; Hiyama, Satoshi; Tsujii, Yoshiki; Maekawa, Akira; Kawai, Shoichiro; Fujinaga, Tetsuji; Araki, Maekawa; Shinzaki, Shinichiro; Watabe, Kenji; Nishida, Tsutomu; Iijima, Hideki; Takehara, Tetsuo

    2015-04-01

    Recent studies have demonstrated that cancer stem cells (CSCs) can initiate and sustain tumor growth and exhibit resistance to clinical cytotoxic therapies. Therefore, CSCs represent the main target of anticancer therapy. Interleukin-6 (IL-6) promotes cellular proliferation and drug resistance in colorectal cancer, and its serum levels correlate with patient survival. Therefore, IL-6 and its downstream signaling molecule the signal transducer and activator of transcription-3 (STAT3) represent potential molecular targets. In the present study, we investigated the effects of IL-6 and its downstream signaling components on stem cell biology, particularly the chemoresistance of CSCs, to explore potential molecular targets for cancer therapy. The colon cancer cell line WiDr was cultured in serum-free, non-adherent, and three-dimensional spheroid-forming conditions to enrich the stem cell-like population. Spheroid-forming cells slowly proliferated and expressed high levels of Oct-4, Klf4, Bmi-1, Lgr5, IL-6, and Notch 3 compared with adherent cells. Treatment with an anti-human IL-6 receptor monoclonal antibody reduced spheroid formation, stem cell-related gene expression, and 5-fluorouracil (5-FU) resistance. In addition, IL-6 treatment enhanced the levels of p-STAT3 (Tyr705), the expression of Oct-4, Klf4, Lgr5, and Notch 3, and chemoresistance to 5-FU. siRNA targeting Notch 3 suppressed spheroid formation, Oct-4 and Lgr5 expression, and 5-FU chemoresistance, whereas STAT3 inhibition enhanced Oct-4, Klf4, Lgr5, and Notch 3 expression and 5-FU chemoresistance along with reduced spheroid growth. Taken together, these results indicate that IL-6 functions in dichotomous pathways involving Notch 3 induction and STAT3 activation. The former pathway is involved in cancer stem-like cell biology and enhanced chemoresistance, and the latter pathway leads to accelerated proliferation and reduced chemoresistance. Thus, an anti-human IL-6 receptor monoclonal antibody or Notch 3

  4. Contribution of Fibroblast and Mast Cell (Afferent) and Tumor (Efferent) IL-6 Effects within the Tumor Microenvironment

    OpenAIRE

    Hugo, Honor J.; Lebret, Stephanie; Tomaskovic-Crook, Eva; Ahmed, Nuzhat; Blick, Tony; Newgreen, Donald F.; Thompson, Erik W.; Ackland, M. Leigh

    2012-01-01

    Hyperactive inflammatory responses following cancer initiation have led to cancer being described as a ‘wound that never heals’. These inflammatory responses elicit signals via NFκB leading to IL-6 production, and IL-6 in turn has been shown to induce epithelial to mesenchymal transition in breast cancer cells in vitro, implicating a role for this cytokine in cancer cell invasion. We previously have shown that conditioned medium derived from cancer-associated fibroblasts induced an Epithelial...

  5. Selective, α2β1 integrin-dependent secretion of il-6 by connective tissue mast cells.

    Science.gov (United States)

    McCall-Culbreath, Karissa D; Li, Zhengzhi; Zhang, Zhonghua; Lu, Lucy X; Orear, Lynda; Zutter, Mary M

    2011-01-01

    Mast cells, critical mediators of inflammation and anaphylaxis, are poised as one of the first lines of defense against external assault. Mast cells release several classes of preformed and de novo synthesized mediators. Cross-linking of the high-affinity FcεRI results in degranulation and the release of preformed, proinflammatory mediators including histamine and serotonin. We previously demonstrated that mast cell activation by Listeria monocytogenes requires the α2β1 integrin for rapid IL-6 secretion both in vivo and in vitro. However, the mechanism of IL-6 release is unknown. Here, we demonstrate the Listeria- and α2β1 integrin-mediated mast cell release of preformed IL-6 without the concomitant release of histamine or β-hexosaminidase. α2β1 integrin-dependent mast cell activation and IL-6 release is calcium independent. In contrast, IgE cross-linking-mediated degranulation is calcium dependent and does not result in IL-6 release, demonstrating that distinct stimuli result in the release of specific mediator pools. These studies demonstrate that IL-6 is presynthesized and stored in connective tissue mast cells and can be released from mast cells in response to distinct, α2β1 integrin-dependent stimulation, providing the host with a specific innate immune response without stimulating an allergic reaction.

  6. Interleukin-6 (IL-6) production by astrocytes: autocrine regulation by IL-6 and the soluble IL-6 receptor.

    Science.gov (United States)

    Van Wagoner, N J; Oh, J W; Repovic, P; Benveniste, E N

    1999-07-01

    In the CNS, astrocytes are a major inducible source of interleukin-6 (IL-6). Although IL-6 has beneficial effects in the CNS because of its neurotrophic properties, its overexpression is generally detrimental, adding to the pathophysiology associated with CNS disorders. Many factors have been shown to induce IL-6 expression by astrocytes, particularly the cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1beta). However, the role of IL-6 in its own regulation in astrocytes has not been determined. In this study, we examined the influence of IL-6 alone or in combination with TNF-alpha or IL-1beta on IL-6 expression. IL-6 alone had no effect on IL-6 expression; however, the addition of the soluble IL-6 receptor (sIL-6R) induced IL-6 transcripts. Addition of TNF-alpha or IL-1beta plus IL-6/sIL-6R led to synergistic increases in IL-6 expression. This synergy also occurred in the absence of exogenously added IL-6, attributable to TNF-alpha- or IL-1beta-induced endogenous IL-6 protein production. IL-6 upregulation seen in the presence of TNF-alpha or IL-1beta plus IL-6/sIL-6R was transcriptional, based on nuclear run-on analysis. Experiments were extended to other IL-6 family members to determine their role in IL-6 regulation in astrocytes. Oncostatin M (OSM) induced IL-6 alone and synergized with TNF-alpha for enhanced expression. These results demonstrate that IL-6/sIL-6R and OSM play an important role in the regulation of IL-6 expression within the CNS, particularly in conjunction with the proinflammatory cytokines TNF-alpha and IL-1beta.

  7. Role of IL-6 in exercise training- and cold-induced UCP1 expression in subcutaneous white adipose tissue

    DEFF Research Database (Denmark)

    Knudsen, Jakob Grunnet; Murholm, Maria; Carey, Andrew L.;

    2014-01-01

    Expression of brown adipose tissue (BAT) associated proteins like uncoupling protein 1 (UCP1) in inguinal WAT (iWAT) has been suggested to alter iWAT metabolism. The aim of this study was to investigate the role of interleukin-6 (IL-6) in exercise training and cold exposure-induced iWAT UCP1 expr...

  8. Effects of miR-223 on expression of IL-1β and IL-6 in human gingival fibroblasts.

    Science.gov (United States)

    Matsui, Sari; Ogata, Yorimasa

    2016-01-01

    MicroRNAs (miRNAs) are small non-coding RNAs that regulate post-transcriptional expression by translational inhibition or mRNA degradation. miRNAs bind to target mRNAs through partial complementarity, and can regulate many genes. In the present study, we investigated the effects of miR-223 on the expression of inflammatory cytokines in human gingival fibroblasts (HGF). To determine the effects of miR-223 on the expressions of interleukin-1β (IL-1β) and IL-6, HGF were stimulated by IL-1β (1 ng/mL) or tumor necrosis factor-α (TNF-α; 10 ng/mL) and transfected with a miR-223 expression plasmid. Levels of mRNA for IL-1β, IL-6, inhibitor of kappa-B kinase α (IKKα) and mitogen-activated protein kinase phosphatase-5 (MKP-5) were measured by real-time PCR, and levels IL-1β, IL-6 and IKKα protein were determined by enzyme-linked immunosorbent assay and Western blotting. Expression of IL-1β and IL-6 mRNAs was induced by IL-1β and TNF-α and further increased by miR-223 overexpression. IL-1β and TNF-α induced the expression of IL-1β and IL-6 mRNAs, and this was reduced by miR-223 inhibitor. Overexpression of miR-223 decreased the levels of IKKα protein and MKP-5 mRNA in HGF. These findings indicate that miR-223 might control the inflammatory response via IKKα and MKP-5 in periodontal tissue. (J Oral Sci 58, 101-108, 2016).

  9. Expression of TNF-α and IL-6 cytokines in the choroid and sclera of hypercholesterolemic rabbits

    Directory of Open Access Journals (Sweden)

    Rogil José de Almeida Torres

    2014-06-01

    Full Text Available Objetivo: Avaliar a expressão das citocinas inflamatórias TNF-α e IL-6 na esclera e coroide de coelhos hipercolesterolêmicos. Método: Coelhos New Zealand foram organizados em dois grupos: GN recebeu ração padrão para coelhos; GH recebeu dieta rica em colesterol a 1%. Foi realizada a dosagem sérica de colesterol total, triglicerídeos, HDL colesterol, glicemia de jejum no início do experimento e no momento da eutanásia. Ao final da 4ª semana para o GN e 8ª semana para o GH foi realizada a eutanásia dos animais. Os olhos foram submetidos à análise imuno-histoquímica com os anticorpos TNF-α e IL-6. Resultados: O GH manifestou significativo aumento do colesterol total e triglicerídeos em relação ao GN (p<0,001. Houve significativo aumento da expressão da TNF-α (p<0,001 e da IL-6 (p=0,002 na coroide e esclera dos animais do GH em relação ao GN. Conclusão: Este estudo demonstra que a dieta hipercolesterolêmica induz ao aumento da expressão das citocinas TNF-α e IL-6 na coroide e esclera de coelhos.

  10. A novel TLR4-mediated signaling pathway leading to IL-6 responses in human bladder epithelial cells.

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    Jeongmin Song

    2007-04-01

    Full Text Available The vigorous cytokine response of immune cells to Gram-negative bacteria is primarily mediated by a recognition molecule, Toll-like receptor 4 (TLR4, which recognizes lipopolysaccharide (LPS and initiates a series of intracellular NF-kappaB-associated signaling events. Recently, bladder epithelial cells (BECs were reported to express TLR4 and to evoke a vigorous cytokine response upon exposure to LPS. We examined intracellular signaling events in human BECs leading to the production of IL-6, a major urinary cytokine, following activation by Escherichia coli and isolated LPS. We observed that in addition to the classical NF-kappaB-associated pathway, TLR4 triggers a distinct and more rapid signaling response involving, sequentially, Ca(2+, adenylyl cyclase 3-generated cAMP, and a transcriptional factor, cAMP response element-binding protein. This capacity of BECs to mobilize secondary messengers and evoke a more rapid IL-6 response might be critical in their role as first responders to microbial challenge in the urinary tract.

  11. IL-6 Antibody and RGD Peptide Conjugated Poly(amidoamine) Dendrimer for Targeted Drug Delivery of HeLa Cells.

    Science.gov (United States)

    Mekuria, Shewaye Lakew; Debele, Tilahun Ayane; Chou, Hsiao-Ying; Tsai, Hsieh-Chih

    2016-01-14

    In this study, PAMAM dendrimer (G4.5) was conjugated with two targeting moieties, IL-6 antibody and RGD peptide (G4.5-IL6 and G4.5-RGD conjugates). Doxorubicin anticancer drug was physically loaded onto G4.5-IL6 and G4.5-RGD with the encapsulation efficiency of 51.3 and 30.1% respectively. The cellular internalization and uptake efficiency of G4.5-IL6/DOX and G4.5-RGD/DOX complexes was observed and compared by confocal microscopy and flow cytometry using HeLa cells, respectively. The lower IC50 value of G4.5-IL6/DOX in comparison to G4.5-RGD/DOX is indication that higher drug loading and faster drug release rate corresponded with greater cytotoxicity. The cytotoxic effect was further verified by increment in late apoptotic/necrotic cells due to delivery of drug through receptor-mediated endocytosis. On the basis of these results, G4.5-IL6 is a better suited carrier for targeted drug delivery of DOX to cervical cancer cells.

  12. Expression of hepcidin at the choroid plexus in normal aging rats is associated with IL-6/Stat3 signaling pathway.

    Science.gov (United States)

    Liu, Chong-Bin; Wang, Rui; Dong, Miao-Wu; Gao, Xi-Ren; Yu, Feng

    2014-12-25

    Accumulating evidence has revealed that brain iron concentrations increase with aging, and the choroid plexus (CP) may be at the basis of iron-mediated toxicity and the increase in inflammation and oxidative stress that occurs with aging. The mechanism involves not only hepcidin, the key hormone in iron metabolism, but also iron-related proteins and signaling-transduction molecules, such as IL-6 and signal transducer and activator of transcription 3 (Stat3). The aim of the present study was to investigate the correlation between the IL-6/Stat3 signaling pathway and hepcidin at the CP in normal aging. Quantitative real time PCR and Western blot were used to determine the alterations in specific mRNA and corresponding protein changes at the CP at ages of 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33 and 36 months in Brown-Norway/Fischer (B-N/F) rats. The results demonstrated that hepcidin mRNA level at the CP kept stable in young rats (from 3 to 18 months), and increased with aging (from 21 to 36 months). The alterations of IL-6/p-Stat3 mRNA and protein expressions in normal aging were in accordance with that of hepcidin mRNA. Our data suggest that IL-6 may regulate hepcidin expression at the CP, upon interaction with the cognate cellular receptor, and through the Stat3 signaling transduction pathway.

  13. Cytokines TNF-α, IL-6, IL-17F, and IL-4 Differentially Affect Osteogenic Differentiation of Human Adipose Stem Cells

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    Angela P. Bastidas-Coral

    2016-01-01

    Full Text Available During the initial stages of bone repair, proinflammatory cytokines are released within the injury site, quickly followed by a shift to anti-inflammatory cytokines. The effect of pro- and anti-inflammatory cytokines on osteogenic differentiation of mesenchymal stem cells is controversial. Here, we investigated the effect of the proinflammatory cytokines TNF-α, IL-6, IL-8, and IL-17F and the anti-inflammatory cytokine IL-4 on proliferation and osteogenic differentiation of human adipose stem cells (hASCs. hASCs were treated with TNF-α, IL-6, IL-8, IL-17F, or IL-4 (10 ng/mL for 72 h mimicking bone repair. TNF-α reduced collagen type I gene expression but increased hASC proliferation and ALP activity. IL-6 also strongly enhanced ALP activity (18-fold, as well as bone nodule formation by hASCs. IL-8 did not affect proliferation or osteogenic gene expression but reduced bone nodule formation. IL-17F decreased hASC proliferation but enhanced ALP activity. IL-4 enhanced osteocalcin gene expression and ALP activity but reduced RUNX2 gene expression and bone nodule formation. In conclusion, all cytokines studied have both enhancing and reducing effects on osteogenic differentiation of hASCs, even when applied for 72 h only. Some cytokines, specifically IL-6, may be suitable to induce osteogenic differentiation of mesenchymal stem cells as a strategy for enhancing bone repair.

  14. Role of IL-6 in exercise training- and cold-induced UCP1 expression in subcutaneous white adipose tissue

    DEFF Research Database (Denmark)

    Knudsen, Jakob Grunnet; Murholm, Maria; Carey, Andrew L.

    2014-01-01

    Expression of brown adipose tissue (BAT) associated proteins like uncoupling protein 1 (UCP1) in inguinal WAT (iWAT) has been suggested to alter iWAT metabolism. The aim of this study was to investigate the role of interleukin-6 (IL-6) in exercise training and cold exposure-induced iWAT UCP1...... expression. The effect of daily intraperitoneal injections of IL-6 (3 ng/g) in C57BL/6 mice for 7 days on iWAT UCP1 expression was examined. In addition, the expression of UCP1 in iWAT was determined in response to 3 days of cold exposure (4°C) and 5 weeks of exercise training in wild type (WT) and whole...

  15. Polarized secretion of interleukin (IL-6 and IL-8 by human airway epithelia 16HBE14o- cells in response to cationic polypeptide challenge.

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    Alison Wai-ming Chow

    Full Text Available BACKGROUND: The airway epithelium participates in asthmatic inflammation in many ways. Target cells of the epithelium can respond to a variety of inflammatory mediators and cytokines. Damage to the surface epithelium occurs following the secretion of eosinophil-derived, highly toxic cationic proteins. Moreover, the surface epithelium itself is responsible for the synthesis and release of cytokines that cause the selective recruitment, retention, and accumulation of various inflammatory cells. To mimic the damage seen during asthmatic inflammation, the bronchial epithelium can be challenged with highly charged cationic polypeptides such as poly-L-arginine. METHODOLOGY/PRINCIPAL FINDINGS: In this study, human bronchial epithelial cells, 16HBE14o- cells, were "chemically injured" by exposing them to poly-l-arginine as a surrogate of the eosinophil cationic protein. Cytokine antibody array data showed that seven inflammatory mediators were elevated out of the 40 tested, including marked elevation in interleukin (IL-6 and IL-8 secretion. IL-6 and IL-8 mRNA expression levels were elevated as measured with real-time PCR. Cell culture supernatants from apical and basolateral compartments were collected, and the IL-6 and IL-8 production was quantified with ELISA. IL-6 and IL-8 secretion by 16HBE14o- epithelia into the apical compartment was significantly higher than that from the basolateral compartment. Using specific inhibitors, the production of IL-6 and IL-8 was found to be dependent on p38 MAPK, ERK1/2 MAPK, and NF-kappaB pathways. CONCLUSIONS/SIGNIFICANCE: The results clearly demonstrate that damage to the bronchial epithelia by poly-L-arginine stimulates polarized IL-6 and IL-8 secretion. This apically directed secretion of cytokines may play an important role in orchestrating epithelial cell responses to inflammation.

  16. Gene expression profile favoring phenotypic reversion:a clue for mechanism of tumor suppression by NF-IL6 3'UTR

    Institute of Scientific and Technical Information of China (English)

    DING GAN LIU; QIU HONG JIANG; YUN YI WEI; LI SUN; BEI BEI FU; FU KUN ZHAO; QIONG ZHOU

    2003-01-01

    Transfection of cDNA in 3'untranslated region of human nuclear factor for interleukin-6(NF-IL6 3'UTR)induced tumor suppression in a human hepatoma cell line.cDNA array analysis was used to reveal changes in gene expression profile leading to tumor suppression The results indicate that this suppression was not due to activation of dsRNA-dependent protein kinase,nor to inactivation ofoncogenes; rather,all the changes in expression of known genes,induced by NF-IL6 3'UTR cDNA may be ascribed to the suppression of cellular malignancy.Therefore,our results imply that this 3'untranslated region may have played role of a regulator of gene expression profile.

  17. Cutting edge: trans-signaling via the soluble IL-6R abrogates the induction of FoxP3 in naive CD4+CD25 T cells.

    Science.gov (United States)

    Dominitzki, Sabine; Fantini, Massimo C; Neufert, Clemens; Nikolaev, Alexei; Galle, Peter R; Scheller, Jürgen; Monteleone, Giovanni; Rose-John, Stefan; Neurath, Markus F; Becker, Christoph

    2007-08-15

    Chronic inflammatory diseases may develop when regulatory T cells (Tregs) fail to control the balance between tolerance and immunity. Alternatively, activated immune cells might prevent the induction or activation of Tregs in such diseases. In this study, we demonstrate that trans-signaling into T cells via the soluble IL-6 receptor completely abrogates the de novo induction of adaptive Tregs. Mechanistically, IL-6 trans-signaling augmented the expression of the TGF-beta signaling inhibitor SMAD7. Consequently, SMAD7 overexpression in T cells using newly created transgenic mice rendered CD4(+)CD25(-) T cells resistant to the induction of FoxP3. Finally, IL-6 trans-signaling inhibited Treg-mediated suppression in a murine model of colitis. In summary, IL-6 trans-signaling into T cells emerges as a key pathway for blockade of the development of adaptive Tregs and thus may play a pivotal role in shifting the balance between effector and regulatory T cell numbers in chronic inflammatory and autoimmune diseases.

  18. The effect of 17beta-estradiol on IL-6 secretion and NF-kappaB DNA-binding activity in human retinal pigment epithelial cells.

    Science.gov (United States)

    Paimela, Tuomas; Ryhänen, Tuomas; Mannermaa, Eliisa; Ojala, Johanna; Kalesnykas, Giedrius; Salminen, Antero; Kaarniranta, Kai

    2007-06-15

    Toll-like receptors (TLRs) and inflammatory cascades participate in the pathology of age-related macular degeneration (AMD). The effect of estrogens on the development of AMD is poorly understood, although many studies indicate that these compounds can modulate inflammatory responses. In this study, we investigated the regulatory role of TLR agonists and 17beta-estradiol (E(2)) on IL-6 expression and NF-kappaB DNA-binding activity in human retinal pigment epithelial cells (ARPE-19). The inflammatory response of ARPE-19 cells to various TLR agonists, e.g. Pam, zymosan, flagellin, SLTA and lipopolysaccharide (LPS) exposures were examined via the secretion of IL-6 cytokine as analyzed by ELISA. In addition, the IL-6 responses to the estrogen-receptor agonist, E(2), and to the estrogen-receptor antagonist ICI 182.780 as well as to the NF-kappaB inhibitor helenalin were compared. The DNA-binding activity of NF-kappaB transcription factor of nuclear cell extracts was analyzed by the gel mobility shift assay (EMSA). TLR4 gene expression was studied by quantitave PCR. The TLR4 agonist, LPS, caused a clear IL-6 response that was attenuated by E(2) in ARPE-19-cells. The anti-inflammatory properties of E(2) were mediated through estrogen receptors and were associated with decreased NF-kappaB DNA-binding activity. The level of TLR4 gene expression was not affected by LPS exposure. Our results indicate that IL-6 expression is regulated through NF-kappaB transcription factor and stereoid-receptor signalling pathways in ARPE-19 cells.

  19. IL-6 triggers IL-21 production by human CD4+ T cells to drive STAT3-dependent plasma cell differentiation in B cells.

    Science.gov (United States)

    Diehl, Sean A; Schmidlin, Heike; Nagasawa, Maho; Blom, Bianca; Spits, Hergen

    2012-09-01

    Interleukin (IL)-21-producing CD4(+)T cells are central to humoral immunity. Deciphering the signals that induce IL-21 production in CD4(+) T cells and those triggered by IL-21 in B cells are, therefore, of importance for understanding the generation of antibody (Ab) responses. Here, we show that IL-6 increased IL-21 production by human CD4(+) T cells, particularly in those that express the transcriptional regulator B cell lymphoma (BCL)6, which is required in mice for the development of C-X-C chemokine receptor type 5 (CXCR5(+)) IL-21-producing T follicular helper (T(FH)) cells. However, retroviral overexpression of BCL6 in total human CD4(+) T cells only transiently increased CXCR5, the canonical T(FH)-defining surface marker. We show here that IL-21 was required for the induction of Ab production by IL-6. In IL-21-treated B cells, signal transducer and activator of transcription (STAT)3 was required for optimal immunoglobulin production and upregulation of PR domain containing 1 (PRDM1(+)), the master plasma cell factor. These results, therefore, demonstrate the critical importance of STAT3 activation in B cells during IL-21-driven humoral immunity and suggest that BCL6 expression, although not sufficient, may serve as a platform for the acquisition of a T(FH)-like phenotype by human CD4(+) T cells.

  20. Effect of increased occlusal force on the expression of IL-6 mRNA in the rat periodontium%牙合力增强对大鼠牙周组织IL-6 mRNA表达影响的研究

    Institute of Scientific and Technical Information of China (English)

    袁林; 周伟东; 赵云凤

    2001-01-01

    目的:检测不同牙合力状态下,大鼠牙周膜成纤维细胞和牙槽骨成骨细胞中IL-6 mRNA的动态表达,探讨IL-6在牙周组织改建过程中的分子机制。方法:选用Wistar大鼠建立正常牙合力、牙合力增强的动物模型,采用原位杂交的方法,观察成纤维细胞和成骨细胞中IL-6 mRNA表达的动态变化。结果:牙合力增强诱导成纤维细胞和成骨细胞中IL-6 mRNA表达较正常牙合力时明显增强。结论:牙合力增强,促使牙周组织中的成纤维细胞和成骨细胞产生IL-6 mRNA明显增多,且出现一定的规律性变化,提示IL-6在牙合力影响牙周组织改建的过程中起着重要的调节作用。%AIM: To study the expression of IL-6 mRNA in rat periodontal ligament cells (PDLC) and osteoblasts under different occlusal forces, in order to explain the molecular mechanism of periodontium remodeling. METHODS: A rat model of different occlusal force was established by extracting the left maxillary molars, so that the left mandibular molar area was used as the bite force lost model and the right mandibular molar area as the bite force increased model. The untreated rats' mandibular molar area used as normal bite force model. The prepared tissue specimens were processed to study the expression of IL-6 mRNA in PDLC and osteoblasts with in situ hybridization technique. RESULTS: In the group of increased occlusal force the expression of IL-6 mRNA in PDLC and osteoblasts enhanced apparently than the group of normal occlusal force. CONCLUSION: The result of the increased occlusal force enhanced the expression of IL-6 mRNA in PDLC and osteoblasts suggested that the IL-6 may play important roles in the process of periodontium remodeling initiated by different occlusal force.

  1. Metallothionein treatment reduces proinflammatory cytokines IL-6 and TNF-alpha and apoptotic cell death during experimental autoimmune encephalomyelitis (EAE).

    Science.gov (United States)

    Penkowa, M; Hidalgo, J

    2001-07-01

    Experimental autoimmune encephalomyelitis (EAE) is an animal model for the human autoimmune disease multiple sclerosis (MS). Proinflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) are considered important for induction and pathogenesis of EAE/MS disease, which is characterized by significant inflammation and neuroglial damage. We have recently shown that the exogenous administration of the antioxidant protein zinc-metallothionein-II (Zn-MT-II) significantly decreased the clinical symptoms, mortality, and leukocyte infiltration of the CNS during EAE. However, it is not known how EAE progression is regulated nor how cytokine production and cell death can be reduced. We herewith demonstrate that treatment with Zn-MT-II significantly decreased the CNS expression of IL-6 and TNF-alpha during EAE. Zn-MT-II treatment could also significantly reduce apoptotic cell death of neurons and oligodendrocytes during EAE, as judged by using TUNEL and immunoreactivity for cytochrome c and caspases 1 and 3. In contrast, the number of apoptotic lymphocytes and macrophages was less affected by Zn-MT-II treatment. The Zn-MT-II-induced decrease in proinflammatory cytokines and apoptosis during EAE could contribute to the reported diminution of clinical symptoms and mortality in EAE-immunized rats receiving Zn-MT-II treatment. Our results demonstrate that MT-II reduces the CNS expression of proinflammatory cytokines and the number of apoptotic neurons during EAE in vivo and that MT-II might be a potentially useful factor for treatment of EAE/MS.

  2. Baicalin downregulates Porphyromonas gingivalis lipopolysaccharide-upregulated IL-6 and IL-8 expression in human oral keratinocytes by negative regulation of TLR signaling.

    Directory of Open Access Journals (Sweden)

    Wei Luo

    Full Text Available Periodontal (gum disease is one of the main global oral health burdens and severe periodontal disease (periodontitis is a leading cause of tooth loss in adults globally. It also increases the risk of cardiovascular disease and diabetes mellitus. Porphyromonas gingivalis lipopolysaccharide (LPS is a key virulent attribute that significantly contributes to periodontal pathogenesis. Baicalin is a flavonoid from Scutellaria radix, an herb commonly used in traditional Chinese medicine for treating inflammatory diseases. The present study examined the modulatory effect of baicalin on P. gingivalis LPS-induced expression of IL-6 and IL-8 in human oral keratinocytes (HOKs. Cells were pre-treated with baicalin (0-80 µM for 24 h, and subsequently treated with P. gingivalis LPS at 10 µg/ml with or without baicalin for 3 h. IL-6 and IL-8 transcripts and proteins were detected by real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The expression of nuclear factor-κB (NF-κB, p38 mitogen-activated protein kinase (MAPK and c-Jun N-terminal kinase (JNK proteins was analyzed by western blot. A panel of genes related to toll-like receptor (TLR signaling was examined by PCR array. We found that baicalin significantly downregulated P. gingivalis LPS-stimulated expression of IL-6 and IL-8, and inhibited P. gingivalis LPS-activated NF-κB, p38 MAPK and JNK. Furthermore, baicalin markedly downregulated P. gingivalis LPS-induced expression of genes associated with TLR signaling. In conclusion, the present study shows that baicalin may significantly downregulate P. gingivalis LPS-upregulated expression of IL-6 and IL-8 in HOKs via negative regulation of TLR signaling.

  3. MicroRNA let-7a ameliorates con A-induced hepatitis by inhibiting IL-6-dependent Th17 cell differentiation.

    Science.gov (United States)

    Zhang, Yingying; Wang, Xiangmin; Zhong, Min; Zhang, Mengying; Suo, Qifeng; Lv, Kun

    2013-04-01

    In this study we explored the effects of microRNA let-7a on Con A-induced hepatitis and its possible mechanisms involved. We demonstrated that IL-6 and IL-17 expression were significantly upregulated in the liver following Con A treatment and IL-6 level was correlated with the IL-17 expression. To explore whether let-7a may have therapeutic effect on Con A-induced hepatitis, mice was infected with a lentiviral vector containing the let-7a sequence 7 days before Con A treatment. Significantly reduced Th17 cells and remarkably increased regulatory T cells frequency in the liver tissue were found as compared to control mice. It was accompanied by a significant decreased level of inflammatory cytokines as TNF-α, IL-6 and IFN-γ in the serum, and an decreased level of Th17 lineage-specific genes such as Il17a, Il17f, Il21 and Il23r. let-7a was further found to inhibit Th17 differentiation by downregulating IL-6 secretion. It may represent as a novel therapeutic strategy in treating immune-mediated inflammatory hepatitis.

  4. Autophagy pathway is required for IL-6 induced neuroendocrine differentiation and chemoresistance of prostate cancer LNCaP cells.

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    Pei-Ching Chang

    Full Text Available Prostate cancer (PCa cells undergoing neuroendocrine differentiation (NED are clinically relevant to the development of relapsed castration-resistant PCa. Increasing evidences show that autophagy involves in the development of neuroendocrine (NE tumors, including PCa. To clarify the effect of autophagy on NED, androgen-sensitive PCa LNCaP cells were examined. Treatment of LNCaP cells with IL-6 resulted in an induction of autophagy. In the absence of androgen, IL-6 caused an even stronger activation of autophagy. Similar result was identified in NED induction. Inhibition of autophagy with chloroquine (CQ markedly decreased NED. This observation was confirmed by beclin1 and Atg5 silencing experiments. Further supporting the role of autophagy in NED, we found that LC3 was up-regulated in PCa tissue that had relapsed after androgen-deprivation therapy when compared with their primary tumor counterpart. LC3 staining in relapsed PCa tissue showed punctate pattern similar to the staining of chromogranin A (CgA, a marker for NED cells. Moreover, autophagy inhibition induced the apoptosis of IL-6 induced NE differentiated PCa cells. Consistently, inhibition of autophagy by knockdown of beclin1 or Atg5 sensitized NE differentiated LNCaP cells to etoposide, a chemotherapy drug. To identify the mechanisms, phosphorylation of IL-6 downstream targets was analyzed. An increase in phospho-AMPK and a decrease in phospho-mTOR were found, which implies that IL-6 regulates autophagy through the AMPK/mTOR pathway. Most important to this study is the discovery of REST, a neuronal gene-specific transcriptional repressor that is involved in autophagy activation. REST was down-regulated in IL-6 treatment. Knockdown experiments suggest that REST is critical to NED and autophagy activation by IL-6. Together, our studies imply that autophagy is involved in PCa progression and plays a cytoprotective role when NED is induced in PCa cells by IL-6 treatment. These results

  5. Autophagy Pathway Is Required for IL-6 Induced Neuroendocrine Differentiation and Chemoresistance of Prostate Cancer LNCaP Cells

    Science.gov (United States)

    Chang, Yi-Ting; Chu, Cheng-Ying; Lee, Chin-Ling; Hsu, Hung-Wei; Zhou, Tyng-An; Wu, Zhaoju; Kim, Randie H.; Desai, Sonal J.; Liu, Shangqin; Kung, Hsing-Jien

    2014-01-01

    Prostate cancer (PCa) cells undergoing neuroendocrine differentiation (NED) are clinically relevant to the development of relapsed castration-resistant PCa. Increasing evidences show that autophagy involves in the development of neuroendocrine (NE) tumors, including PCa. To clarify the effect of autophagy on NED, androgen-sensitive PCa LNCaP cells were examined. Treatment of LNCaP cells with IL-6 resulted in an induction of autophagy. In the absence of androgen, IL-6 caused an even stronger activation of autophagy. Similar result was identified in NED induction. Inhibition of autophagy with chloroquine (CQ) markedly decreased NED. This observation was confirmed by beclin1 and Atg5 silencing experiments. Further supporting the role of autophagy in NED, we found that LC3 was up-regulated in PCa tissue that had relapsed after androgen-deprivation therapy when compared with their primary tumor counterpart. LC3 staining in relapsed PCa tissue showed punctate pattern similar to the staining of chromogranin A (CgA), a marker for NED cells. Moreover, autophagy inhibition induced the apoptosis of IL-6 induced NE differentiated PCa cells. Consistently, inhibition of autophagy by knockdown of beclin1 or Atg5 sensitized NE differentiated LNCaP cells to etoposide, a chemotherapy drug. To identify the mechanisms, phosphorylation of IL-6 downstream targets was analyzed. An increase in phospho-AMPK and a decrease in phospho-mTOR were found, which implies that IL-6 regulates autophagy through the AMPK/mTOR pathway. Most important to this study is the discovery of REST, a neuronal gene-specific transcriptional repressor that is involved in autophagy activation. REST was down-regulated in IL-6 treatment. Knockdown experiments suggest that REST is critical to NED and autophagy activation by IL-6. Together, our studies imply that autophagy is involved in PCa progression and plays a cytoprotective role when NED is induced in PCa cells by IL-6 treatment. These results reveal the

  6. Vaccination with p53 peptide-pulsed dendritic cells is associated with disease stabilization in patients with p53 expressing advanced breast cancer; monitoring of serum YKL-40 and IL-6 as response biomarkers

    DEFF Research Database (Denmark)

    Svane, Inge Marie; Pedersen, Anders E; Johansen, Julia S;

    2007-01-01

    p53 Mutations are found in up to 30% of breast cancers and peptides derived from over-expressed p53 protein are presented by class I HLA molecules and may act as tumor-associated epitopes in cancer vaccines. A dendritic cell (DC) based p53 targeting vaccine was analyzed in HLA-A2+ patients...... with progressive advanced breast cancer. DCs were loaded with 3 wild-type and 3 P2 anchor modified HLA-A2 binding p53 peptides. Patients received up to 10 sc vaccinations with 5 x 10(6) p53-peptide loaded DC with 1-2 weeks interval. Concomitantly, 6 MIU/m(2) interleukine-2 was administered sc. Results from a phase...... II trial including 26 patients with verified progressive breast cancer are presented. Seven patients discontinued treatment after only 2-3 vaccination weeks due to rapid disease progression or death. Nineteen patients were available for first evaluation after 6 vaccinations; 8/19 evaluable patients...

  7. A study on the effect of IL-6 gene polymorphism on the prognosis of non-small-cell lung cancer

    Directory of Open Access Journals (Sweden)

    Jia W

    2015-09-01

    Full Text Available Wei Jia, Guang-He Fei, Jie-Gui Hu, Xian-Wei Hu Pulmonary Department, First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China Background: Lung cancer is one of the most commonly diagnosed clinical diseases. IL-6 is a multifunctional cytokine that is related to chemotactic factors and tumor biological regulation. -174G/C polymorphism in the promoter region of the IL-6 gene single-nucleotide polymorphism is the -174 position change from G to C. However, the relationship between the IL-6 gene polymorphism and prognosis of lung cancer is elusive. Therefore, the aim of this study was to evaluate the effect of -174G/C polymorphism on the prognosis of patients with non-small-cell lung cancer (NSCLC.Methods: DNA was extracted from the peripheral blood of 434 cases diagnosed with NSCLC by cytologic or histologic examination. Polymerase chain reaction–restriction fragment length polymorphism (NlaIII was used to detect the genotype of -174G/C. Based on the functional activity of the IL-6 gene polymorphism, genotypes were divided into G vector (CG/GG (high yield and CC genotype (low yield. Prognosis of patients was analyzed and independent risk factors evaluated. A quantitative analysis of the degree of pain after diagnosis was performed to evaluate the correlations between gene polymorphisms and the degree of pain and use of analgesics.Results: Survival analysis showed that survival of the patients carrying the G allele (CG/GG was significantly lower than that of patients with CC genotype (42.31 versus 62.79 months; P=0.032. The IL-6 gene promoter region revealed the presence of polymorphic variants, which may be associated with changes in the gene transcription process that affect the level of serum cytokines. IL-6 -174G/C gene polymorphism is associated with a significant morphine equivalent daily dose (IL-6 GG, 69.61; GC, 73.17; CC, 181.67; P=0.004. Homozygous IL-6 -174C/C genotype carriers required higher doses of

  8. Growth regulation of simian and human AIDS-related non-Hodgkin's lymphoma cell lines by TGF-β1 and IL-6

    Directory of Open Access Journals (Sweden)

    Levy Laura S

    2007-02-01

    Full Text Available Abstract Background AIDS-related non-Hodgkin's lymphoma (AIDS-NHL is the second most frequent cancer associated with AIDS, and is a frequent cause of death in HIV-infected individuals. Experimental analysis of AIDS-NHL has been facilitated by the availability of an excellent animal model, i.e., simian Acquired Immunodeficiency Syndrome (SAIDS in the rhesus macaque consequent to infection with simian immunodeficiency virus. A recent study of SAIDS-NHL demonstrated a lymphoma-derived cell line to be sensitive to the growth inhibitory effects of the ubiquitous cytokine, transforming growth factor-beta (TGF-beta. The authors concluded that TGF-beta acts as a negative growth regulator of the lymphoma-derived cell line and, potentially, as an inhibitory factor in the regulatory network of AIDS-related lymphomagenesis. The present study was conducted to assess whether other SAIDS-NHL and AIDS-NHL cell lines are similarly sensitive to the growth inhibitory effects of TGF-beta, and to test the hypothesis that interleukin-6 (IL-6 may represent a counteracting positive influence in their growth regulation. Methods Growth stimulation or inhibition in response to cytokine treatment was quantified using trypan blue exclusion or colorimetric MTT assay. Intracellular flow cytometry was used to analyze the activation of signaling pathways and to examine the expression of anti-apoptotic proteins and distinguishing hallmarks of AIDS-NHL subclass. Apoptosis was quantified by flow cytometric analysis of cell populations with sub-G1 DNA content and by measuring activated caspase-3. Results Results confirmed the sensitivity of LCL8664, an immunoblastic SAIDS-NHL cell line, to TGF-beta1-mediated growth inhibition, and further demonstrated the partial rescue by simultaneous treatment with IL-6. IL-6 was shown to activate STAT3, even in the presence of TGF-beta1, and thereby to activate proliferative and anti-apoptotic pathways. By comparison, human AIDS-NHL cell lines

  9. Functional IL6R 358Ala allele impairs classical IL-6 receptor signaling and influences risk of diverse inflammatory diseases.

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    Ricardo C Ferreira

    2013-04-01

    Full Text Available Inflammation, which is directly regulated by interleukin-6 (IL-6 signaling, is implicated in the etiology of several chronic diseases. Although a common, non-synonymous variant in the IL-6 receptor gene (IL6R Asp358Ala; rs2228145 A>C is associated with the risk of several common diseases, with the 358Ala allele conferring protection from coronary heart disease (CHD, rheumatoid arthritis (RA, atrial fibrillation (AF, abdominal aortic aneurysm (AAA, and increased susceptibility to asthma, the variant's effect on IL-6 signaling is not known. Here we provide evidence for the association of this non-synonymous variant with the risk of type 1 diabetes (T1D in two independent populations and confirm that rs2228145 is the major determinant of the concentration of circulating soluble IL-6R (sIL-6R levels (34.6% increase in sIL-6R per copy of the minor allele 358Ala; rs2228145 [C]. To further investigate the molecular mechanism of this variant, we analyzed expression of IL-6R in peripheral blood mononuclear cells (PBMCs in 128 volunteers from the Cambridge BioResource. We demonstrate that, although 358Ala increases transcription of the soluble IL6R isoform (P = 8.3×10⁻²² and not the membrane-bound isoform, 358Ala reduces surface expression of IL-6R on CD4+ T cells and monocytes (up to 28% reduction per allele; P≤5.6×10⁻²². Importantly, reduced expression of membrane-bound IL-6R resulted in impaired IL-6 responsiveness, as measured by decreased phosphorylation of the transcription factors STAT3 and STAT1 following stimulation with IL-6 (P≤5.2×10⁻⁷. Our findings elucidate the regulation of IL-6 signaling by IL-6R, which is causally relevant to several complex diseases, identify mechanisms for new approaches to target the IL-6/IL-6R axis, and anticipate differences in treatment response to IL-6 therapies based on this common IL6R variant.

  10. Paracrine SDF-1α signaling mediates the effects of PSCs on GEM chemoresistance through an IL-6 autocrine loop in pancreatic cancer cells.

    Science.gov (United States)

    Zhang, Hui; Wu, Huanwen; Guan, Jian; Wang, Li; Ren, Xinyu; Shi, Xiaohua; Liang, Zhiyong; Liu, Tonghua

    2015-02-20

    Pancreatic cancer exhibits the poorest prognosis among all tumors and is characterized by high resistance to the currently available chemotherapeutic agents. Our previous studies have suggested that stromal components could promote the chemoresistance of pancreatic cancer cells (PCCs). Here, we explored the roles of pancreatic stellate cells (PSCs) and the SDF-1α/CXCR4 axis in pancreatic cancer chemoresitance. Our results showed that primary PSCs typically expressed SDF-1α, whereas its receptor CXCR4 was highly expressed in PCCs. PSC-conditioned medium (PSC-CM) inhibited Gemcitabine (GEM)-induced cytotoxicity and apoptosis in the human PCC line Panc-1, which was antagonized by an SDF-1α neutralizing Ab. Recombinant human SDF-1α (rhSDF-1α) increased IL-6 expression and secretion in Panc-1 cells in a time and dose-dependent manner, and this effect was suppressed by the CXCR4 antagonist AMD3100. rhSDF-1α protected Panc-1 cells from GEM-induced apoptosis, and the protective effect was significantly reduced by blocking IL-6 using a neutralizing antibody. Moreover, rhSDF-1α increased FAK, ERK1/2, AKT and P38 phosphorylation in Panc-1 cells, and either FAK or ERK1/2 inhibition suppressed SDF-1α-upregulated IL-6 expression. SDF-1α-induced AKT activation was almost completely blocked by FAK inhibition. In conclusion, we demonstrate for the first time that PSCs promote the chemoresistance of PCCs to GEM, and this effect is mediated by paracrine SDF-1α/CXCR4 signaling-induced activation of the intracellular FAK-AKT and ERK1/2 signaling pathways and a subsequent IL-6 autocrine loop in PCCs. Our findings indicate that blocking the PSC-PCC interaction by inhibiting SDF-1α/CXCR4 signaling may be a promising therapeutic strategy for overcoming chemoresistance in pancreatic cancer.

  11. 血管平滑肌细胞坏死释放IL-1β及其对IL-6和细胞增殖的影响%Effect of IL-1βReleased by Necrotic Cells on IL-6 and Proliferation of Vascular Smooth Muscle Cells

    Institute of Scientific and Technical Information of China (English)

    孟亮; 杨帆; 王文刚; 李立杰; 李敬; 刘丽楠; 韩冰; 贾璇

    2013-01-01

    [目的]观察坏死的血管平滑肌细胞对周围正常细胞IL-6表达和增殖能力的影响,同时探讨其可能的作用机制。[方法]采用无血清无糖低氧条件制备血管平滑肌细胞坏死模型,收集坏死细胞培养上清液干预正常细胞。实验设置无血清低糖DM EM培养的对照组(control组)、坏死上清干预组(NCS组)、坏死上清与IL-1拮抗剂联合干预组(NCS+IL-IRA组)、坏死上清与IL-6拮抗剂联合干预组(NCS+ IL-6 RA组)、IL-1β干预组(IL-1β组)以及 IL-6干预组(IL-6组)。CCK-8和BrdU ELISA 方法检测细胞增殖能力变化;ELISA方法和RT-PCR方法检测各组细胞培养上清液中IL-6分泌及细胞中IL-6 mRNA表达情况;Western blot方法检测各组细胞p21Ras、ERK、p-ERK蛋白的表达。[结果]与对照组相比,NCS组和IL-1β组处理下血管平滑肌细胞IL-6表达有所升高( P <0.05),NCS组、IL-1β组和IL-6组细胞增殖能力存在显著性增加( P <0.05),同时,p21Ras和p-ERK的表达也存在增加趋势,而NCS+IL-1 RA组和NCS+IL-6 RA组细胞增殖能力较NCS组及IL-1β组、IL-6组细胞增殖能力有所下降( P <0.05),p21Ras和p-ERK的表达也相应有所降低。[结论]坏死的血管平滑肌细胞可能通过释放 IL-1β促进了周围正常细胞 IL-6的表达,并通过Ras/ERK/C/EBP信号通路促进细胞增殖。%[Objective] To observe the effect of necrotic vascular smooth muscle cell (VSMC) on the ex-pression of IL-6 and the proliferation of surrounding normal cells ,and to explore the possible mechanism .[Methods] VSMC necrosis model was established under hypoxia and serum-and glucose-deprived condition . The necrotic cell supernatant(NCS) was collected to intervene normal cells .There were non-serum and low-glucose DMEM control group ,NCS group ,NCS combined with IL-1 antagonist group ,NCS combined with IL-6 antagonist group ,IL-1βgroup and IL-6 group .CCK-8

  12. IL-17 induces autoantibody overproduction and peripheral blood mononuclear cell overexpression of IL-6 in lupus nephritis patients

    Institute of Scientific and Technical Information of China (English)

    董光富; 叶任高; 史伟; 刘双信; 汪涛; 阳晓; 杨念生; 余学清

    2003-01-01

    Objective To investigate the role of IL-17 in the overproduction of autoantibodies and IL-6 overexpression by peripheral blood mononuclear cells (PBMC) of lupus nephritis (LN) patients.Methods Fifteen consecutively hospitalized LN patients were selected as subjects and 15 healthy adults as normal controls. PBMC were obtained by Ficoll density gradient centrifugation. IgG, anti-dsDNA antibody and IL-6 protein levels were assessed using enzyme-linked immunosorbent assays (ELISA) on the supernatant of cultured PBMC of LN patients or normal controls. IL-6 mRNA levels in PBMC were measured using reverse transcription-polymerase chain reaction (RT-PCR).Results In medium culture, IgG, anti-dsDNA and IL-6 protein levels of the supernatant of PBMC from LN patients were significantly higher than those from normal controls (1492.1±73.2 ng/ml vs 636.7±51.9 ng/ml for IgG, 306.6±53.7 IU/ml vs 95.8±11.6 IU/ml for anti-dsDNA and 50.92±15.92 ng/ml vs 1.77±0.73 ng/ml for IL-6, all P<0.001). In LN patients, IgG, anti-dsDNA and IL-6 protein levels were higher in the supernatants of PBMC in the IL-17-stimulated culture than the medium culture, but in normal controls, only the IL-6 protein levels were significantly higher. The increase in IgG, anti-dsDNA and IL-6 protein levels induced by IL-17 was dose-dependent and could be completely blocked by IL-17 monoclonal antibody mIgG28 and partially blocked by dexamethasone. Similarly, IL-6 mRNA overexpression of PBMC in LN patients or normal controls induced by IL-17 was both dose- and time-dependent. During medium culture, IL-6 mRNA levels in LN patients were significantly higher than those in normal controls (1.80±0.11 vs 0.36±0.07). During stimulation with IL-17, IL-6 mRNA levels in LN patients were higher than those in normal controls (3.21±0.24 vs 1.30±0.14, P<0.05) and also significantly higher when comparing the stimulated culture with the medium culture either in LN patients or normal control.Conclusions IL-17 may play an

  13. SNAP-23 and VAMP-3 contribute to the release of IL-6 and TNFα from a human synovial sarcoma cell line.

    Science.gov (United States)

    Boddul, Sanjay V; Meng, Jianghui; Dolly, James Oliver; Wang, Jiafu

    2014-02-01

    Fibroblast-like synoviocytes are important mediators of inflammatory joint damage in arthritis through the release of cytokines, but it is unknown whether their exocytosis from these particular cells is SNARE-dependent. Here, the complement of soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) in human synovial sarcoma cells (SW982) was examined with respect to the secretion of interleukin-6 (IL-6) and tumour necrosis factor α (TNFα), before and after knockdown of a synaptosome-associated protein of molecular mass 23 kDa (SNAP-23) or the vesicle-associated membrane protein 3 (VAMP-3). Wild-type SW982 cells expressed SNAP-23, VAMP-3, syntaxin isoforms 2-4 and synaptic vesicle protein 2C (SV2C). These cells showed Ca²⁺-dependent secretion of IL-6 and TNFα when stimulated by interleukin-1β (IL-1β) or in combination with K⁺ depolarization. Specific knockdown of SNAP-23 or VAMP-3 decreased the exocytosis of IL-6 and TNFα; the reduced expression of SNAP-23 caused accumulation of SV2 in the peri-nuclear area. A monoclonal antibody specific for VAMP-3 precipitated SNAP-23 and syntaxin-2 (and syntaxin-3 to a lesser extent). The formation of SDS-resistant complexes by SNAP-23 and VAMP-3 was reduced upon knockdown of SNAP-23. Although the syntaxin isoforms 2, 3 and 4 are expressed in SW982 cells, knockdown of each did not affect the release of cytokines. Collectively, these results show that SNAP-23 and VAMP-3 participate in IL-1β-induced Ca²⁺-dependent release of IL-6 and TNFα from SW982 cells.

  14. Fiber type specific expression of TNF-alpha, IL-6 and IL-18 in human skeletal muscles

    DEFF Research Database (Denmark)

    Plomgaard, Peter; Penkowa, Milena; Pedersen, Bente K

    2005-01-01

    Skeletal muscle is now recognized as an endocrine organ with the capacity to produce signal peptides in response to muscle contractions. Here we demonstrate that resting healthy human muscles express cytokines in a fiber type specific manner. Human muscle biopsies from seven healthy young males...... were obtained from m. triceps, m. quadriceps vastus lateralis and m. soleus. Type I fibers contributed (mean +/- SE) 24.0 +/- 2.5% in triceps of total fibers, 51.3 +/- 2.4% in vastus and 84.9 +/- 22% in soleus. As expected, differences in the fiber type composition were accompanied by marked...... differences between the three muscles with regard to MHC I and MHC IIa mRNA expression. Immunohistochemistry demonstrated that tumor necrosis factor (TNF)-alpha and interleukin (IL)-18 were solely expressed by type II fibers, whereas the expression of IL-6 was more prominent in type I compared to type II...

  15. Glycine tomentella Hayata inhibits IL-1β and IL-6 production, inhibits MMP-9 activity, and enhances RAW264.7 macrophage clearance of apoptotic cells

    Directory of Open Access Journals (Sweden)

    Sun Yu-Shu

    2010-11-01

    Full Text Available Abstract Background To assess the effects of Glycine tomentella Hayata (GTH, a traditional herbal medicine for treatment of rheumatic diseases on the expression of the proinflammatory cytokines and on the clearance of apoptotic cells by macrophages. Methods RAW264.7 cells were cultured with lipopolysaccharide (LPS in the presence or absence of ethanol extract of GTH. The expression of proinflammatory cytokines IL-1β, IL-6, and TNF-α, and inducible nitric oxide synthase (iNOS and transglutaminase 2 (TG2 were assayed by reverse transcriptase-polymerase chain reaction (RT-PCR and enzyme-linked immunosorbent assay (ELISA. Matrix metalloproteinase (MMP-2 and MMP-9 were assayed by gelatin zymography. For detecting uptake of apoptotic cells, RAW264.7 cells were cultured with carboxyfluorescein diacetate (CFDA-stained apoptotic cells and assayed by flow cytometry. Results The major components of GTH analyzed by high-performance liquid chromatography (HPLC chromatogram were daidzein (42.5%, epicatechin (28.8%, and naringin (9.4%. GTH treatment inhibited the expression of proinflammatory cytokines IL-1β, IL-6 and MMP-9 but did not affect the expression of TNF-α and iNOS. GTH significantly enhanced the expression of TG2 and the clearance of apoptotic cells by RAW264.7 macrophages. Conclusions GTH inhibits proinflammatory cytokine secretion and MMP-9 activity, enhances apoptotic cell uptake and up-regulates TG2 expression. Our data show that GTH might have beneficial effects on rheumatic diseases.

  16. Minocycline Effects on IL-6 Concentration in Macrophage and Microglial Cells in a Rat Model of Neuropathic Pain

    Science.gov (United States)

    Moini-Zanjani, Taraneh; Ostad, Seyed-Nasser; Labibi, Farzaneh; Ameli, Haleh; Mosaffa, Nariman; Sabetkasaei, Masoumeh

    2016-01-01

    Background: Evidence indicates that neuropathic pain pathogenesis is not confined to changes in the activity of neuronal systems but involves interactions between neurons, inflammatory immune and immune-like glial cells. Substances released from immune cells during inflammation play an important role in development and maintenance of neuropathic pain. It has been found that minocycline suppresses the development of neuropathic pain. Here, we evaluated the analgesic effect of minocycline in a chronic constriction injury (CCI) model of neuropathic pain in rat and assessed IL-6 concentration from cultured macrophage and microglia cells. Methods: Male Wistar rat (n=6, 150-200 g) were divided into three different groups: 1) CCI+vehicle, 2) sham+vehicle, and 3) CCI+drug. Minocycline (10, 20, and 40 mg/kg) was injected one hour before surgery and continued daily to day 14 post ligation. Von Frey filaments and acetone, as pain behavioral tests, were used for mechanical allodynia and cold allodynia, respectively. Experiments were performed on day 0 (before surgery) and days 1, 3, 5, 7, 10, and 14 post -injury. At day 14, rats were killed and monocyte-derived macrophage from right ventricle and microglia from lumbar part of the spinal cord were isolated and cultured in RPMI and Leibovitz’s media, respectively. IL-6 concentration was evaluated in cell culture supernatant after 24 h. Results: Minocycline (10, 20, and 40 mg/kg) attenuated pain behavior, and a decrease in IL-6 concentration was observed in immune cells compared to CCI vehicle-treated animals. Conclusion: Minocycline reduced pain behavior and decreased IL-6 concentration in macrophage and microglial cells. PMID:27221523

  17. Construction and Purification of Prokaryotic Expression of Fusion Protein IL6-OmpW%融合蛋白IL6-OmpW的质粒构建及表达纯化

    Institute of Scientific and Technical Information of China (English)

    黄浦江; 黄郁葱; 简纪常; 吴灶和; 鲁义善; 黄瑜; 樊云霞

    2013-01-01

    以重组质粒pMD18-T/IL6和pMD18-T/OmpW为模板,分别扩增红笛鲷IL-6基因和哈维氏弧菌外膜蛋白OmpW 基因,运用 PCR 重叠延伸剪切技术,将 IL-6和 OmpW 基因融合,将融合基因定向克隆到原核表达载体pET-32a(+),转化大肠杆菌BL21(DE3)感受态,经异丙基-β-D-硫代半乳糖苷(IPTG)诱导融合蛋白高效表达,融合蛋白分子质量约为66.6 ku。优化后表达条件为温度37℃,IPTG 浓度0.2 mmol · L-1,诱导时间5 h。用HisTrap™ HP 亲和柱纯化重组蛋白,最佳咪唑洗脱浓度为400 mmol · L-1,纯化蛋白的质量浓度为480µg · mL-1。Western-blot分析显示,该融合蛋白可与鼠抗His-tag单克隆抗体发生特异反应,表明目的蛋白得以正确表达。%The fusion gene IL6-(Gly4Ser)3-OmpW was constructed with the DNA fragments of the red snapper IL-6 gene and Vibrio harveyi outer membrane protein OmpW gene which from recombinant plasmid pMD18-T/IL6 and pMD18-T/OmpW by Gene-SOEing method. The full length product was then cloned into the prokaryotic expression vector pET-32a(+) for protein expression in Escherichia coli strain BL21(DE3). The molecular weight of expression fusion protein IL6-(Gly4Ser)3-OmpW was about 66.6 ku. The recombinant protein was high expressed under induction conditions of exposure at 37℃, in 0.2 mmol·L-1 of IPTG for 5 h. The fusion protein was purified using HisTrap™HP affinity column and the best elution concentration of imidazole was 400 mmol·L-1. The concentration of purified fusion protein was 480 µg·mL-1. Western-blot analysis showed that the recombinant fusion protein could be combined with mouse anti-His-Tag Mab, indicating that the aim protein was expressed successfully. These results could provide a foundation for further study of its biological activity.

  18. p21-activated kinase 1 determines stem-like phenotype and sunitinib resistance via NF-κB/IL-6 activation in renal cell carcinoma.

    Science.gov (United States)

    Zhu, Y; Liu, H; Xu, L; An, H; Liu, W; Liu, Y; Lin, Z; Xu, J

    2015-02-12

    The p21-activated kinase 1 (PAK1), a serine/threonine kinase that orchestrates cytoskeletal remodeling and cell motility, has been shown to function as downstream node for various oncogenic signaling pathways to promote cell proliferation, regulate apoptosis and accelerate mitotic abnormalities, resulting in tumor formation and invasiveness. Although alterations in PAK1 expression and activity have been detected in various human malignancies, its potential biological and clinical significance in renal cell carcinoma (RCC) remains obscure. In this study, we found increased PAK1 and phosphorylated PAK1 levels in tumor tissues according to TNM stage progression. Elevated phosphorylated PAK1 levels associated with progressive features and indicated unfavorable overall survival (OS) as an independent adverse prognosticator for patients with RCC. Moreover, PAK1 kinase activation with constitutive active PAK1 mutant T423E promoted growth, colony formation, migration, invasion and stem-like phenotype of RCC cells, and vice versa, in PAK1 inhibition by PAK1 kinase inactivation with specific PAK1 shRNA, dead kinase PAK1 mutant K299R or allosteric inhibitor IPA3. Stem-like phenotype due to sunitinib administration via increased PAK1 kinase activation could be ameliorated by PAK1 shRNA, PAK1 mutant K299R and IPA3. Furthermore, nuclear factor-κB (NF-κB)/interleukin-6 (IL-6) activation was found to be responsible for PAK1-mediated stem-like phenotype following sunitinib treatment. Both IL-6 neutralizing antibody and IPA3 administration enhanced tumor growth inhibition effect of sunitinib treatment on RCC cells in vitro and in vivo. Our results unraveled that oncogenic activation of PAK1 defines an important mechanism for maintaining stem-like phenotype and sunitinib resistance through NF-κB/IL-6 activation in RCC, lending PAK1-mediated NF-κB/IL-6 activation considerable appeal as novel pharmacological therapeutic targets against sunitinib resistance.

  19. S100B modulates IL-6 release and cytotoxicity from hypothermic brain cells and inhibits hypothermia-induced axonal outgrowth.

    Science.gov (United States)

    Schmitt, Katharina R L; Kern, Claudia; Lange, Peter E; Berger, Felix; Abdul-Khaliq, Hashim; Hendrix, Sven

    2007-09-01

    Brain protection is essential during neonatal and pediatric cardiac surgery. Deep hypothermia is still the most important method for achieving neuroprotection during cardiopulmonary bypass. Previously, we could demonstrate that deep hypothermia induces substantial cytotoxicity in brain cells as well as increased release of the pro-inflammatory cytokine interleukin-6 (IL-6), which plays an important role in neuroprotection and neuroregeneration. Deep hypothermia is also associated with increased levels of the astrocytic protein S100B in the serum and cerebrospinal fluid of patients. Since S100B may modulate pro-inflammatory cytokines and may stimulate neurite outgrowth, we have tested the hypothesis that nanomolar concentrations of S100B may increase IL-6 release from brain cells and support axonal outgrowth from organotypic brain slices under hypothermic conditions. S100B administration substantially reduced neuronal and glial cytotoxicity under hypothermic conditions. In the presence of S100B hypothermia-induced IL-6 release in primary astrocytes was significantly increased but reduced in BV-2 microglial cells and primary neurons. Surprisingly, deep hypothermia increased axonal outgrowth from brain slices and--in contrast to our hypothesis--this hypothermia-induced neurite outgrowth was inhibited by S100B. These data suggest that S100B differentially influences cytokine release and cytotoxicity from distinct brain cells and may inhibit neuroregeneration by suppressing hypothermia-induced axonal outgrowth.

  20. 雌激素与IL-6、IL-8在卵巢癌细胞中的调节作用%Regulation of estrogen, interleukin-6 and interleukin-8 in ovarian cancer cells

    Institute of Scientific and Technical Information of China (English)

    王越; 杨洁; 高燕; 东莉洁; 姚智

    2008-01-01

    Objective To discover the reciprocal regulation and its molecular mechanism of estro-gen, IL-6 and IL-8 in ovarian cancer cells. Methods Based on our previous studies, the effect of 17β-estradiol (E2) on the expression levels of IL-6, IL-8 and their respective receptors was investigated. Mean-while, the effect of IL-6/IL-8 on estrogen receptor (ER) expression and estrogen-dependent transcriptional activation was analyzed. Gene expression profile analysis revealed that CAOV-3 and OVCAR-3 cells, which express ER, IL-6 and IL-8 receptors, were suitable models for this study. Results We found that E2 not only enhanced IL-6/IL-8 secretion via NF-κB signaling pathway, but also modulated IL-6 and IL-8 receptors expression. Tamoxifen (Txf), an ER antagonist, completely abolished E2-stimulated IL-6/IL-8 expression. On the other hand, in the absence of estrogen, both cytokines increased ERα expression, decreased ERβ ex-pression, and activated estrogen-dependent transcriptional activation, which was completely blocked by Txf. Pretreatment of OVCAR-3 with p38 MAPK, MEK1/2 or ErbB2 MAPK inhihitors, respectively, IL-6-media-ted ER activation was blocked, while IL-8-indueed ER activation was blocked by Src inhibitor. Conclusion These data suggest that estrogen, IL-6 and IL-8 may form a mutual amplifying signaling which contributes to the growth and development of ovarian carcinoma.%目的 探讨雌激素与IL-6、IL-8在卵巢癌细胞中的交互调节作用及作用机制.方法 选择兼有雌激素受体(estrogen receptor,ER)及IL-6、IL-8受体表达的卵巢癌细胞系CAOV-3和OVCAR-3作为研究模型,分别探讨17B-雌二醇(estradiol,E2)对IL-6、IL-8及其受体表达的作用以及IL-6、IL-8对EB表达及ER转录活性的作用.结果 一方面E2不仅可经NF-κB途径促进卵巢癌细胞IL-6、IL-8分泌,而且还对二者受体的表达具有一定的调节作用.E2诱导的促IL-6、IL-8分泌作用可被其受体阻断剂他莫昔芬(tamoxifen,Txf)完

  1. Interaction between IL-6 and TNF-α genotypes associated with bacteremia in multiple myeloma patients submitted to autologous stem cell transplantation (ASCT).

    Science.gov (United States)

    Trigo, Fernanda M B; Luizon, Marcelo R; Dutra, Hélio S; Maiolino, Angelo; Nucci, Márcio; Simões, Belinda P

    2014-01-01

    Stem cell transplantation affects patient׳s vulnerability to infections due to immunological changes related to chemotherapy. Multiple myeloma is characterized by susceptibility to infections, and IL-6 and TNF-α increased levels affect immune response (IR). Polymorphisms in promoter region of cytokine genes may alter expression levels and affect IR. We performed interaction analysis of IL-6 (-174G/C) and TNF-α (-308G/A) polymorphisms with infection susceptibility in 148 patients classified accordingly to infection status and found an interaction when compared groups with and without bacteremia (p=0.0380). The interaction may be more important than single effects for the IR associated with the infection susceptibility in ASCT.

  2. IL-6 Improves the Nitric Oxide-Induced Cytotoxic CD8+ T Cell Dysfunction in Human Chagas Disease

    Science.gov (United States)

    Sanmarco, Liliana Maria; Visconti, Laura Marina; Eberhardt, Natalia; Ramello, Maria Cecilia; Ponce, Nicolás Eric; Spitale, Natalia Beatriz; Vozza, Maria Lola; Bernardi, Germán Andrés; Gea, Susana; Minguez, Angel Ramón; Aoki, Maria Pilar

    2016-01-01

    Reactive oxygen and nitrogen species are important microbicidal agents and are also involved in lymphocyte unresponsiveness during experimental infections. Many of the biological effects attributed to nitric oxide are mediated by peroxynitrites, which induce the nitration of immune cells, among others. Our group has demonstrated that nitric oxide is involved in the suppressive activity of myeloid-derived suppressor cells in Trypanosoma cruzi-infected mice, with a higher number of CD8+ T cells suffering surface-nitration compared to uninfected controls. Studying the functional and phenotypic features of peripheral CD8+ T cells from chagasic patients and human cells experimentally infected with T. cruzi, we found that different regulatory mechanisms impaired the effector functions of T cytotoxic population from seropositive patients. Peripheral leukocytes from chagasic patients showed increased nitric oxide production concomitant with increased tyrosine nitration of CD8+ T cells. Additionally, this cytotoxic population exhibited increased apoptotic rate, loss of the TCRζ-chain, and lower levels of CD107a, a marker of degranulation. Strikingly, IL-6 stimulation of in vitro-infected peripheral blood mononuclear cells obtained from healthy donors, blunted T. cruzi-induced nitration of CD3+CD8+ cells, and increased their survival. Furthermore, the treatment of these cultures with an IL-6 neutralizing antibody increased the percentage of T. cruzi-induced CD8+ T cell nitration and raised the release of nitric oxide. The results suggest that the under-responsiveness of cytotoxic T cell population observed in the setting of long-term constant activation of the immune system could be reverted by the pleiotropic actions of IL-6, since this cytokine improves its survival and effector functions. PMID:28066435

  3. IL-6 deficiency leads to reduced metallothionein-I+II expression and increased oxidative stress in the brain stem after 6-aminonicotinamide treatment

    DEFF Research Database (Denmark)

    Penkowa, M; Hidalgo, J

    2000-01-01

    We examined the effects of interleukin-6 (IL-6) deficiency on brain inflammation and the accompanying bone marrow (BM) leukopoiesis and spleen immune reaction after systemic administration of a niacin antagonist, 6-aminonicotinamide (6-AN), which causes both astroglial degeneration/cell death...... in brain stem gray matter areas and BM toxicity. In both normal and genetically IL-6-deficient mice (IL-6 knockout (IL-6KO) mice), the extent of astroglial degeneration/cell death in the brain stem was similar as determined from disappearance of GFAP immunoreactivity. In 6-AN-injected normal mice reactive...... astrocytosis encircled gray matter areas containing astroglial degeneration/cell death, which were infiltrated by several macrophages and some T-lymphocytes. Reactive astrocytes and a few macrophages increased significantly the antioxidants metallothionein-I+II (MT-I+II) and moderately the MT-III isoform. In 6...

  4. Fiber type specific expression of TNF-alpha, IL-6 and IL-18 in human skeletal muscles.

    Science.gov (United States)

    Plomgaard, Peter; Penkowa, Milena; Pedersen, Bente K

    2005-01-01

    Skeletal muscle is now recognized as an endocrine organ with the capacity to produce signal peptides in response to muscle contractions. Here we demonstrate that resting healthy human muscles express cytokines in a fiber type specific manner. Human muscle biopsies from seven healthy young males were obtained from m. triceps, m. quadriceps vastus lateralis and m. soleus. Type I fibers contributed (mean +/- SE) 24.0 +/- 2.5% in triceps of total fibers, 51.3 +/- 2.4% in vastus and 84.9 +/- 22% in soleus. As expected, differences in the fiber type composition were accompanied by marked differences between the three muscles with regard to MHC I and MHC IIa mRNA expression. Immunohistochemistry demonstrated that tumor necrosis factor (TNF)-alpha and interleukin (IL)-18 were solely expressed by type II fibers, whereas the expression of IL-6 was more prominent in type I compared to type II fibers. The fiber type specificity was found in triceps, vastus and soleus indicating that the level of daily muscle activity did not influence basal cytokine expression. The specificity of cytokine expression in different muscle fiber types in healthy young males suggests that cytokines may play specific regulatory roles in normal physiology.

  5. Expression of IL-1β, IL-6, TNF-α, and iNOS in pregnant women with periodontal disease.

    Science.gov (United States)

    Otenio, C C M; Fonseca, I; Martins, M F; Ribeiro, L C; Assis, N M S P; Ferreira, A P; Ribeiro, R A

    2012-12-17

    Periodontal disease is one of the most prevalent oral diseases. An association between this disease and pregnancy has been suggested, but available findings are controversial. We evaluated the expression levels of interleukins (IL-1β and IL-6), tumor necrosis factor-alpha (TNF-α), and inducible nitric oxide synthase (iNOS) in pregnant women with and without periodontal disease in comparison with non-pregnant women with and without periodontal disease since studies have suggested a relationship between periodontitis and the expression levels of these genes. The women in the sample were distributed into four groups: pregnant and non-pregnant women, with or without periodontal disease, a total of 32 women. The periodontal condition was evaluated according to the probing depth, clinical attachment level and bleeding on probing. Analysis of gene expression was performed by real-time PCR. Comparisons were made of the level of gene expression among the four groups. Expression of IL-1β in the non-pregnant women with periodontal disease was 12.6 times higher than in the non-pregnant women without periodontal disease (P periodontal disease was 3.5 times higher than in the pregnant women with periodontal disease (P periodontal disease in comparison with expression of the same genes in non-pregnant women with and without periodontal disease, suggesting that periodontal disease is not influenced by pregnancy.

  6. Syndecan-1 (CD138 modulates triple-negative breast cancer stem cell properties via regulation of LRP-6 and IL-6-mediated STAT3 signaling.

    Directory of Open Access Journals (Sweden)

    Sherif A Ibrahim

    Full Text Available Syndecan-1 (CD138, a heparan sulfate proteoglycan, acts as a coreceptor for growth factors and chemokines and is a molecular marker associated with epithelial-mesenchymal transition during development and carcinogenesis. Resistance of Syndecan-1-deficient mice to experimentally-induced tumorigenesis has been linked to altered Wnt-responsive precursor cell pools, suggesting a potential role of Syndecan-1 in breast cancer cell stem function. However, the precise molecular mechanism is still elusive. Here, we decipher the functional impact of Syndecan-1 knockdown using RNA interference on the breast cancer stem cell phenotype of human triple-negative MDA-MB-231 and hormone receptor-positive MCF-7 cells in vitro employing an analytical flow cytometric approach. Successful Syndecan-1 siRNA knockdown was confirmed by flow cytometry. Side population measurement by Hoechst dye exclusion and Aldehyde dehydrogenase-1 activity revealed that Syndecan-1 knockdown in MDA-MB-231 cells significantly reduced putative cancer stem cell pools by 60% and 27%, respectively, compared to controls. In MCF-7 cells, Syndecan-1 depletion reduced the side population by 40% and Aldehyde dehydrogenase-1 by 50%, repectively. In MDA-MB-231 cells, the CD44(+CD24(-/low phenotype decreased significantly by 6% upon siRNA-mediated Syndecan-1 depletion. Intriguingly, IL-6, its receptor sIL-6R, and the chemokine CCL20, implicated in regulating stemness-associated pathways, were downregulated by >40% in Syndecan-1-silenced MDA-MB-231 cells, which showed a dysregulated response to IL-6-induced shifts in E-cadherin and vimentin expression. Furthermore, activation of STAT-3 and NFkB transcription factors and expression of a coreceptor for Wnt signaling, LRP-6, were reduced by >45% in Syndecan-1-depleted cells compared to controls. At the functional level, Syndecan-1 siRNA reduced the formation of spheres and cysts in MCF-7 cells grown in suspension culture. Our study demonstrates the

  7. Syndecan-1 (CD138) modulates triple-negative breast cancer stem cell properties via regulation of LRP-6 and IL-6-mediated STAT3 signaling.

    Science.gov (United States)

    Ibrahim, Sherif A; Hassan, Hebatallah; Vilardo, Laura; Kumar, Sampath Katakam; Kumar, Archana Vijaya; Kelsch, Reinhard; Schneider, Cornelia; Kiesel, Ludwig; Eich, Hans Theodor; Zucchi, Ileana; Reinbold, Rolland; Greve, Burkhard; Götte, Martin

    2013-01-01

    Syndecan-1 (CD138), a heparan sulfate proteoglycan, acts as a coreceptor for growth factors and chemokines and is a molecular marker associated with epithelial-mesenchymal transition during development and carcinogenesis. Resistance of Syndecan-1-deficient mice to experimentally-induced tumorigenesis has been linked to altered Wnt-responsive precursor cell pools, suggesting a potential role of Syndecan-1 in breast cancer cell stem function. However, the precise molecular mechanism is still elusive. Here, we decipher the functional impact of Syndecan-1 knockdown using RNA interference on the breast cancer stem cell phenotype of human triple-negative MDA-MB-231 and hormone receptor-positive MCF-7 cells in vitro employing an analytical flow cytometric approach. Successful Syndecan-1 siRNA knockdown was confirmed by flow cytometry. Side population measurement by Hoechst dye exclusion and Aldehyde dehydrogenase-1 activity revealed that Syndecan-1 knockdown in MDA-MB-231 cells significantly reduced putative cancer stem cell pools by 60% and 27%, respectively, compared to controls. In MCF-7 cells, Syndecan-1 depletion reduced the side population by 40% and Aldehyde dehydrogenase-1 by 50%, repectively. In MDA-MB-231 cells, the CD44(+)CD24(-/low) phenotype decreased significantly by 6% upon siRNA-mediated Syndecan-1 depletion. Intriguingly, IL-6, its receptor sIL-6R, and the chemokine CCL20, implicated in regulating stemness-associated pathways, were downregulated by >40% in Syndecan-1-silenced MDA-MB-231 cells, which showed a dysregulated response to IL-6-induced shifts in E-cadherin and vimentin expression. Furthermore, activation of STAT-3 and NFkB transcription factors and expression of a coreceptor for Wnt signaling, LRP-6, were reduced by >45% in Syndecan-1-depleted cells compared to controls. At the functional level, Syndecan-1 siRNA reduced the formation of spheres and cysts in MCF-7 cells grown in suspension culture. Our study demonstrates the viability of flow

  8. Acidic environment augments FcεRI-mediated production of IL-6 and IL-13 in mast cells

    Energy Technology Data Exchange (ETDEWEB)

    Kamide, Yosuke, E-mail: m08702012@gunma-u.ac.jp [Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi (Japan); Clinical Research Center for Allergy and Rheumatology, Sagamihara National Hospital, Sagamihara (Japan); Ishizuka, Tamotsu [Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui (Japan); Tobo, Masayuki [Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi (Japan); Tsurumaki, Hiroaki [Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi (Japan); Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi (Japan); Aoki, Haruka; Mogi, Chihiro [Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi (Japan); Nakakura, Takashi [Department of Anatomy, Graduate School of Medicine, Teikyo University, Tokyo (Japan); Yatomi, Masakiyo; Ono, Akihiro; Koga, Yasuhiko [Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi (Japan); Sato, Koichi [Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi (Japan); Hisada, Takeshi [Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi (Japan); Dobashi, Kunio [Gunma University Graduate School of Health Sciences, Maebashi (Japan); Yamada, Masanobu [Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi (Japan); Okajima, Fumikazu [Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi (Japan)

    2015-08-28

    Although blood pH is maintained in a narrow range of around pH 7.4 in living organisms, inflammatory loci are characterized by acidic conditions. Mast cells tend to reside close to the surface of the body in areas such as the mucosa and skin where they may be exposed to exogenous acids, and they play an important role in immune responses. However, little is known about the effects of extracellular acidification on the functions of mast cell. Here, we found that extracellular acidification increased the dinitrophenyl-conjugated human serum albumin (DNP-HSA)-induced production of interleukin (IL)-6 and IL-13 in MC/9 cells or bone marrow-derived mouse mast cells sensitized with anti-DNP IgE. Extracellular acidification also inhibited migration of MC/9 cells toward DNP-HSA. In addition, acidic pH stimulated antigen-induced activation of p38 mitogen-activated protein kinase (MAPK) and protein kinase B (Akt). These findings suggest that extracellular acidification augmented antigen/IgE-induced and FcεRI-mediated production of IL-6 and IL-13 in mast cells, and that this was associated with the enhancement of p38 MAPK and Akt activation. - Highlights: • Antigen-induced IL-6 and IL-13 production was augmented by acidic pH in mast cells. • Acidic pH-induced actions were associated with activation of p38 MAPK and Akt. • Inhibition of p38 MAPK and Akt attenuated cytokine responses to acidic pH. • Acidic pH effects are not attributable to actions of known proton-sensing GPCRs.

  9. Effects of Nogo-A Silencing on TNF-α and IL-6 Secretion and TH Downregulation in Lipopolysaccharide-Stimulated PC12 Cells

    Directory of Open Access Journals (Sweden)

    Jianbin Zhong

    2015-01-01

    Full Text Available Parkinson’s disease (PD is a common degenerative disease that lacks efficient treatment. Myelin-associated neurite outgrowth inhibitor A (Nogo-A is relevant with inhibition of nerve regeneration and may play vital role in pathogenesis of PD. The study aimed to establish the shRNA expression plasmids of Nogo-A gene and explore the regulatory effects of Nogo-A silencing on the expression of inflammation factor tumor necrosis factor-alpha (TNF-alpha and interleukin-6 (IL-6 as well as tyrosine hydroxylase (TH in lipopolysaccharide- (LPS- stimulated rat PC12 cells. The results showed that both mRNA and protein levels of Nogo-A in pGenesil-nogoA-shRNA group were downregulated. The viabilities of PC12 cells decreased with increase of LPS concentrations. LPS significantly increased the supernatant TNF-alpha and IL-6 concentrations and reduced TH protein expression in PC12 cells, while silencing Nogo-A could block these effects. These results suggested that LPS can activate PC12 cells to secrete inflammatory cytokines and lower the TH expression, which can be regulated by Nogo-A gene silencing. Nogo-A silencing might provide new ideas for PD treatment in the future.

  10. Genetic evidence for an essential role of neuronally expressed IL-6 signal transducer gp130 in the induction and maintenance of experimentally induced mechanical hypersensitivity in vivo and in vitro.

    Science.gov (United States)

    Quarta, Serena; Vogl, Christian; Constantin, Cristina E; Üçeyler, Nurcan; Sommer, Claudia; Kress, Michaela

    2011-09-27

    Tenderness and mechanical allodynia are key symptoms of malignant tumor, inflammation and neuropathy. The proinflammatory cytokine interleukin-6 (IL-6) is causally involved in all three pathologies. IL-6 not only regulates innate immunity and inflammation but also causes nociceptor sensitization and hyperalgesia. In general and in most cell types including immune cells and sensory neurons, IL-6 binds soluble μ receptor subunits which heteromerizes with membrane bound IL-6 signal transducer gp130. In the present study, we used a conditional knock-out strategy to investigate the importance of signal transducer gp130 expressed in C nociceptors for the generation and maintenance of mechanical hypersensitivity. Nociceptors were sensitized to mechanical stimuli by experimental tumor and this nociceptor sensitization was preserved at later stages of the pathology in control mice. However, in mice with a conditional deletion of gp130 in Nav1.8 expressing nociceptors mechanical hypersensitivity by experimental tumor, nerve injury or inflammation recovery was not preserved in the maintenance phase and nociceptors exhibited normal mechanical thresholds comparable to untreated mice. Together, the results argue for IL-6 signal transducer gp130 as an essential prerequisite in nociceptors for long-term mechanical hypersensitivity associated with cancer, inflammation and nerve injury.

  11. Genetic evidence for an essential role of neuronally expressed IL-6 signal transducer gp130 in the induction and maintenance of experimentally induced mechanical hypersensitivity in vivo and in vitro

    Directory of Open Access Journals (Sweden)

    Constantin Cristina E

    2011-09-01

    Full Text Available Abstract Tenderness and mechanical allodynia are key symptoms of malignant tumor, inflammation and neuropathy. The proinflammatory cytokine interleukin-6 (IL-6 is causally involved in all three pathologies. IL-6 not only regulates innate immunity and inflammation but also causes nociceptor sensitization and hyperalgesia. In general and in most cell types including immune cells and sensory neurons, IL-6 binds soluble μ receptor subunits which heteromerizes with membrane bound IL-6 signal transducer gp130. In the present study, we used a conditional knock-out strategy to investigate the importance of signal transducer gp130 expressed in C nociceptors for the generation and maintenance of mechanical hypersensitivity. Nociceptors were sensitized to mechanical stimuli by experimental tumor and this nociceptor sensitization was preserved at later stages of the pathology in control mice. However, in mice with a conditional deletion of gp130 in Nav1.8 expressing nociceptors mechanical hypersensitivity by experimental tumor, nerve injury or inflammation recovery was not preserved in the maintenance phase and nociceptors exhibited normal mechanical thresholds comparable to untreated mice. Together, the results argue for IL-6 signal transducer gp130 as an essential prerequisite in nociceptors for long-term mechanical hypersensitivity associated with cancer, inflammation and nerve injury.

  12. IL-6 Inhibition With MEDI5117 Decreases The Fraction of Head and Neck Cancer Stem Cells and Prevents Tumor Recurrence

    Directory of Open Access Journals (Sweden)

    Kelsey A. Finkel

    2016-05-01

    Full Text Available Head and neck squamous cell carcinomas (HNSCC exhibit a small population of uniquely tumorigenic cancer stem cells (CSC endowed with self-renewal and multipotency. We have recently shown that IL-6 enhances the survival and tumorigenic potential of head and neck cancer stem cells (i.e. ALDHhighCD44high cells. Here, we characterized the effect of therapeutic inhibition of IL-6 with a novel humanized anti-IL-6 antibody (MEDI5117 using three low-passage patient-derived xenograft (PDX models of HNSCC. We observed that single agent MEDI5117 inhibited the growth of PDX-SCC-M1 tumors (P < .05. This PDX model was generated from a previously untreated HNSCC. In contrast, MEDI5117 was not effective at reducing overall tumor volume for PDX models representing resistant disease (PDX-SCC-M0, PDX-SCC-M11. Low dose MEDI5117 (3 mg/kg consistently decreased the fraction of cancer stem cells in PDX models of HNSCC when compared to IgG-treated controls, as follows: PDX-SCC-M0 (P < .001, PDX-SCC-M1 (P < .001, PDX-SCC-M11 (P = .04. Interestingly, high dose MEDI5117 (30 mg/kg decreased the CSC fraction in the PDX-SCC-M11 model (P = .002, but not in PDX-SCC-M0 and PDX-SCC-M1. MEDI5117 mediated a dose-dependent decrease in the number of orospheres generated by ALDHhighCD44high cells cultured in ultra-low attachment plates (P < .05, supporting an inhibitory effect on head and neck cancer stem cells. Notably, single agent MEDI5117 reduced the overall recurrence rate of PDX-SCC-M0, a PDX generated from the local recurrence of human HNSCC. Collectively, these data demonstrate that therapeutic inhibition of IL-6 with low-dose MEDI5117 decreases the fraction of cancer stem cells, and that adjuvant MEDI5117 inhibits recurrence in preclinical models of HNSCC.

  13. CD38 Ligation in Peripheral Blood Mononuclear Cells of Myeloma Patients Induces Release of Protumorigenic IL-6 and Impaired Secretion of IFNγ Cytokines and Proliferation

    Directory of Open Access Journals (Sweden)

    Giorgio Fedele

    2013-01-01

    Full Text Available CD38, a surface receptor that controls signals in immunocompetent cells, is densely expressed by cells of multiple myeloma (MM. The immune system of MM patients appears as functionally impaired, with qualitative and quantitative defects in T cell immune responses. This work answers the issue whether CD38 plays a role in the impairment of T lymphocyte response. To this aim, we analyzed the signals implemented by monoclonal antibodies (mAb ligation in peripheral blood mononuclear cells (PBMC obtained from MM patients and compared to benign monoclonal gammopathy of undetermined significance (MGUS. PBMC from MM both failed to proliferate and secrete IFNγ induced by CD38 ligation while it retained the ability to respond to TCR/CD3. The impaired CD38-dependent proliferative response likely reflects an arrest in the progression of cell cycle, as indicated by the reduced expression of PCNA. CD38 signaling showed an enhanced ability to induce IL-6 secretion. PBMC from MM patients displays a deregulated response possibly due to defects of CD38 activation pathways and CD38 may be functionally involved in the progression of this pathology via the secretion of high levels of IL-6 that protects neoplastic cells from apoptosis.

  14. Th17-type cytokines, IL-6 and TNF-α synergistically activate STAT3 and NF-kB to promote colorectal cancer cell growth.

    Science.gov (United States)

    De Simone, V; Franzè, E; Ronchetti, G; Colantoni, A; Fantini, M C; Di Fusco, D; Sica, G S; Sileri, P; MacDonald, T T; Pallone, F; Monteleone, G; Stolfi, C

    2015-07-01

    Colorectal cancers (CRCs) often show a dense infiltrate of cytokine-producing immune/inflammatory cells. The exact contribution of each immune cell subset and cytokine in the activation of the intracellular pathways sustaining CRC cell growth is not understood. Herein, we isolate tumor-infiltrating leukocytes (TILs) and lamina propria mononuclear cells (LPMCs) from the tumor area and the macroscopically unaffected, adjacent, colonic mucosa of patients who underwent resection for sporadic CRC and show that the culture supernatants of TILs, but not of LPMCs, potently enhance the growth of human CRC cell lines through the activation of the oncogenic transcription factors signal transducer and activator of transcription 3 (STAT3) and nuclear factor-kappa B (NF-kB). Characterization of immune cell complexity of TILs and LPMCs reveals no differences in the percentages of T cells, natural killer T cells, natural killer (NK) cells, macrophages and B cells. However, T cells from TILs show a functional switch compared with those from LPMCs to produce large amounts of T helper type 17 (Th17)-related cytokines (that is, interleukin-17A (IL-17A), IL-17F, IL-21 and IL-22), tumor necrosis factor-α (TNF-α) and IL-6. Individual neutralization of IL-17A, IL-17F, IL-21, IL-22, TNF-α or IL-6 does not change TIL-derived supernatant-driven STAT3 and NF-kB activation, as well as their proproliferative effect in CRC cells. In contrast, simultaneous neutralization of both IL-17A and TNF-α, which abrogates NF-kB signaling, and IL-22 and IL-6, which abrogates STAT3 signaling, reduces the mitogenic effect of supernatants in CRC cells. IL-17A, IL-21, IL-22, TNF-α and IL-6 are also produced in excess in the early colonic lesions in a mouse model of sporadic CRC, associated with enhanced STAT3/NF-kB activation. Mice therapeutically given BP-1-102, an orally bioavailable compound targeting STAT3/NF-kB activation and cross-talk, exhibit reduced colon tumorigenesis and diminished expression of

  15. LPS-induced production of TNF-α and IL-6 in mast cells is dependent on p38 but independent of TTP.

    Science.gov (United States)

    Hochdörfer, Thomas; Tiedje, Christopher; Stumpo, Deborah J; Blackshear, Perry J; Gaestel, Matthias; Huber, Michael

    2013-06-01

    The production of the proinflammatory cytokines TNF-α and IL-6 is regulated by various mRNA-binding proteins, influencing stability and translation of the respective transcripts. Research in macrophages has shown the importance of the p38-MK2-tristetraprolin (TTP) axis for regulation of TNF-α mRNA stability and translation. In the current study we examined a possible involvement of p38 and TTP in LPS-induced cytokine production in bone marrow-derived mast cells (BMMCs). Using pharmacological inhibitors we initially found a strong dependence of LPS-induced TNF-α and IL-6 production on p38 activation, whereas activation of the Erk pathway appeared dispensable. LPS treatment also induced p38-dependent expression of the TTP gene. This prompted us to analyze the proinflammatory cytokine response in BMMCs generated from TTP-deficient mice. Unexpectedly, there were no significant differences in cytokine production between TTP-deficient and WT BMMCs in response to LPS. Gene expression and cytokine production of TNF-α and IL-6 as well as stability of the TNF-α transcript were comparable between TTP-deficient and WT BMMCs. In contrast to TTP mRNA expression, TTP protein expression could not be detected in BMMCs. While we successfully precipitated and detected TTP from lysates of LPS-stimulated RAW 264.7 macrophages, this was not accomplished from BMMC lysates. In contrast, we found mRNA and protein expressions of the other TIS11 family members connected to regulation of mRNA stability, BRF1 and BRF2, and detected their interaction with 14-3-3 proteins. These data suggest that control of cytokine mRNA stability and translation in MCs is exerted by proteins different from TTP.

  16. Soluble interleukin 6 receptor (sIL-6R) mediates colonic tumor cell adherence to the vascular endothelium: a mechanism for metastatic initiation?

    LENUS (Irish Health Repository)

    Dowdall, J F

    2012-02-03

    The mechanisms by which surgery increases metastatic proliferation remain poorly characterized, although endotoxin and immunocytes play a role. Recent evidence suggests that endothelial adherence of tumor cells may be important in the formation of metastases. Soluble receptors of interleukin-6 (sIL-6R) shed by activated neutrophils exert IL-6 effects on endothelial cells, which are unresponsive under normal circumstances. This study examined the hypothesis that sIL-6R released by surgical stress increases tumor cell adherence to the endothelium. Neutrophils (PMN) were stimulated with lipopolysaccharide, C-reactive protein (CRP), and tumor necrosis factor-alpha. Soluble IL-6R release was measured by enzyme-linked immunosorbent assay. Colonic tumor cells transfected with green fluorescent protein and endothelial cells were exposed to sIL-6R, and tumor cell adherence and transmigration were measured by fluorescence microscopy. Basal release of sIL-6R from PMN was 44.7 +\\/- 8.2 pg\\/ml at 60 min. This was significantly increased by endotoxin and CRP (131 +\\/- 16.8 and 84.1 +\\/- 5.3, respectively; both P < 0.05). However, tumor necrosis factor-alpha did not significantly alter sIL-6R release. Endothelial and tumor cell exposure to sIL-6R increased tumor cell adherence by 71.3% within 2 h but did not significantly increase transmigration, even at 6 h. Mediators of surgical stress induce neutrophil release of a soluble receptor for IL-6 that enhances colon cancer cell endothelial adherence. Since adherence to the endothelium is now considered to be a key event in metastatic genesis, these findings have important implications for colon cancer treatment strategies.

  17. Modulation of the IL-6 Receptor α Underlies GLI2-Mediated Regulation of Ig Secretion in Waldenström Macroglobulinemia Cells.

    Science.gov (United States)

    Jackson, David A; Smith, Timothy D; Amarsaikhan, Nansalmaa; Han, Weiguo; Neil, Matthew S; Boi, Shannon K; Vrabel, Anne M; Tolosa, Ezequiel J; Almada, Luciana L; Fernandez-Zapico, Martin E; Elsawa, Sherine F

    2015-09-15

    Ig secretion by terminally differentiated B cells is an important component of the immune response to foreign pathogens. Its overproduction is a defining characteristic of several B cell malignancies, including Waldenström macroglobulinemia (WM), where elevated IgM is associated with significant morbidity and poor prognosis. Therefore, the identification and characterization of the mechanisms controlling Ig secretion are of great importance for the development of future therapeutic approaches for this disease. In this study, we define a novel pathway involving the oncogenic transcription factor GLI2 modulating IgM secretion by WM malignant cells. Pharmacological and genetic inhibition of GLI2 in WM malignant cells resulted in a reduction in IgM secretion. Screening for a mechanism identified the IL-6Rα (gp80) subunit as a downstream target of GLI2 mediating the regulation of IgM secretion. Using a combination of expression, luciferase, and chromatin immunoprecipitation assays we demonstrate that GLI2 binds to the IL-6Rα promoter and regulates its activity as well as the expression of this receptor. Additionally, we were able to rescue the reduction in IgM secretion in the GLI2 knockdown group by overexpressing IL-6Rα, thus defining the functional significance of this receptor in GLI2-mediated regulation of IgM secretion. Interestingly, this occurred independent of Hedgehog signaling, a known regulator of GLI2, as manipulation of Hedgehog had no effect on IgM secretion. Given the poor prognosis associated with elevated IgM in WM patients, components of this new signaling axis could be important therapeutic targets.

  18. IL-4 Downregulates IL-1β and IL-6 and Induces GATA3 in Psoriatic Epidermal Cells: Route of Action of a Th2 Cytokine.

    Science.gov (United States)

    Onderdijk, Armanda J; Baerveldt, Ewout M; Kurek, Dorota; Kant, Marius; Florencia, Edwin F; Debets, Reno; Prens, Errol P

    2015-08-15

    Clinical improvement of psoriasis induced by IL-4 treatment has been ascribed to changes in dermal inflammatory cells, such as activation of Th2 cells and tolerization of dendritic cells by suppressing IL-23 production. The pathologic epidermal alterations in psoriatic lesional skin include increased epidermal expression of IL-1β, IL-6, S100A7, and human β-defensin 2 (hBD2) and a downregulated expression of the epidermal transcription factor GATA3. Effects of IL-4 on the epidermal compartment of psoriasis lesions were not previously investigated. Therefore, we investigated whether IL-4 directly affects abovementioned psoriatic markers in the epidermal compartment. We cultured freshly isolated psoriatic epidermal cells, whole psoriatic and healthy skin biopsies, human keratinocytes and Langerhans cells with IL-4. The secretion of IL-1β and IL-6 by psoriatic epidermal cells was inhibited by IL-4 via transcriptional and posttranscriptional mechanisms, respectively. In normal skin, IL-4 inhibited IL-1β- and IL-17A-induced hBD2 expression in vitro. In addition, IL-4 reduced the protein expression of hBD2 in psoriatic skin biopsies and induced phospho-STAT6 protein. Epidermal GATA3 mRNA and protein were significantly upregulated by IL-4 in epidermal cells and keratinocytes. Our data argue that IL-4 improves psoriasis not only via modification/induction of Th2 cells and type II dendritic cells, but also via direct inhibition of inflammatory cytokines in resident IL-4R-expressing epidermal cells and thereby alters the psoriatic skin phenotype toward a healthy skin phenotype.

  19. Glioma Stem Cells but Not Bulk Glioma Cells Upregulate IL-6 Secretion in Microglia/Brain Macrophages via Toll-like Receptor 4 Signaling.

    Science.gov (United States)

    a Dzaye, Omar Dildar; Hu, Feng; Derkow, Katja; Haage, Verena; Euskirchen, Philipp; Harms, Christoph; Lehnardt, Seija; Synowitz, Michael; Wolf, Susanne A; Kettenmann, Helmut

    2016-05-01

    Peripheral macrophages and resident microglia constitute the dominant glioma-infiltrating cells. The tumor induces an immunosuppressive and tumor-supportive phenotype in these glioma-associated microglia/brain macrophages (GAMs). A subpopulation of glioma cells acts as glioma stem cells (GSCs). We explored the interaction between GSCs and GAMs. Using CD133 as a marker of stemness, we enriched for or deprived the mouse glioma cell line GL261 of GSCs by fluorescence-activated cell sorting (FACS). Over the same period of time, 100 CD133(+ )GSCs had the capacity to form a tumor of comparable size to the ones formed by 10,000 CD133(-) GL261 cells. In IL-6(-/-) mice, only tumors formed by CD133(+ )cells were smaller compared with wild type. After stimulation of primary cultured microglia with medium from CD133-enriched GL261 glioma cells, we observed an selective upregulation in microglial IL-6 secretion dependent on Toll-like receptor (TLR) 4. Our results show that GSCs, but not the bulk glioma cells, initiate microglial IL-6 secretion via TLR4 signaling and that IL-6 regulates glioma growth by supporting GSCs. Using human glioma tissue, we could confirm the finding that GAMs are the major source of IL-6 in the tumor context.

  20. Increased expression of interleukin (IL-6 family members and receptors in urinary bladder with cyclophosphamide (CYP-induced bladder inflammation in female rats

    Directory of Open Access Journals (Sweden)

    Beatrice eGirard

    2011-02-01

    Full Text Available Recent studies suggest that JAK-STAT signaling pathways contribute to increased voiding frequency and referred pain of CYP-induced cystitis in rats. Potential upstream chemical mediator(s that may be activated by CYP-induced cystitis to stimulate JAK/STAT signaling are not known in detail. In these studies, members of the interleukin (IL-6 family of cytokines including, leukemia inhibitory factor (LIF, IL-6 and ciliary neurotrophic factor (CNTF and associated receptors, IL-6 receptor (R α, LIFR and gp130 were examined in the urinary bladder in control and CYP-treated rats. Cytokine and receptor transcript and protein expression and distribution were determined in urinary bladder after cyclophosphamide (CYP-induced cystitis using quantitative, real-time polymerase chain reaction (Q-PCR, western blotting and immunohistochemistry. Acute (4 hr; 150 mg/kg; i.p., intermediate (48 hr; 150 mg/kg; i.p. or chronic (75 mg/kg; i.p., once every 3 days for 10 days cystitis was induced in adult, female Wistar rats with CYP treatment. Q-PCR analyses revealed significant (p ≤ 0.01 CYP duration- and tissue- (e.g., urothelium, detrusor dependent increases in LIF, IL-6, IL-6Rα, LIFR and gp130 mRNA expression. Western blotting demonstrated significant (p ≤ 0.01 increases in IL-6, LIF and gp130 protein expression in whole urinary bladder with CYP treatment. CYP-induced cystitis significantly (p ≤ 0.01 increased LIF-immunoreactivity (IR in urothelium, detrusor, and suburothelial plexus whereas increased gp130-IR was only observed in urothelium and detrusor. These studies suggest that IL-6 and LIF may be potential upstream chemical mediators that activate JAK/STAT signaling in urinary bladder pathways.

  1. Mesenchymal stem cells enhance ovarian cancer cell infiltration through IL6 secretion in an amniochorionic membrane based 3D model

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    Touboul Cyril

    2013-01-01

    Full Text Available Abstract Background The early peritoneal invasion of epithelial ovarian cancer (EOC by tumoral aggregates presents in ascites is a major concern. The role of the microenvironment seems to be important in this process but the lack of adequate models to study cellular interactions between cancer cells and stromal cells does not allow to uncover the molecular pathways involved. Our goal was to study the interactions between ovarian cancer cells (OCC and mesenchymal stem cells (MSC using a 3D model. Methods We used millimetric pieces of amniochorionic membrane - referred to as amniotic membrane scaffold (AMS - to create 3D peritoneal nodules mimicking EOC early invasion. We were able to measure the distribution and the depth of infiltration using confocal microsopy. We extracted MSC from the amniochorionic membrane using the markers CD34-, CD45-, CD73+, CD90+, CD105+ and CD29+ at the Fluorescence Activated Cell Sorting (FACS analysis. We used transwell and wound healing tests to test OCC migration and invasion in vitro. Results Here we show that OCC tumors were located in regions rich in MSC (70%. The tumors infiltrated deeper within AMS in regions rich in MSC (p Conclusions The use of tridimensional models using AMS could be a useful tool to decipher early molecular events in ovarian cancer metastasis. Cytokine inhibitors interrupting the cross-talk between OCCs and MSCs such as IL6 should be investigated as a new therapeutic approach in ovarian cancer.

  2. Increased IL-6 Expression in Osteoclasts Is Necessary But Not Sufficient for the Development of Paget’s Disease of Bone

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    Teramachi, Jumpei; Zhou, Hua; Subler, Mark A; Kitagawa, Yukiko; Galson, Deborah L; Dempster, David W; Windle, Jolene J; Kurihara, Noriyoshi; Roodman, G David

    2015-01-01

    Measles virus nucleocapsid protein (MVNP) expression in osteoclasts (OCLs) and mutation of the SQSTM1 (p62) gene contribute to the increased OCL activity in Paget’s disease (PD). OCLs expressing MVNP display many of the features of PD OCLs. Interleukin-6 (IL-6) production is essential for the pagetic phenotype, because transgenic mice with MVNP targeted to OCLs develop pagetic OCLs and lesions, but this phenotype is absent when MVNP mice are bred to IL-6−/− mice. In contrast, mutant p62 expression in OCL precursors promotes receptor activator of NF-κB ligand (RANKL) hyperresponsivity and increased OCL production, but OCLs that form have normal morphology, are not hyperresponsive to 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3), nor produce elevated levels of IL-6. We previously generated p62P394L knock-in mice (p62KI) and found that although OCL numbers were increased, the mice did not develop pagetic lesions. However, mice expressing both MVNP and p62KI developed more exuberant pagetic lesions than mice expressing MVNP alone. To examine the role of elevated IL-6 in PD and determine if MVNP mediates its effects primarily through elevation of IL-6, we generated transgenic mice that overexpress IL-6 driven by the tartrate-resistant acid phosphatase (TRAP) promoter (TIL-6 mice) and produce IL-6 at levels comparable to MVNP mice. These were crossed with p62KI mice to determine whether IL-6 overexpression cooperates with mutant p62 to produce pagetic lesions. OCL precursors from p62KI/TIL-6 mice formed greater numbers of OCLs than either p62KI or TIL-6 OCL precursors in response to 1,25-(OH)2D3. Histomorphometric analysis of bones from p62KI/TIL-6 mice revealed increased OCL numbers per bone surface area compared to wild-type (WT) mice. However, micro-quantitative CT (μQCT) analysis did not reveal significant differences between p62KI/TIL-6 and WT mice, and no pagetic OCLs or lesions were detected in vivo. Thus, increased IL-6 expression in OCLs from p62KI mice

  3. Monocyte Subsets Coregulate Inflammatory Responses by Integrated Signaling through TNF and IL-6 at the Endothelial Cell Interface

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    Chimen, Myriam; Yates, Clara M.; McGettrick, Helen M.; Ward, Lewis S. C.; Harrison, Matthew J.; Apta, Bonita; Dib, Lea H.; Imhof, Beat A.; Harrison, Paul; Nash, Gerard B.

    2017-01-01

    Two major monocyte subsets, CD14+CD16− (classical) and CD14+/dimCD16+ (nonclassical/intermediate), have been described. Each has different functions ascribed in its interactions with vascular endothelial cells (EC), including migration and promoting inflammation. Although monocyte subpopulations have been studied in isolated systems, their influence on EC and on the course of inflammation has been ignored. In this study, using unstimulated or cytokine-activated EC, we observed significant differences in the recruitment, migration, and reverse migration of human monocyte subsets. Associated with this, and based on their patterns of cytokine secretion, there was a difference in their capacity to activate EC and support the secondary recruitment of flowing neutrophils. High levels of TNF were detected in cocultures with nonclassical/intermediate monocytes, the blockade of which significantly reduced neutrophil recruitment. In contrast, classical monocytes secreted high levels of IL-6, the blockade of which resulted in increased neutrophil recruitment. When cocultures contained both monocyte subsets, or when conditioned supernatant from classical monocytes cocultures (IL-6hi) was added to nonclassical/intermediate monocyte cocultures (TNFhi), the activating effects of TNF were dramatically reduced, implying that when present, the anti-inflammatory activities of IL-6 were dominant over the proinflammatory activities of TNF. These changes in neutrophil recruitment could be explained by regulation of E-selectin on the cocultured EC. This study suggests that recruited human monocyte subsets trigger a regulatory pathway of cytokine-mediated signaling at the EC interface, and we propose that this is a mechanism for limiting the phlogistic activity of newly recruited monocytes. PMID:28193827

  4. Upregulation of Salmonella-Induced IL-6 Production in Caco-2 Cells by PJ-34, PARP-1 Inhibitor: Involvement of PI3K, p38 MAPK, ERK, JNK, and NF-κB

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    Fu-Chen Huang

    2009-01-01

    Full Text Available Following Salmonella invasion, intestinal epithelial cells release a distinct array of proinflammatory cytokines. Interleukin (IL-6 produced by enterocytes may have anti-inflammatory and cell-protective effects, and may counteract some of the injurious effects of sepsis and endotoxemia. Recent studies in a variety of rodent models of experimental colitis by using PJ-34, a potent poly (ADP-ribose polymerase-1 (PARP-1 inhibitor, support the concept that the marked beneficial effect of PJ-34 can be exploited to treat human inflammatory diseases. The present study was to investigate the effect of PJ-34 on Salmonella-induced enterocyte IL-6 production and its mechanisms. We found that PJ-34 enhanced Salmonella-induced IL-6 production in Caco-2 cells, either secreted protein or mRNA expression. PJ-34 treatment enhanced the activity of NF-κB in Salmonella-infected Caco-2 cells. Besides, the involvement of PJ-34 in up-regulating IL-6 production in S. typhimurium-infected Caco-2 cells might be also through the ERK but not p38 MAPK, JNK or PI3K/Akt pathways, as demonstrated by Western blot of phosphorylated ERK, p38, JNK and Akt proteins. It suggests that PJ-34 may exert its protective effect on intestinal epithelial cells against invasive Salmonella infection by up-regulating IL-6 production through ERK and NF-κB but not P38 MAPK, JNK or PI3K/Akt signal pathways.

  5. Induction of IL-6 and CCL5 (RANTES in human respiratory epithelial (A549 cells by clinical isolates of respiratory syncytial virus is strain specific

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    Levitz Ruth

    2012-09-01

    Full Text Available Abstract Background Respiratory syncytial virus (RSV is the major respiratory pathogen of infants and young children. During each seasonal epidemic, multiple strains of both subgroup A and B viruses circulate in the community. Like other RNA viruses, RSV genome replication is prone to errors that results in a heterogeneous population of viral strains some of which may possess differences in virulence. We sought to determine whether clinical isolates of RSV differ in their capacity to induce inflammatory cytokines IL-6 and CCL5 (previously known as RANTES [regulated upon activation, normal T-cell expressed and secreted protein], which are known to be induced in vitro and in vivo in response to RSV, during infection of A549 cells. Results Screening of subgroup A and B isolates revealed heterogeneity among strains to induce IL-6 and CCL5. We chose two subgroup B strains, New Haven (NH1067 and NH1125, for further analysis because of their marked differences in cytokine inducing properties and because subgroup B strains, in general, are less genetically heterogeneous as compared to subgroup A strains. At 12 and 24 hours post infection RSV strains, NH1067 and NH1125 differed in their capacity to induce IL-6 by an order of magnitude or more. The concentrations of IL-6 and CCL5 were dependent on the dose of infectious virus and the concentration of these cytokines induced by NH1125 was greater than that of those induced by NH1067 when the multiplicity of infection of NH1067 used was as much as 10-fold higher than that of NH1125. The induction of IL-6 was dependent on viable virus as infection with UV-inactivated virus did not induce IL-6. The difference in IL-6 induction most likely could not be explained by differences in viral replication kinetics. The intracellular level of RSV RNA, as determined by quantitative RT-PCR, was indistinguishable between the 2 strains though the titer of progeny virus produced by NH1125 was greater than that produced by

  6. Interleukin-23 Receptor Gene Polymorphism May Enhance Expression of the IL-23 Receptor, IL-17, TNF-α and IL-6 in Behcet's Disease.

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    Zhengxuan Jiang

    Full Text Available Recent studies identified an association between Behcet's disease (BD and the IL-23R gene polymorphism (rs17375018 in different populations. This study examined whether this IL-23R gene polymorphism is associated with enhanced inflammatory responses.We recruited 27 BD patients and 32 controls with three genotypes. Peripheral blood mononuclear cells (PBMCs were seeded with or without anti-CD3 and CD28. Cells were incubated for 24 hours, and then supernatants were collected and stored at -20◦C until analyzed. Levels of interferon (IFN-γ, tissue necrosis factor (TNF-α, interleukin (IL-17 and IL-6 were detected by ELISA. IL-23R expression was assessed by quantitative real-time polymerase chain reaction (RT-PCR.The expression of IL-23R was significantly higher in both BD patients and healthy controls with the GG genotype compared to the AG and AA genotype with anti-CD3 and CD28 stimulation (all P-value < 0.05. Among the PBMCs cultured with anti-CD3 and CD28 stimulation, there was an elevated secretion of TNF-α, IL-6 and IL-17 in BD patients and healthy controls with the GG genotype. However, there was no significant change in secretion of IFN- γ in BD patients and healthy controls among the genotype of this IL-23R gene polymorphism.The results suggest that the GG genotype of the rs17375018 variant in the IL-23R gene enhances pro-inflammatory cytokine responses.

  7. A COMPARISON OF DIFFERENT LIPOPOLYSACCHARIDE CHEMOTYPES FROM ESCHERICHIA COLI AND SALMONELLA UPON SYNTHESIS OF TNFα AND IL-6 BY MACROPHAGE-LIKE THP-1 CELLS

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    E. V. Voloshina

    2009-01-01

    Full Text Available Abstract. Present study was performed to investigate the influence of polysaccharide fragment or lipid A upon induction of TNFα and IL-6 cytokines. The study was performed with human THP-1 monocytic leukemia cells that were induced to differentiate into macrophage-like cells using PMA treatment. Bacterial lipopolysaccharides from S. typhimurium (S-chemotype form, S. typhimurium SL1181 (R-chemotype, Re-mutant, E. coli O55:B5 (S-chemotype, and E. coli JM103 (R-chemotype, Re-mutant were used in this study. A decreased molar ratio for lipid A-KDO in S-form of LPS from E. coli is accompanied by diminished TNFα and IL-6 expression. By the contrast, for S-form of LPS from Salmonella, a decrease in lipid A-KDO molar ratio did cause a sufficient enhancement of TNFα expression. A contribution of lipid A structure into biological activity of LPS is more significant for Re-chemotype than for S-chemotype, independently on bacterial species.

  8. The effect of valtrex on T cell subset and IL2, IL6 and IL10 level in patients with herpes zoster

    Institute of Scientific and Technical Information of China (English)

    Gui-E Wang; Jian Chen; Ling Chen

    2015-01-01

    Objective:To explore the effects of valtrex on T cell subset and IL2, IL6 and IL10 level in patients with herpes zoster.Methods: 120 patients with herpes zoster in our hospital were analyzed. The serum T cell subset and IL2, IL6 and IL10 were detected by Western Blotting. Healthy volunteers were enrolled as control group.Results: The CD4+ level was increased significantly while the CD8+ decreased significantly, and the ratio of the two increased too (P all<0.01). The IL6 and IL10 levels were increased significantly (P<0.01). But no significant change in IL2 level was observed.Conclusion:Valtrex is effective on herpes zoster by regulating T cell subset, IL6 and IL10 levels.

  9. 内毒素对大鼠淋巴细胞表达TLR4及NF-κB与分泌IL-6的影响%Effects of endotoxin on expression of TLR4 and NF-κB and secretion of IL-6 in rat lymphocytes

    Institute of Scientific and Technical Information of China (English)

    段吉明; 李文星; 张毅; 温勃阳; 申素纲; 魏星; 尹金祥

    2014-01-01

    Objective To investigate the changing of expression of TLR4 mRNA and NF-κB mRNA and secretion of IL-6 when rat lymphocytes were intervened by endotoxin, and to study the effect and mechanism of lymphocytes in the progress of SIRS. Methods Healthy male Wistar Rat spleen lymphocytes were prepared and cultivated to exponential phase, and were divided into control and experimental group randomly. Control group did not received any treatment. Experimental groups were adjusted the concentration of low concentration group (10 ng/ml) and high concentration group (100 ng/ml) by adding different amounts of endotoxin, and cultivated the cells to 3 h, 6 h and 12 h. RT-PCR technology was used to detect the expressional levels of TLR4 mRNA and NF-κB mRNA, and ELISA technology detected the secretion of IL-6. Results When cells were intervened in 3 hours later, the mRNA expression of TLR4 and NF-κB compared with the control group had no significant difference (P>0.05), and the secretion of IL-6 compared with the control group was statistically significant (P0.05) in the high concentration group. When cells were intervened in 6 and 12 hours later, mRNA expression of TLR4 and NF-κB and secretion of IL-6 compared with the control group respectively had significant difference in low or high concentration group (P<0.05). In addition, mRNA expression of TLR4 and NF-κB and secretion of IL-6 increased with time increasing. Conclusion Endotoxin can stimulate rat lymphocytes to express high TLR4 and NF-κB and secret all kinds of cytokines and inflammatory mediators, including the IL-6, promote the development of SIRS further.%目的:研究内毒素干预离体大鼠淋巴细胞后TLR4 mRNA、NF-κB mRNA的表达及IL-6分泌的变化,探讨淋巴细胞在全身炎症反应综合征(SIRS)发生及进展中的作用机制。方法制备健康雄性Wistar大鼠脾脏淋巴细胞,培养至对数期,随机分为对照组和实验组。对照组不做处理。实验组加入不

  10. Synergistic cooperation between methamphetamine and HIV-1 gsp120 through the P13K/Akt pathway induces IL-6 but not IL-8 expression in astrocytes.

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    Ankit Shah

    Full Text Available HIV-1 envelope protein gp120 has been extensively studied for neurotoxic effects that have been attributed to the increased expression of various proinflammatory cytokines in the CNS. Recently we have shown that methamphetamine (MA also increases expression of proinflammatory cytokines in astrocytes. However, combined effect of gp120 and MA is not known. The present study was undertaken to determine cumulative effect and the mechanism(s/pathways involved in the functional interaction between gp120 and MA in SVGA astrocytes. Our results clearly suggest that gp120 and MA affect IL-6 but not IL-8 in a synergistic manner and this synergy was mediated by PI3K/Akt and NF-κB pathways. Inhibition of either of these pathways could abrogate the increased expression of IL-6 due to MA or gp120 alone, as well as the increased expression of IL-6 when the astrocytes were treated with both gp120 and MA. These results were confirmed by both, using chemical inhibitors/siRNA as well as western blotting. This study therefore provides novel information regarding the interaction between MA and gp120 in terms of the expression of IL-6 and the mechanisms underlying potential synergy between MA and gp120 in astrocytes.

  11. Theobroma cacao increases cells viability and reduces IL-6 and sVCAM-1 level in endothelial cells induced by plasma from preeclamptic patients.

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    Rahayu, Budi; Baktiyani, Siti Candra Windu; Nurdiana, Nurdiana

    2016-01-01

    This study aims to investigate whether an ethanolic extract of Theobroma cacao bean is able to increase cell viability and decrease IL-6 and sVCAM-1 in endothelial cells induced by plasma from preeclamptic patients. Endothelial cells were obtained from human umbilical vascular endothelial cells. At confluency, endothelial cells were divided into six groups, which included control (untreated), endothelial cells exposed to plasma from normal pregnancy, endothelial cells exposed to 2% plasma from preeclamptic patients (PP), endothelial cells exposed to PP in the presence of ethanolic extract of T. cacao (PP+TC) at the following three doses: 25, 50, and 100 ppm. The analysis was performed in silico using the Hex 8.0, LigPlus and LigandScout 3.1 software. Analysis on IL-6 and sVCAM-1 levels were done by enzyme linked immunosorbent assay (ELISA). We found that seven of them could bind to the protein NFκB (catechin, leucoanthocyanidin, niacin, phenylethylamine, theobromine, theophylline, and thiamin). This increase in IL-6 was significantly (Pcacao extract. Plasma from PP significantly increased sVCAM-1 levels compared to untreated cells. This increase in sVCAM-1 was significantly attenuated by all doses of the extract. In conclusion, T. cacao extract prohibits the increase in IL-6 and sVCAM-1 in endothelial cells induced by plasma from preeclamptic patients. Therefore this may provide a herbal therapy for attenuating the endothelial dysfunction found in preeclampsia.

  12. Leprosy Reactions Show Increased Th17 Cell Activity and Reduced FOXP3+ Tregs with Concomitant Decrease in TGF-β and Increase in IL-6.

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    Chaman Saini

    2016-04-01

    Full Text Available 50% of leprosy patients suffer from episodes of Type 1/ reversal reactions (RR and Type 2/ Erythema Nodosum Leprosum (ENL reactions which lead to morbidity and nerve damage. CD4+ subsets of Th17 cells and CD25+FOXP3+ regulatory T cells (Tregs have been shown to play a major role in disease associated immunopathology and in stable leprosy as reported by us and others. The aim of our study was to analyze their role in leprosy reactions.Quantitative reverse transcribed PCR (qPCR, flowcytometry and ELISA were used to respectively investigate gene expression, cell phenotypes and supernatant levels of cytokines in antigen stimulated PBMC cultures in patients with stable disease and those undergoing leprosy reactions. Both types of reactions are associated with significant increase of Th17 cells and associated cytokines IL-17A, IL-17F, IL-21, IL-23 and chemokines CCL20, CCL22 as compared to matching stable forms of leprosy. Concurrently patients in reactions show reduction in FOXP3+ Treg cells as well as reduction in TGF-β and increase in IL-6. Moreover, expression of many T cell markers, cytokines, chemokines and signaling factors were observed to be increased in RR as compared to ENL reaction patients.Patients with leprosy reactions show an imbalance in Th17 and Treg populations. The reduction in Treg suppressor activity is associated withhigherTh17cell activity. The combined effect of reduced TGF-β and enhanced IL-6, IL-21 cytokines influence the balance between Th17 or Treg cells in leprosy reactions as reported in the murine models and autoimmune diseases. The increase in Th17 cell associated cytokines may contribute to lesional inflammation.

  13. Leprosy Reactions Show Increased Th17 Cell Activity and Reduced FOXP3+ Tregs with Concomitant Decrease in TGF-β and Increase in IL-6

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    Saini, Chaman; Siddiqui, Anisuddin; Ramesh, Venkatesh; Nath, Indira

    2016-01-01

    Background 50% of leprosy patients suffer from episodes of Type 1/ reversal reactions (RR) and Type 2/ Erythema Nodosum Leprosum (ENL) reactions which lead to morbidity and nerve damage. CD4+ subsets of Th17 cells and CD25+FOXP3+ regulatory T cells (Tregs) have been shown to play a major role in disease associated immunopathology and in stable leprosy as reported by us and others. The aim of our study was to analyze their role in leprosy reactions. Methodology and Principle Findings Quantitative reverse transcribed PCR (qPCR), flowcytometry and ELISA were used to respectively investigate gene expression, cell phenotypes and supernatant levels of cytokines in antigen stimulated PBMC cultures in patients with stable disease and those undergoing leprosy reactions. Both types of reactions are associated with significant increase of Th17 cells and associated cytokines IL-17A, IL-17F, IL-21, IL-23 and chemokines CCL20, CCL22 as compared to matching stable forms of leprosy. Concurrently patients in reactions show reduction in FOXP3+ Treg cells as well as reduction in TGF-β and increase in IL-6. Moreover, expression of many T cell markers, cytokines, chemokines and signaling factors were observed to be increased in RR as compared to ENL reaction patients. Conclusions Patients with leprosy reactions show an imbalance in Th17 and Treg populations. The reduction in Treg suppressor activity is associated withhigherTh17cell activity. The combined effect of reduced TGF-β and enhanced IL-6, IL-21 cytokines influence the balance between Th17 or Treg cells in leprosy reactions as reported in the murine models and autoimmune diseases. The increase in Th17 cell associated cytokines may contribute to lesional inflammation. PMID:27035913

  14. Long-term aerobic exercise protects against cisplatin-induced nephrotoxicity by modulating the expression of IL-6 and HO-1.

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    Mariana Yasue Saito Miyagi

    Full Text Available Nephrotoxicity is substantial side effect for 30% of patients undergoing cancer therapy with cisplatin and may force them to change or even abandon the treatment. Studies regarding aerobic exercise have shown its efficacy for the treatment of many types of diseases and its capacity to reduce tumors. However, little is known about the impact of physical exercise on cisplatin-induced acute kidney injury (AKI. In the present study, our aim was to investigate the role of physical exercise in AKI induced by cisplatin. We submitted C57Bl6 male mice to seven weeks of chronic exercise on a training treadmill and treated them with single i.p. injection of cisplatin (20 mg/kg in the last week. Exercise efficacy was confirmed by an increased capillary-to-fiber ratio in the gastrocnemius muscle of exercised groups (EX and CIS-EX. The group submitted to exercise before cisplatin administration (CIS-EX exhibited less weight loss and decreased serum urea levels compared to the cisplatin group (CIS. Exercise also showed a protective role against cisplatin-induced cell death in the kidney. The CIS-EX group showed a lower inflammatory response, with less TNF and IL-10 expression in the kidney and serum. In the same group, we observed an increase of IL-6 and HO-1 expression in the kidney. Taken together, our results indicate that chronic aerobic exercise is able to attenuate AKI by inducing IL-6 and HO-1 production, which results in lower inflammatory and apoptotic profiles in the kidney.

  15. Trypanosoma cruzi infection induces the expression of CD40 in murine cardiomyocytes favoring CD40 ligation-dependent production of cardiopathogenic IL-6.

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    Ayala, Mariela Alejandra Moreno; Casasco, Agustina; González, Mariela; Postan, Miriam; Corral, Ricardo Santiago; Petray, Patricia Beatriz

    2016-02-01

    The inflammatory response in the myocardium is an important aspect of the pathogenesis of Chagas' heart disease raised by Trypanosoma cruzi. CD40, a transmembrane type I receptor belonging to the tumor necrosis factor receptor (TNFR) family, is expressed in a broad spectrum of cell types and is crucial in several inflammatory and autoimmune diseases. Activation of CD40 through ligation to CD40L (CD154) induces multiple effects, including the secretion of proinflammatory molecules. In the present study, we examined the ability of T. cruzi to trigger the expression of CD40 in cardiac myocytes in vitro and in a murine model of chagasic cardiomyopathy. Our results indicate, for the first time, that T. cruzi is able to induce the expression of CD40 in HL-1 murine cardiomyocytes. Moreover, ligation of CD40 receptor upregulated interleukin-6 (IL-6), associated with inflammation. Furthermore, the induction of this costimulatory molecule was demonstrated in vivo in myocardium of mice infected with T. cruzi. This suggests that CD40-bearing cardiac muscle cells could interact with CD40L-expressing lymphocytes infiltrating the heart, thus contributing to inflammatory injury in chagasic cardiomyopathy.

  16. PDTC对LPS诱导小鼠肝组织IL-6表达的抑制作用%Inhibitory Effect of PDTC on Expression of IL-6 Induced by LPS in Mouse Liver Tissues

    Institute of Scientific and Technical Information of China (English)

    王永堂; 鲁秀敏; 李关荣; 伍亚民

    2003-01-01

    以小鼠肝组织为材料,采用酶联免疫吸附测定法检测不同剂量LPS诱导肝组织中IL-6水平的动态变化,并观察了抗氧化剂吡咯啉烷二硫代氨基甲酸盐(Pyrrolidine dithiocarbamate, PDTC)对肝组织IL-6表达的影响.结果表明:注射5 mg/kg LPS后3 h,肝组织IL-6的水平达峰值,PDTC能有效抑制肝组织中IL-6的表达.因此,抗氧化剂有望成为炎症疾病治疗中一类很有应用前景的药物.

  17. Adhesion-independent synergy of monocytes and endothelial cells in cytokine production: regulation of IL-6 and GM–CSF production by PAF

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    C. Lacasse

    1996-01-01

    Full Text Available Co-Cultures of monocytes (MO and endothelial cells (EC were studied for their capacity to synergize in the production of interleukin-6 (IL-6 and granulocyte-macrophage colony-stimulating factor (GM–CSF, two cytokines potentially important in vascular physiopathology. Resting monocytes produced detectable amounts of IL-6 but no GM–CSF, whereas confluent EC produced significant quantities of GM–CSF, but minimal IL-6. In co-cultures without stimuli, additive synthesis of both cytokines was observed. When EC were pretreated, however, with either PAF, TNF or both stimuli, before addition of MO, synergistic production of IL-6 was observed. In contrast, GM–CSF production was not enhanced by coculture of monocytes with activated EC. When either cell population was fixed with paraformaldehyde or killed by freeze-thawing before addition to the co-culture, cytokine levels reverted to those produced by the unaffected population alone. On the other hand, separating the two cell populations by a cell-impermeable membrane in transwell cultures did not affect the synergistic production of the cytokines. Taken together, our data suggest that EC and MO can synergize in response to stimuli by producing IL-6 and that this synergy is dependent on the integrity of both cell populations, but independent of cell-cell contact.

  18. Expression of IL-8, IL-6 and IL-1β in tears as a main characteristic of the immune response in human microbial keratitis.

    Science.gov (United States)

    Santacruz, Concepcion; Linares, Marisela; Garfias, Yonathan; Loustaunau, Luisa M; Pavon, Lenin; Perez-Tapia, Sonia Mayra; Jimenez-Martinez, Maria C

    2015-03-03

    Corneal infections are frequent and potentially vision-threatening diseases, and despite the significance of the immunological response in animal models of microbial keratitis (MK), it remains unclear in humans. The aim of this study was to describe the cytokine profile of tears in patients with MK. Characteristics of ocular lesions such as size of the epithelial defect, stromal infiltration, and hypopyon were analyzed. Immunological evaluation included determination of interleukine (IL)-1β, IL-6, IL-8, IL-10, IL-12 and tumor necrosis factor (TNF)-α in tear samples obtained from infected eyes of 28 patients with MK and compared with their contralateral non-infected eyes. Additionally, frequency of CD4+, CD8+, CD19+ and CD3-CD56+ cells was also determined in peripheral blood mononuclear cells in patients with MK, and compared with 48 healthy controls. Non-significant differences were observed in the size of the epithelial defect, stromal infiltration, and hypopyon. Nevertheless, we found an immunological profile apparently related to MK etiology. IL-8 > IL-6 in patients with bacterial keratitis; IL-8 > IL-6 > IL-1β and increased frequency of circulating CD3-CD56+ NK cells in patients with gram-negative keratitis; and IL-8 = IL-6 > IL-1β in patients with fungal keratitis. Characterization of tear cytokines from patients with MK could aid our understanding of the immune pathophysiological mechanisms underlying corneal damage in humans.

  19. IL-6 Induces Pancreatic β Cell Apoptosis via Down-regulation of Sirt1 and Activation of p53/caspase-3 Pathway%IL-6通过Sirt1/p53/caspase-3通路介导胰岛β细胞凋亡

    Institute of Scientific and Technical Information of China (English)

    刘波; 林雅军; 黎健

    2011-01-01

    目的 探讨炎性因子IL-6是否通过Sirt1/p53/caspase-3通路介导胰岛β细胞凋亡.方法 Western 印迹检测Sirt1在小鼠各组织器官和胰岛β细胞系NIT-1细胞中的表达,免疫荧光法检测Sirt1在细胞中的定位.IL-6(10 ng/ml)处理NIT-1细胞48 h,Hoechst3334染色及流式细胞仪检测细胞凋亡,Western印迹检测细胞内Sirt1、P53、乙酰化P53(acety-P53)、caspase-3和cleaved caspase-3的水平变化.结果 Sirt1在小鼠各组织器官和胰岛β细胞中均有表达,主要定位于细胞核.IL-6处理NIT-1细胞后,伴随Sirt1表达的显著减少,acety-P53明显上调,p53/caspase-3通路活化,NIT-1细胞凋亡增加.结论 IL-6通过下调Sirt1进而激活p53/caspase-3信号通路引起胰岛β细胞凋亡.%Objective To investigate whether IL-6 induces pancreatic β cell apoptosis through down-regulation of Sirt1 and activation of p53/caspase-3 pathway. Methods Sirt1 expression in diverse mouse organs and pancreatic β cell line NIT-1 was detected by Western blot. The location of Sirtl in NIT-1 cells was observed by immunofluorescence. After treated with 1Ong/ml IL-6 for 48 h,apoptosis of NIT-1 cells was detected by Hoechst3334 staining and flow cytometry. Western blot was used to analyze the levels of Sirt1, p53, acety-p53, caspase-3 and cleaved caspase-3, respectively. Results Sirt1 was expressed in diverse mouse organs and pancreatic β cell line NIT-1. and mainly located in the nucleus. Treatment of NIT-1 cells with 1Ong/ml IL-6 for 48 h induced apoptosis, accompanied with decreased Sirt1 level. enhanced acety-p53 and activation of p53/caspase3. Conclusion IL-6 induces NIT-1 cell apoptosis via down-regulation of Sirt1 and activation of p53/caspase -3 pathway.

  20. Human Mesenchymal Stem Cell-Educated Macrophages Are a Distinct High IL-6-Producing Subset that Confer Protection in Graft-versus-Host-Disease and Radiation Injury Models.

    Science.gov (United States)

    Bouchlaka, Myriam N; Moffitt, Andrea B; Kim, Jaehyup; Kink, John A; Bloom, Debra D; Love, Cassandra; Dave, Sandeep; Hematti, Peiman; Capitini, Christian M

    2017-02-28

    Mesenchymal stem cells (MSCs) have immunosuppressive and tissue repair properties, but clinical trials using MSCs to prevent or treat graft-versus-host disease (GVHD) have shown mixed results. Macrophages (MØs) are important regulators of immunity and can promote tissue regeneration and remodeling. We have previously shown that MSCs can educate MØs toward a unique anti-inflammatory immunophenotype (MSC-educated macrophages [MEMs]); however, their implications for in vivo models of inflammation have not been studied yet. We now show that in comparison with MØs, MEMs have increased expression of the inhibitory molecules PD-L1, PD-L2, in addition to markers of alternatively activated macrophages: CD206 and CD163. RNA-Seq analysis of MEMs, as compared with MØs, show a distinct gene expression profile that positively correlates with multiple pathways important in tissue repair. MEMs also show increased expression of IL-6, transforming growth factor-β, arginase-1, CD73, and decreased expression of IL-12 and tumor necrosis factor-α. We show that IL-6 secretion is controlled in part by the cyclo-oxygenase-2, arginase, and JAK1/STAT1 pathway. When tested in vivo, we show that human MEMs significantly enhance survival from lethal GVHD and improve survival of mice from radiation injury. We show these effects could be mediated in part through suppression of human T cell proliferation and may have attenuated host tissue injury in part by enhancing murine fibroblast proliferation. MEMs are a unique MØ subset with therapeutic potential for the management of GVHD and/or protection from radiation-induced injury.

  1. IL-6 Inhibition Reduces STAT3 Activation and Enhances the Antitumor Effect of Carboplatin

    Science.gov (United States)

    Wang, Zhi-Yong; Zhang, Jun-Ai; Wu, Xian-Jin; Liang, Yan-Fang; Lu, Yuan-Bin; Gao, Yu-Chi; Dai, You-Chao; Yu, Shi-Yan; Jia, Yan; Fu, Xiao-Xia; Rao, Xiaoquan; Xu, Jun-Fa

    2016-01-01

    Recent studies suggest that tumor-associated macrophage-produced IL-6 is an important mediator within the tumor microenvironment that promotes tumor growth. The activation of IL-6/STAT3 axis has been associated with chemoresistance and poor prognosis of a variety of cancers including colorectal carcinoma and thus serves as a potential immunotherapeutic target for cancer treatment. However, it is not fully understood whether anticytokine therapy could reverse chemosensitivity and enhance the suppressive effect of chemotherapy on tumor growth. In this study, we aimed to investigate the effect of IL-6 inhibition therapy on the antitumor effect of carboplatin. Enhanced expression of IL-6 and activation of STAT3 were observed in human colorectal carcinoma samples compared to normal colorectal tissue, with higher levels of IL-6/STAT3 in low grade carcinomas. Treatment of carboplatin (CBP) dose-dependently increased IL-6 production and STAT3 activation in human colorectal LoVo cells. Blockade of IL-6 with neutralizing antibody enhanced chemosensitivity of LoVo cells to carboplatin as evidenced by increased cell apoptosis. IL-6 blockade abolished carboplatin-induced STAT3 activation. IL-6 blockade and carboplatin synergistically reduced cyclin D1 expression and enhanced caspase-3 activity in LoVo cells. Our results suggest that inhibition of IL-6 may enhance chemosensitivity of colon cancers with overactive STAT3 to platinum agents. PMID:27006530

  2. IL-6 Inhibition Reduces STAT3 Activation and Enhances the Antitumor Effect of Carboplatin

    Directory of Open Access Journals (Sweden)

    Zhi-Yong Wang

    2016-01-01

    Full Text Available Recent studies suggest that tumor-associated macrophage-produced IL-6 is an important mediator within the tumor microenvironment that promotes tumor growth. The activation of IL-6/STAT3 axis has been associated with chemoresistance and poor prognosis of a variety of cancers including colorectal carcinoma and thus serves as a potential immunotherapeutic target for cancer treatment. However, it is not fully understood whether anticytokine therapy could reverse chemosensitivity and enhance the suppressive effect of chemotherapy on tumor growth. In this study, we aimed to investigate the effect of IL-6 inhibition therapy on the antitumor effect of carboplatin. Enhanced expression of IL-6 and activation of STAT3 were observed in human colorectal carcinoma samples compared to normal colorectal tissue, with higher levels of IL-6/STAT3 in low grade carcinomas. Treatment of carboplatin (CBP dose-dependently increased IL-6 production and STAT3 activation in human colorectal LoVo cells. Blockade of IL-6 with neutralizing antibody enhanced chemosensitivity of LoVo cells to carboplatin as evidenced by increased cell apoptosis. IL-6 blockade abolished carboplatin-induced STAT3 activation. IL-6 blockade and carboplatin synergistically reduced cyclin D1 expression and enhanced caspase-3 activity in LoVo cells. Our results suggest that inhibition of IL-6 may enhance chemosensitivity of colon cancers with overactive STAT3 to platinum agents.

  3. Co-stimulation of cultured peripheral blood mononuclear cells from intrinsic asthmatics with exogenous recombinant IL-6 produce high levels of IL-4-dependent IgE.

    Science.gov (United States)

    Sánchez-Guerrero, I M; Herrero, N; Muro, M; Vegara, R P; Campos, M; García-Alonso, A M; Alvarez, M R

    1997-09-01

    Asthma is an inflammatory airway disorder, traditionally subdivided into extrinsic, immunoglobulin E (IgE)-mediated, and intrinsic asthma of unknown aetiology. IgE synthesis requires contact between T- and B-cells and a signal provided by interleukin (IL)-4, which can be modulated by IL-6. The objective of this study was to evaluate the effects of IL-4 and IL-6 on total IgE synthesis by peripheral blood mononuclear cells from intrinsic and extrinsic asthmatics. Peripheral blood mononuclear cells from intrinsic and extrinsic asthmatic patients and from healthy subjects were cultured and stimulated with pokeweed mitogen, recombinant IL-4 and IL-6. The IgE level in serum and supernatants was measured by an enzyme-linked immunoassay. Serum IgE was significantly lower in intrinsic asthma than in extrinsic asthma, but significantly higher than in control subjects. IgE production by cultured mononuclear cells from extrinsic asthmatics was not modified after exogenous IL-4 and IL-6 addition. However, intrinsic asthmatics showed enhancement of IgE synthesis in response to IL-4 stimulation, reaching a threefold increase of the spontaneous IgE values, when simultaneous recombinant IL-4 plus IL-6 stimulus was used. Our results indicate that exogenous recombinant interleukin-6 can significantly upregulate the interleukin-4-dependent immunoglobulin E synthesis in intrinsic asthma. This suggests that immunoglobulin E could also play a role in the pathogenesis of intrinsic asthma, in which an interleukin-6 threshold would be critical.

  4. Hypoxic preconditioning induces neuroprotective stanniocalcin-1 in brain via IL-6 signaling

    DEFF Research Database (Denmark)

    Westberg, Johan A; Serlachius, Martina; Lankila, Petri

    2007-01-01

    . Increased expression of IL-6 is evident, particularly in the lungs of animals subjected to hypoxic preconditioning. Stanniocalcin-1 (STC-1) is a 56-kDa homodimeric glycoprotein originally discovered in bony fish, where it regulates calcium/phosphate homeostasis and protects against toxic hypercalcemia. We...... mRNA levels in brains of wild-type and IL-6 deficient mice. Furthermore, we monitored the Stc-1 response in brains of wild-type and transgenic mice, overexpressing IL-6 in the astroglia, before and after induced brain injury. RESULTS: Hypoxic preconditioning induced an upregulated expression of Stc......-1 in brains of wild-type but not of IL-6-deficient mice. Induced brain injury elicited a stronger STC-1 response in brains of transgenic mice, with targeted astroglial IL-6 expression, than in brains of wild-type mice. Moreover, IL-6 induced STC-1 expression via MAPK signaling in neural Paju cells...

  5. Function of Integrin-Linked Kinase in Modulating the Stemness of IL-6–Abundant Breast Cancer Cells by Regulating γ-Secretase–Mediated Notch1 Activation in Caveolae

    Directory of Open Access Journals (Sweden)

    En-Chi Hsu

    2015-06-01

    Full Text Available Interleukin-6 (IL-6 and Notch signaling are important regulators of breast cancer stem cells (CSCs, which drive the malignant phenotype through self-renewal, differentiation, and development of therapeutic resistance. We investigated the role of integrin-linked kinase (ILK in regulating IL-6–driven Notch1 activation and the ability to target breast CSCs through ILK inhibition. Ectopic expression/short hairpin RNA-mediated knockdown of ILK, pharmacological inhibition of ILK with the small molecule T315, Western blot analysis, immunofluorescence, and luciferase reporter assays were used to evaluate the regulation of IL-6–driven Notch1 activation by ILK in IL-6–producing triple-negative breast cancer cell lines (MDA-MB-231, SUM-159 and in MCF-7 and MCF-7IL-6 cells. The effects of ILK on γ-secretase complex assembly and cellular localization were determined by immunofluorescence, Western blots of membrane fractions, and immunoprecipitation. In vivo effects of T315-induced ILK inhibition on CSCs in SUM-159 xenograft models were assessed by mammosphere assays, flow cytometry, and tumorigenicity assays. Results show that the genetic knockdown or pharmacological inhibition of ILK suppressed Notch1 activation and the abundance of the γ-secretase components presenilin-1, nicastrin, and presenilin enhancer 2 at the posttranscriptional level via inhibition of caveolin-1-dependent membrane assembly of the γ-secretase complex. Accordingly, knockdown of ILK inhibited breast CSC-like properties in vitro and the breast CSC subpopulation in vivo in xenograft tumor models. Based on these findings, we propose a novel function of ILK in regulating γ-secretase–mediated Notch1 activation, which suggests the targeting of ILK as a therapeutic approach to suppress IL-6–induced breast CSCs.

  6. Overexpression of S100A7 protects LPS-induced mitochondrial dysfunction and stimulates IL-6 and IL-8 in HaCaT cells.

    Directory of Open Access Journals (Sweden)

    Wenyan Sun

    Full Text Available S100A7 (or psoriasin is distributed in the cytoplasm of keratinocytes of normal human epidermis, and it is overexpressed in many epidermal inflammatory diseases. Lipopolysaccharide (LPS induces mitochondrial function changes, which play important roles in multiple cellular mechanisms including inflammation. Although S100A7 expression is regulated by various factors in the human epidermis during inflammation, whether S100A7 interacts with mitochondria in keratinocytes is not clear.Our study was designed to investigate whether S100A7 could prohibit mitochondrial dysfunction and stimulate cytokines in cultured normal HaCaT cells treated with LPS.We generated HaCaT cells that constitutively express enhanced green fluorescence protein (EGFP-S100A7 (S100A7-EGFP or EGFP alone, as a control. Here, we show that S100A7-EGFP HaCaT cells exhibit an increase in mitochondrial DNA (mtDNA copy number and mitochondrial membrane potential (MMP. qRT-PCR revealed that expression of three main mitochondrial biogenesis-associated genes was significantly increased: PPAR-coactivator-1alpha (PGC-1α, the mitochondrial transcription factor A (Tfam and nuclear respiratory factor-1 (NRF1. S100A7 overexpression increased mtDNA content and effectively increased intracellular adenosine 5'-triphosphate (ATP production, while decreasing reactive oxygen species (ROS generation. S100A7 overexpression also significantly decreased the expression of Mfn2 and increased DRP1 expression compared with control EGFP cells. S100A7 down-regulated the expression of the autophagy-related proteins Beclin-1 and LC3B. S100A7 also increased expression of IL-6 and IL-8 cytokines. Knockdown of S100A7 decreased MMP and disrupted mitochondrial homeostasis.These findings demonstrate that S100A7 stimulates mitochondrial biogenesis and increases mitochondrial function in HaCaT cells treated with LPS; and S100A7 also promotes secretion of IL-6 and IL-8.

  7. Muscle glycogen depletion following 75-km of cycling is not linked to increased muscle IL-6, IL-8, and MCP-1 mRNA expression and protein content

    Directory of Open Access Journals (Sweden)

    David Christopher Nieman

    2016-09-01

    Full Text Available The cytokine response to heavy exertion varies widely for unknown reasons, and this study evaluated the relative importance of glycogen depletion, muscle damage, and stress hormone changes on blood and muscle cytokine measures. Cyclists (N=20 participated in a 75-km cycling time trial (168±26.0 min, with blood and vastus lateralis muscle samples collected before and after. Muscle glycogen decreased 77.2±17.4%, muscle IL-6, IL-8, and MCP-1 mRNA increased 18.5±2.8-, 45.3±7.8-, and 8.25±1.75-fold, and muscle IL-6, IL-8, and MCP-1 protein increased 70.5±14.1%, 347±68.1%, and 148±21.3%, respectively (all, P<0.001. Serum myoglobin and cortisol increased 32.1±3.3 to 242±48.3 mg/mL, and 295±27.6 to 784±63.5 nmol/L, respectively (both P<0.001. Plasma IL-6, IL-8, and MCP-1 increased 0.42±0.07 to 18.5±3.8, 4.07±0.37 to 17.0±1.8, and 96.5±3.7 to 240±21.6 pg/mL, respectively (all P<0.001. Increases in muscle IL-6, IL-8, and MCP-1 mRNA were unrelated to any of the outcome measures. Muscle glycogen depletion was related to change in plasma IL-6 (r=0.462, P=0.040, with change in myoglobin related to plasma IL-8 (r=0.582, P=0.007 and plasma MCP-1 (r=0.457, P=0.043, and muscle MCP-1 protein (r=0.588, P=0.017; cortisol was related to plasma IL-8 (r=0.613, P=0.004, muscle IL-8 protein (r=0.681, P=0.004, and plasma MCP-1 (r=0.442, P=0.050. In summary, this study showed that muscle IL-6, IL-8, and MCP-1 mRNA expression after 75-km cycling was unrelated to glycogen depletion and muscle damage, with change in muscle glycogen related to plasma IL-6, and changes in serum myoglobin and cortisol related to the chemotactic cytokines IL-8 and MCP-1.

  8. Knocking out IL-6 by vaccination

    DEFF Research Database (Denmark)

    Galle, Pia; Hougs, Lotte; Barington, Torben;

    2004-01-01

    Inappropriate expression of IL-6 plays a role in various inflammatory conditions, degenerative diseases, and cancers. Several model systems have been developed that can specifically block IL-6-receptor interactions. Here we present a simple and highly effective approach based on vaccination...

  9. Activation of a pro-survival pathway IL-6/JAK2/STAT3 contributes to glial fibrillary acidic protein induction during the cholera toxin-induced differentiation of C6 malignant glioma cells.

    Science.gov (United States)

    Shu, Minfeng; Zhou, Yuxi; Zhu, Wenbo; Wu, Sihan; Zheng, Xiaoke; Yan, Guangmei

    2011-06-01

    Differentiation-inducing therapy has been proposed to be a novel potential approach to treat malignant gliomas. Glial fibrillary acidic protein (GFAP) is a well-known specific astrocyte biomarker and acts as a tumor suppressor gene (TSG) in glioma pathogenesis. Previously we reported that a traditional biotoxin cholera toxin could induce malignant glioma cell differentiation characterized by morphologic changes and dramatic GFAP expression. However, the molecular mechanisms underlying GFAP induction are still largely unknown. Here we demonstrate that an oncogenic pathway interleukin-6/janus kinase-2/signal transducer and activator of transcription 3 (IL-6/JAK2/STAT3) cascade mediates the cholera toxin-induced GFAP expression. Cholera toxin dramatically stimulated GFAP expression at the transcriptional level in C6 glioma cells. Meanwhile, phosphorylation of STAT3 and JAK2 was highly induced in a time-dependent manner after cholera toxin incubation, whereas no changes of STAT3 and JAK2 were observed. Furthermore, the IL-6 gene was quickly induced by cholera toxin and subsequent IL-6 protein secretion was stimulated. Importantly, exogenous recombinant rat IL-6 can also induce phosphorylation of STAT3 concomitant with GFAP expression while JAK2 specific inhibitor AG490 could effectively block both cholera toxin- and IL-6-induced GFAP expression. Given that the methylation of the STAT3 binding element can suppress GFAP expression, we detected the methylation status of the critical recognition sequence of STAT3 in the promoter of GFAP gene (-1518 ∼ -1510) and found that it was unmethylated in C6 glioma cells. In addition, neither DNA methyltransferase1 (DNMT1) inhibitor 5-Aza-2'-deoxycytidine (5-AZa-CdR) nor silencing DNMT1 can stimulate GFAP expression, indicating that the loss of GFAP expression in C6 cells is not caused by its promoter hypermethylation. Taken together, our findings suggest that activation of a pro-survival IL-6/JAK2/STAT3 cascade contributes to

  10. Herbal Extract SH003 Suppresses Tumor Growth and Metastasis of MDA-MB-231 Breast Cancer Cells by Inhibiting STAT3-IL-6 Signaling

    Directory of Open Access Journals (Sweden)

    Youn Kyung Choi

    2014-01-01

    Full Text Available Cancer inflammation promotes cancer progression, resulting in a high risk of cancer. Here, we demonstrate that our new herbal extract, SH003, suppresses both tumor growth and metastasis of MDA-MB-231 breast cancer cells via inhibiting STAT3-IL-6 signaling path. Our new herbal formula, SH003, mixed extract from Astragalus membranaceus, Angelica gigas, and Trichosanthes kirilowii Maximowicz, suppressed MDA-MB-231 tumor growth and lung metastasis in vivo and reduced the viability and metastatic abilities of MDA-MB-231 cells in vitro. Furthermore, SH003 inhibited STAT3 activation, which resulted in a reduction of IL-6 production. Therefore, we conclude that SH003 suppresses highly metastatic breast cancer growth and metastasis by inhibiting STAT3-IL-6 signaling path.

  11. Microglia-induced IL-6 protects against neuronal loss following HSV-1 infection of neural progenitor cells.

    Science.gov (United States)

    Chucair-Elliott, Ana J; Conrady, Christopher; Zheng, Min; Kroll, Chandra M; Lane, Thomas E; Carr, Daniel J J

    2014-09-01

    Herpes virus type 1 (HSV-1) is one of the most widespread human pathogens and accounts for more than 90% of cases of herpes simplex encephalitis (HSE) causing severe and permanent neurologic sequelae among surviving patients. We hypothesize such CNS deficits are due to HSV-1 infection of neural progenitor cells (NPCs). In vivo, HSV-1 infection was found to diminish NPC numbers in the subventricular zone. Upon culture of NPCs in conditions that stimulate their differentiation, we found HSV-1 infection of NPCs resulted in the loss of neuronal precursors with no significant change in the percentage of astrocytes or oligodendrocytes. We propose this is due a direct effect of HSV-1 on neuronal survival without alteration of the differentiation process. The neuronal loss was prevented by the addition of microglia or conditioned media from NPC/microglia co-cultures. Using neutralizing antibodies and recombinant cytokines, we identified interleukin-6 (IL-6) as responsible for the protective effect by microglia, likely through its downstream Signal Transducer and Activator of Transcription 3 (STAT3) cascade.

  12. The Expression of IL-6,IL-8 and TNF-αin Plasma of Breast Cancer Patients%乳腺癌患者血浆中IL-6、IL-8及TNF-α的表达

    Institute of Scientific and Technical Information of China (English)

    刘杨; 陈利琴; 王文斌; 缪文青; 黄明; 陈大平

    2016-01-01

    目的:探讨血浆中白细胞介素( IL)-6、IL-8及肿瘤坏死因子-α( TNF- a)与乳腺癌发生发展、临床分期及骨转移的关系。方法:111例乳腺肿瘤患者根据病理结果分为乳腺良性肿瘤组( n=50)、乳腺癌组( n=61),50例健康妇女作为正常对照组,采用酶联免疫吸附( ELISA)法分别检测3组患者血浆中IL-6、IL-8及TNF-α的水平,分析3项指标与乳腺癌临床分析、肿瘤转移以及年龄(≥50岁和<50岁)的关系。结果:乳腺癌组血浆IL-6、IL-8及TNF-α水平明显高于良性肿瘤组和正常对照组( P<0.05);随着乳腺癌临床分期的提高,IL-6、IL-8及TNF-α水平逐渐升高( P<0.05);乳腺癌骨转移患者血浆IL-6、IL-8及TNF-α水平明显高于乳腺癌无转移及乳腺癌其他脏器转移患者( P <0.05);年龄对乳腺癌患者血清 IL-6、IL-8及 TNF-α水平影响不大( P >0.05)。结论:血清IL-6、IL-8及TNF-α水平与乳腺癌的发生发展有关。%Objective:To discussthe relatiohship betweeh plasma ihterleukih(IL)-6,IL-8 ahd tumor hecrosis factor-α( TNF-α)ahd the developmeht,clihical stage ahd bohe metastasis of breast cahcer. Methods:Accordihg to the pathological results,111 cases of breast cahcer patiehtswere divided ihto behigh breast tumor group( n =50 ),breast cahcer group( n =61 ),50 healthy womeh as cohtrol group. Plasma IL-6,IL-8 ahd TNF-α levels of hormal cohtrol group,breast behigh tumor group ahd breast cahcer of 3 groups were measured by ehzyme-lihked immuhosorbeht( ELISA). Theh their cor-relatioh with clihical biological characteristics of breast cahcer was ahalyzed. Results:Plasma IL-6, IL-8 ahd TNF-α levels ih breast cahcer group were sighificahtly higher thah those ih behigh tumor group( P0 . 05 ). Conclusion:Plasma IL-6 ,IL-8 ahd TNF-αlevels may be associated with the developmeht of breast cahcer.

  13. Effect of IL6 and IL23 on double negative T cells and anti ds-DNA in systemic lupus erythematosus patients.

    Science.gov (United States)

    Shaltout, Asmaa S; Sayed, Douaa; Badary, Mohamed S; Nafee, Amany M; El Zohri, Mona H; Bakry, Rania; Ahmed, Shabaan H

    2016-10-01

    Several evidences suggest that DN T cells, IL23 and IL6 play a role in the pathogenesis of SLE. This study aimed to evaluate the frequency of DN T cells in SLE patients and the relation to their activity also to assess the possible role of IL6 and IL23 on DN T cells. Thirty patients with SLE and sixteen healthy blood donor females were enrolled. There was a significant increase in DN T cells in patients than controls (P=0.001). These cells had a significant positive correlation with SLEDAI (r=0.486, P=0.006). DN T cells from SLE patient samples were expanded when stimulated in vitro with RhIL6 or RhIL23 in patients than controls. Furthermore, anti ds-DNA level was found to be increased in supernatant of PBMCs when stimulated by these cytokines in different concentrations. Our findings suggest that IL6 and IL23 may play role in SLE pathogenesis through their effect on DN T cells and anti ds-DNA.

  14. Generation of Th17 cells in response to intranasal infection requires TGF-β1 from dendritic cells and IL-6 from CD301b+ dendritic cells.

    Science.gov (United States)

    Linehan, Jonathan L; Dileepan, Thamotharampillai; Kashem, Sakeen W; Kaplan, Daniel H; Cleary, Patrick; Jenkins, Marc K

    2015-10-13

    Intranasal (i.n.) infections preferentially generate Th17 cells. We explored the basis for this anatomic preference by tracking polyclonal CD4(+) T cells specific for an MHC class II-bound peptide from the mucosal pathogen Streptococcus pyogenes. S. pyogenes MHC class II-bound peptide-specific CD4(+) T cells were first activated in the cervical lymph nodes following i.n. inoculation and then differentiated into Th17 cells. S. pyogenes-induced Th17 formation depended on TGF-β1 from dendritic cells and IL-6 from a CD301b(+) dendritic cell subset located in the cervical lymph nodes but not the spleen. Thus, the tendency of i.n. infection to induce Th17 cells is related to cytokine production by specialized dendritic cells that drain this site.

  15. Effect of IL-13 on expression of IL-6 in acute renal ischemia/reperfusion injury in rats%IL-13对大鼠急性肾缺血再灌注时IL-6表达的影响

    Institute of Scientific and Technical Information of China (English)

    冯振伟; 江黎明; 陈孝文; 杨展; 吴平; 赵家明; 何惠娟

    2012-01-01

    Objective It is to observe the effects of IL - 13 on expression of IL -6 in acute renal ischemia/reperfusion injury in rats. Methods Thirty-seven male Wistar rats were randomly divided into 5 groups: sham group, I/R group, C group, T - S group and T - L group. Models of acute renal ischemic/reperfusion injury were established by blocking up kidneys blood flow in both side for 45 min and reperfusion for 24h in the rats. Rm - IL - 13 was injected into the renal arteries through the abdominal aorta in T - S group and T - L group( T - S 0. 5 μg/kg body weight, T - L 1. 5 μg/kg body weight ),normal saline instead of rm - IL -13 was injected into the renal arteries through the abdominal aorta in control group. The serum level of IL -6 and the renal expression of IL - 6 were determined in each group at 24 h post-ischemia. In addition, BUN, Cr and renal histology were also measured. Results The serum level of IL - 6 gene expression and protein production of IL - 6 in kidney decreased markedly in T - L group. Renal function and histology were significantly improved in T - L group, renal injury scores decreased significantly too. A positive correlation was found between the serum level of IL - 6, gene expression IL - 6 in kidney and BUN, SCr. Conclusion IL - 13 can inhibit the expression of IL - 6 and improve function and histology of kidney in rats with acute renal ischemia/reperfusion injury.%目的 观察白细胞介素13(IL-13)对急性缺血再灌注肾损伤大鼠IL-6表达的影响.方法 将Wistar雄性大鼠37只随机分为假手术组、I/R组、C组、T-S组和T-L组.阻断大鼠双侧肾脏血流45min,再灌注24h建立急性肾缺血再灌注模型;T-S组和T-L组于阻断血流后分别从双侧肾动脉开口注射入鼠重组白细胞介素13 0.5μg/kg和1.5μg/kg;C组以生理盐水代替.检测各组大鼠IL-6血清水平和肾脏表达情况以及肾功能和肾脏病理变化.结果 T-L组肾脏IL-6基因和蛋白表达明显减少,IL-6血清水平也

  16. Expression of IL-6 and IL-23 in Bowel Mucosa of Patients with Irritable Bowel Syndrome%IL-6、IL-23在肠易激综合征患者肠黏膜的表达及意义

    Institute of Scientific and Technical Information of China (English)

    刘修波; 卫红军; 张巍巍; 王青

    2011-01-01

    Objective: To study expression of interlenkin (IL)-6 and IL-23 in the mucosa of ileum as well as in the ascending colon. Methods: The ileum and ascending colon fiom 70 cases of diarrhea type of lBS, 40 cases of constipation group type of lBS and 30 cases of healthy volunteers as control were collected and detected the IL-6 and IL-23 expression using immunohistochemistry. Rasults:Both diarrhea group and constipation group, IL-6 and IL-23 were highly expressed in the mucosa of ileum and ascending colon than control group (P<0.05). Conclusion: The highly expression of IL-6 and IL-23 in the mucosa of ileum and ascending colon may be related to symptoms of IBS.%目的:研究肠易激综合征(irritable bowel syndrome,IBS)患者回肠末端及升结肠黏膜组织中白介素-6(interleukin-6,IL-6)、白介素-23(interleukin-23,IL-23)的表达.方法:70 例腹泻型和 40 例便秘型 IBS 患者及 30 例健康人,用免疫组化法测定回肠末端及升结肠肠黏膜中IL-6及IL-23水平.结果:IL-6及IL-23在腹泻型及便秘型IBS患者回肠末端及升结肠的表达均高于对照组(P<0.05).结论:IBS患者回肠及升结肠黏膜炎性细胞因子表达水平升高,可能与IBS症状有关.

  17. Effects of TGF-beta and glucocorticoids on map kinase phosphorylation, IL-6/IL-11 secretion and cell proliferation in primary cultures of human lung fibroblasts.

    Science.gov (United States)

    Pelaia, Girolamo; Gallelli, Luca; D'Agostino, Bruno; Vatrella, Alessandro; Cuda, Giovanni; Fratto, Donatella; Renda, Teresa; Galderisi, Umberto; Piegari, Elena; Crimi, Nunzio; Rossi, Francesco; Caputi, Mario; Costanzo, Francesco S; Vancheri, Carlo; Maselli, Rosario; Marsico, Serafino A

    2007-02-01

    Transforming growth factor-beta1 (TGF-beta1) is crucially involved in the fibrotic events characterizing interstitial lung diseases (ILDs), as well as in the airway remodeling process typical of asthma. Within such a context, the aim of our study was to investigate, in primary cultures of normal and fibrotic human lung fibroblasts (HLFs), the effects of TGF-beta1 on mitogen-activated protein kinase (MAPK) phosphorylation, cell proliferation, and production of interleukins 6 (IL-6) and 11 (IL-11), in the presence or absence of a pretreatment with budesonide (BUD). MAPK phosphorylation was detected by Western blotting, cell viability and proliferation were evaluated using Trypan blue staining and [(3)H]-thymidine incorporation assay, respectively, and the release of IL-6 and IL-11 into cell culture supernatants was assessed by ELISA. TGF-beta1 (10 ng/ml) significantly stimulated MAPK phosphorylation (P < 0.01), and also enhanced cell proliferation as well as the secretion of both IL-6 and IL-11, which reached the highest increases at the 72nd h of cell exposure to this growth factor. All such effects were prevented by BUD (10(-8) M) and, with the exception of IL-6 release, also by a mixture of MAPK inhibitors. Therefore, our findings suggest that the fibrotic action exerted by TGF-beta1 in the lung is mediated at least in part by MAPK activation and by an increased synthesis of the profibrogenic cytokines IL-6 and IL-11; all these effects appear to be prevented by corticosteroids via inhibition of MAPK phosphorylation.

  18. Reduced expression of glucocorticoid-inducible genes GILZ and SGK-1: high IL-6 levels are associated with reduced hippocampal volumes in major depressive disorder.

    LENUS (Irish Health Repository)

    Frodl, T

    2012-01-01

    Neuroplasticity may have a core role in the pathophysiology of major depressive disorder (MDD), a concept supported by experimental studies that found that excessive cortisol secretion and\\/or excessive production of inflammatory cytokines impairs neuronal plasticity and neurogenesis in the hippocampus. The objective of this study was to examine how changes in the glucocorticoid and inflammatory systems may affect hippocampal volumes in MDD. A multimodal approach with structural neuroimaging of hippocampus and amygdala, measurement of peripheral inflammatory proteins interleukin (IL)-6 and C-reactive protein (CRP), glucocorticoid receptor (GR) mRNA expression, and expression of glucocorticoid-inducible genes (glucocorticoid-inducible genes Leucin Zipper (GILZ) and glucocorticoid-inducible kinase-1 (SGK-1)) was used in 40 patients with MDD and 43 healthy controls (HC). Patients with MDD showed smaller hippocampal volumes and increased inflammatory proteins IL-6 and CRP compared with HC. Childhood maltreatment was associated with increased CRP. Patients with MDD, who had less expression of the glucocorticoid-inducible genes GILZ or SGK-1 had smaller hippocampal volumes. Regression analysis showed a strong positive effect of GILZ and SGK-1 mRNA expression, and further inverse effects of IL-6 concentration, on hippocampal volumes. These findings suggest that childhood maltreatment, peripheral inflammatory and glucocorticoid markers and hippocampal volume are interrelated factors in the pathophysiology of MDD. Glucocorticoid-inducible genes GILZ and SGK-1 might be promising candidate markers for hippocampal volume changes relevant for diseases like MDD. Further studies need to explore the possible clinical usefulness of such a blood biomarker, for example, for diagnosis or prediction of therapy response.

  19. LL-37, HNP-1, and HBD2/3 modulate the secretion of cytokines TNF-α, IL-6, IFN-γ, IL-10 and MMP1 in human primary cell cultures.

    Science.gov (United States)

    Medina Santos, Carlos Erik; López Hurtado, Carmen Nathaly; Rivas Santiago, Bruno; Gonzalez-Amaro, Roberto; Cataño Cañizales, Yolanda Guadalupe; Martínez Fierro, Margarita de la Luz; Enciso-Moreno, José Antonio; García Hernández, Mariana Haydee

    2016-09-01

    The aim of this study was to evaluate the effects of the LL-37, HNP-1 and HBD2/3 peptides on cytokine and MMP production in human polymorphonuclear cells, mononuclear cells and chondrocytes. The levels of cytokines in supernatants from mononuclear and polymorphonuclear cell cultures were measured with a cytometric bead array by flow cytometry. Likewise, the levels of metalloproteinase/MMP-1, 3, and 13 were measured in supernatants from chondrocyte cultures using an ELISA. The expression of RANKL on lymphocytes was analyzed by flow cytometry. We observed increased levels of TNF-α, IL-6 and IL-10 in mononuclear and polymorphonuclear cell cultures stimulated with HBD-2/3. We also observed increased levels of IFN-γ, IL-10, and IL-6 in mononuclear cell cultures stimulated with HNP-1, and increased IL-6 levels were observed in polymorphonuclear cell cultures exposed to HNP-1. We also found that the MMP-1 level increased in the chondrocyte cultures stimulated with HBD-3, whereas the MMP-1 level was decreased in cultures exposed to LL-37. The present report is the first study to determine that HNP-1and HBD2/3 promote the secretion of pro-inflammatory cytokines by polymorphonuclear and mononuclear cells and the secretion of MMP by chondrocytes, whereas LL-37 diminishes MMP1 secretion. Our results suggest that HBD-2/3 and HNP1 might play a pathological role in rheumatoid arthritis, while LL-37 might have a protective role.

  20. Changes in expressions of proinflammatory cytokines IL-1beta, TNF-alpha and IL-6 in the brain of senescence accelerated mouse (SAM) P8.

    Science.gov (United States)

    Tha, K K; Okuma, Y; Miyazaki, H; Murayama, T; Uehara, T; Hatakeyama, R; Hayashi, Y; Nomura, Y

    2000-12-01

    The senescence-accelerated mouse (SAM) is known to be a murine model for accelerated aging. The SAMP8 strain shows age-related deterioration of learning and memory at an earlier age than control mice (SAMR1). In the present study, we investigated the changes in expressions of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in the brain of SAMP8. In the hippocampus of 10 months old SAMP8, the expression of IL-1 mRNA was significantly elevated in comparison with that of SAMR1. In both strains of SAMs, increases in IL-1beta protein in the brain were observed at 10 months of age compared with 2 and 5 months. The only differences found between the strain in protein levels were at 10 months and were elevations in IL-1beta in the hippocampus and hypothalamus, and in TNF-alpha and IL-6 in the cerebral cortex and the hippocampus in SAMP8 as compared with SAMR1. However, lipopolysaccharide-induced increases in the expression of these cytokines in brain did not differ between SAMP8 and SAMR1. Increases in expression of proinflammatory cytokines in the brain may be involved in the age-related neural dysfunction and/or learning deficiency in SAMP8.

  1. Mechanisms of permanent loss of olfactory receptor neurons induced by the herbicide 2,6-dichlorobenzonitrile: Effects on stem cells and noninvolvement of acute induction of the inflammatory cytokine IL-6

    Energy Technology Data Exchange (ETDEWEB)

    Xie, Fang; Fang, Cheng [Laboratory of Molecular Toxicology, Wadsworth Center, New York State Department of Health, Albany, NY 12201 (United States); School of Public Health, State University of New York at Albany, NY 12201 (United States); Schnittke, Nikolai [Department of Anatomy and Cellular Biology, Tufts University School of Medicine, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111 (United States); Program in Cell, Molecular and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111 (United States); Schwob, James E. [Department of Anatomy and Cellular Biology, Tufts University School of Medicine, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111 (United States); Ding, Xinxin, E-mail: xding@wadsworth.org [Laboratory of Molecular Toxicology, Wadsworth Center, New York State Department of Health, Albany, NY 12201 (United States); School of Public Health, State University of New York at Albany, NY 12201 (United States)

    2013-11-01

    We explored the mechanisms underlying the differential effects of two olfactory toxicants, the herbicide 2,6-dichlorobenzonitrile (DCBN) and the anti-thyroid drug methimazole (MMZ), on olfactory receptor neuron (ORN) regeneration in mouse olfactory epithelium (OE). DCBN, but not MMZ, induced inflammation-like pathological changes in OE, and DCBN increased interleukin IL-6 levels in nasal-wash fluid to much greater magnitude and duration than did MMZ. At 24 h after DCBN injection, the population of horizontal basal cells (HBCs; reserve, normally quiescent OE stem cells) lining the DMM became severely depleted as some of them detached from the basal lamina, and sloughed into the nasal cavity along with the globose basal cells (GBCs; heterogeneous population of stem and progenitor cells), neurons, and sustentacular cells of the neuroepithelium. In contrast, the layer of HBCs remained intact in MMZ-treated mice, as only the mature elements of the neuroepithelium were shed. Despite the respiratory metaplasia accompanying the greater severity of the DCBN lesion, residual HBCs that survived intoxication were activated by the injury and contributed to the metaplastic respiratory epithelium, as shown by tracing their descendants in a K5CreEr{sup T2}::fl(stop)TdTomato strain of mice in which recombination causes HBCs to express TdTomato in advance of the lesion. But, contrary to published observations with MMZ, the HBCs failed to form ORNs. A role for IL-6 in suppressing ORN regeneration in DCBN-treated mice was rejected by the failure of the anti-inflammatory drug dexamethasone to prevent the subsequent respiratory metaplasia in the DMM, suggesting that other factors lead to HBC neuro-incompetence. - Highlights: • The herbicide dichlobenil (DCBN) can damage olfactory epithelium stem cells. • Another olfactory toxicant, methimazole, leaves the olfactory stem cells intact. • DCBN, but not methimazole, induces a prolonged increase in nasal IL-6 levels. • Dexamethasone

  2. Effect of Fire-needle Therapy on the Expressions of IL-6 and iNOS in Achilles Tendon Insertion of Rats with Achilles Tendon Enthesiopathy%火针治疗对跟腱末端病大鼠跟腱止点组织IL-6与iNOS表达的影响

    Institute of Scientific and Technical Information of China (English)

    史清钊; 方小芳; 周军; 郭佳佳

    2011-01-01

    纤维软骨区和治疗5组腱骨关节面IL-6阳性细胞数显著低于其各自对照组(P<0.05).(3)对照1、2、3、4、5组和治疗4、5组跟腱、纤维软骨区、钙化软骨区和腱骨关节面软骨中的iNOS阳性细胞数显著高于安静对照组(P<0.01,P<0.05);对照1、2、3组跟骨骨髓区iNOS阳性细胞数显著高于安静对照组(P<0.05).治疗4、5组跟腱区和治疗5组腱骨关节面iNOS阳性细胞数显著低于其各自对照组(P<0.05).结论:采用电击跳跃法成功建立大鼠跟腱末端病模型.火针治疗在一定程度上可降低跟腱末端病大鼠跟腱、纤维软骨区、腱骨关节面软骨区IL-6、iNOS阳性细胞表达的升高,但短时间内作用有限.%Objective To probe into the effect of fire-needle therapy on the 6 - IL and iNOS positive cells expressions in the Achilles tendon insertion of rats with Achilles tendon enthesiopathy. Methods Eighty eight l-month old male SD rats are divided into normal group (C, n = 8) and model group (M,n = 80) at random. Rats in group M were forced to jump using electric stimulation with gradually increasing voltage once a day, 6 days per week, for a total of 8 weeks; The jumping duration was 50 min with 10 min of resting interval. After 8-week jumping, rats in group M were regrouped randomly into 1-puncture treatment per day groups (1P) and their corresponding control groups; and 4--puncture treatment per day group (4P) and their corresponding control groups. Sampling started at day 1, day 2, day 3, and day 4 respectively after puncture for groups 1P; And at day 2 after punctures for group 4P. Sampling was performed at day 1 for control group. Morphological structure (stained with HE) and the expression changes in IL-6 and iNOS positive cells of Achilles tendon and its insertion of rat right rear foot was observed. Results ( 1 ) As compared with normal control group, typical enthesiopathy appeared in group M. (2) IL-6, iNOS positive cells mainly appeared in achilles tendon, fibro cartilage

  3. Factors Associated With Plasma IL-6 Levels During HIV Infection

    DEFF Research Database (Denmark)

    Borges, Álvaro H; O'Connor, Jemma L; Phillips, Andrew N

    2015-01-01

    BACKGROUND: Elevated interleukin 6 (IL-6) levels have been linked to cardiovascular disease, cancer and death. Persons with human immunodeficiency virus (HIV) infection receiving treatment have higher IL-6 levels, but few data are available on factors associated with circulating IL-6. METHODS......: Participants in 3 trials with IL-6 measured at baseline were included (N = 9864). Factors associated with IL-6 were identified by linear regression. Demographic and HIV variables (nadir/entry CD4(+) cell count, HIV RNA level, antiretroviral therapy regimen) were investigated in all 3 trials. In the SMART...... education, whereas black race was associated with lower IL-6. Higher HIV RNA levels were associated with higher IL-6 levels, and higher nadir CD4(+) cell counts with lower IL-6 levels. Compared with efavirenz, protease inhibitors were associated with higher and nevirapine with lower IL-6 levels. Smoking...

  4. Self-renewal of CD133hi cells by IL6/Notch3 signalling regulates endocrine resistance in metastatic breast cancer

    OpenAIRE

    2016-01-01

    The mechanisms of metastatic progression from hormonal therapy (HT) are largely unknown in luminal breast cancer. Here we demonstrate the enrichment of CD133hi/ERlo cancer cells in clinical specimens following neoadjuvant endocrine therapy and in HT refractory metastatic disease. We develop experimental models of metastatic luminal breast cancer and demonstrate that HT can promote the generation of HT-resistant, self-renewing CD133hi/ERlo/IL6hi cancer stem cells (CSCs). HT initially abrogates...

  5. The altered expression of inflammation-related molecules and secretion of IL-6 and IL-8 by HUVEC from newborns with maternal inactive systemic lupus erythematosus is modified by estrogens.

    Science.gov (United States)

    Rodriguez, E; Guevara, J; Paez, A; Zapata, E; Collados, M T; Fortoul, T I; Lopez-Marure, R; Masso, F; Montaño, L F

    2008-12-01

    Systemic lupus erythematosus (SLE) predominantly affects women, especially those in reproductive age. Genetic contributions to disease susceptibility as well as immune dysregulation, particularly persistent inflammatory responses, are considered essential features. Our aim was to determine whether human umbilical vein endothelial cells (HUVEC) isolated from healthy newborns to women with inactive SLE show inflammation-related abnormalities that might lead to an early development of SLE in the offsprings. HUVEC isolated from six women with inactive SLE were stimulated with 2.5 ng/mL of TNF-alpha and/or physiological and pharmacological doses of 17-I(2) estradiol (E2). Then the expression of VCAM-1, ICAM-1, E-selectin, toll-like receptor-9 (TLR-9), heat shock protein 70 (HSP70) and HSP90 were measured. The concentrations of IL-6, IL-8, and IL-10 were also determined in maternal serum and in TNF-alpha stimulated and non-stimulated HUVEC culture supernatant. HUVEC from children with no family history of autoimmune disease served as controls. Our results showed that in HUVEC from SLE+ mothers, a constitutively low expression of adhesion molecules was enhanced by TNF-alpha treatment. The E2 (1 ng/mL) increased the expression of adhesion molecules but had no effect upon TNF-alpha-treated cells. IL-6 was constitutively higher in SLE+ HUVEC, whereas IL-8 was lower; E2 treatment diminished the latter. The E2 had no effect upon IL-6 and IL-8 secretions in TNF-alpha-treated cells. SLE+ HUVEC showed a disordered cytoskeleton and overexpressed HSP70, HSP90, and TLR-9. Our results indicate that endothelial cells of newborns to SLE+ mothers are in a proinflammatory condition which can be upregulated by estrogens.

  6. Interaction between enteric epithelial cells and Peyer's patch lymphocytes in response to lipopolysaccharide: Effect on nitric oxide and IL-6 release

    Institute of Scientific and Technical Information of China (English)

    Jie Chen; Chuen-Pei Ng; Dewi K Rowlands; Peng-Hui Xu; Jie-Ying Gao; Yiu-Wa Chung; Hsiao-Chang Chan

    2006-01-01

    AIM: To investigate the effect of interaction between enteric epithelial cells and lymphocytes of Peyer's patch on the release of nitric oxide (NO) and IL-6 in response to Shigella lipopolysaccharide (LPS).METHODS: Human colonic epithelial cells (Caco-2)were mixed cocultured with lymphocytes of Peyer's patch from wild-type (C57 mice) and inducible NO synthase knockout mice, and challenged with Shigella F2a-12LPS. Release of NO and mIL-6 was measured by Griess colorimetric assay and enzyme-linked immunosorbent assay (ELISA), respectively.RESULTS: In the absence of LPS challenge, NO was detected in the culture medium of Caco-2 epithelial cells but not in lymphocytes of Peyer's patch, and the NO release was further up-regulated in both cocultures with lymphocytes from either the wild-type or iNOS knockout mice, with a significantly higher level observed in the coculture with iNOS knockout lymphocytes. After Shigella F2a-12 LPS challenge for 24-h, NO production was significantly increased in both Caco-2 alone and the coculture with lymphocytes of Peyer's patch from the wild-type mice but not from iNOS knockout mice.LPS was found to stimulate the release of mIL-6 from lymphocytes, which was suppressed by coculture with Caco-2 epithelial cells. The LPS-induced mIL-6production in lymphocytes from iNOS knockout mice was significantly greater than that from the wild-type mice.CONCLUSION: Lymphocytes of Peyer's patch maintain a constitutive basal level of NO production from the enteric epithelial cell Caco-2. LPS-induced mIL-6 release from lymphocytes of Peyer's patch is suppressed by the cocultured epithelial cells. While no changes are detectable in NO production in lymphocytes from both wild-type and iNOS knockout mice before and after LPS challenge, NO from lymphocytes appears to play an inhibitory role in epithelial NO release and their own mIL-6 release in response to LPS.

  7. Direct Injection of Plasmid DNA Expressing IL-6 Gene Improves Recovery of Thrombocytopoiesis in Irradiated Mice%直接注射表达hIL-6基因的质粒DNA促进照射小鼠的血小板生成的恢复

    Institute of Scientific and Technical Information of China (English)

    孙连生

    2001-01-01

    could not obiate the risk of infection .This work tried to determine the possibility of gene therapy with plasmid vectors for radiation -induced hematopoietic injury. After a single intramuscular injection of plasmid hlL-6 Cdna on 6.5 Gy-irradiated mice, the IL-6 level showed less changes in unirradiated mice. Further experiments demonstrated the IL-6 level in 7.5 Gy irradiated mice was about three times higher than that of 5.0 Gy irradiated mice and the expression of Hil-6 in vivo showed significant effect on hematopoietic recovery. Not only the platelet nadir in peripheral blood, but also the number of colony-forming cells in bone marrow rose. It is concluded that radiation could significantly enhance the gene transfer efficiency of plasmid DNA and gene therapy with plasmid vectors for treating radiation-induced hematopoietic injury might be more effective htan other diseases without DNA repair.

  8. Messenger RNA expression of IL-6 and IL-8 in allergen-induced late-phase cutaneous reactions (LPR) in Schneiderian membrane subjects%白细胞介素6(IL-6)和IL-8mRNA在变应原诱导的鼻粘膜晚期反应标本的表达

    Institute of Scientific and Technical Information of China (English)

    吕俊华; 宇丽; 孙英

    2001-01-01

    目的:测定IL-6和IL-8变应原诱导的鼻粘膜晚期反应标本中mRNA的表达。方法:采用原位杂交技术,测定变应原诱导的10例变态反应性鼻炎病人的鼻粘膜标本表达IL-6和IL-8mRNA阳性细胞数。结果:在10例标本中,2种细胞因子的阳性表达率分别为9/10和10/10。与对照相比,变应原诱导的鼻粘膜标本表达IL-6和IL-8mRNA阳性细胞数明显增加(P<0.05和P<0.01)。结论:IL-6和IL-8mRNA表达增加可作为变态反应性鼻炎晚期的标志。%Objective:To detect mRNA expression of IL-6 and IL-8 in allergen-induced late-phase cutaneous reactions in schneiderian membrane subjects. Methods:Cryostat sections from rhinitis biopsies from 24 h allergen-induced late-phase cutaneous reactions (LPR) in 10human atopic subjects were hybridization with 35S-labeled RNA probes for IL-6 and IL-8.Results:mRNA was detected for IL-6 (9/10) and IL8 (10/10).Compared with the control, there were significant increases in the numbers of ce11 expreasing mRNA expression for IL-6 and IL-8(P<0.05, P<0.01). Conclusion: The augmentation of mRNA expression of IL-6 and IL-8 maybe regarded as the mark of rhinits in IL PR.

  9. 白藜芦醇对RSV感染BALB/c小鼠肺泡灌洗液TNF-α,IL-1β,IL-6表达的调控趋势%Regulation trend of resveratrol on TNF-α, IL-1β ,IL-6expressions in bronchoalveolar lavage fluid of RSV-infected BALB/c mice

    Institute of Scientific and Technical Information of China (English)

    李佳曦; 汪受传; 徐建亚; 戴启刚; 徐珊; 孙寒丹; 彭璐璐

    2012-01-01

    Objective: To study the regulation trend of resveratrol on TNF-α, IL-lβ, IL-6 expressions in bronchoalveolar lav-age fluid ( BALF) of RSV-infected BALB/c mice at different time points. Method: RSV-induced BALB/c mice were orally administered with resveratrol. Their BALFs were collected at 24, 72 and 144 h after the first nasal drip with RSV to detect the level of TNF-α, IL-1β, IL-6 by EILSA. Result: The expression of TNF-a, IL-lβ and IL-6 in BALF increased significantly compared with the normal group (P<0.01) in the resveratrol group decreased notably compared with the model group. After 72 hours of infection with RSV, although the expression of TNF-α (P < 0. 05 ) , IL-1β (P < 0.01) and IL-6 (P < 0.01) in BALF in model group were higher than those in the normal group, they were much more lower than at 24 h. The expression of IL-1β and IL-6 (P < 0.05) in the resveratrol groups were down-regulated significantly, but no difference had been shown in TNF-a expression compared with the RSV infection group. After infection with RSV for 144 h, the expression of IL-1β (P<0.01) and IL-6 (P<0. 05) in BALF in the model group were higher than those in the normal group, but there was no difference in the secretion of TNF-α. The expression of TNF-α, IL-1β and IL-6 showed also no remarkable difference between the resveratrol groups and the RSV infection group. Conclusion: Resveratrol can inhibit the over expression of inflammatory factors TNF-α, IL-1β, IL-6 in bronchoalveolar lavage fluid of RSV-induced BALB/c mice and keep them at a low level with the passing of infection time.%目的:研究白藜芦醇(Res)对呼吸道合胞病毒(RSV)感染BALB/c小鼠肺泡灌洗液(BALF)不同时间点肿瘤坏死因子-α(TNF-α),白细胞介素-1β(IL-1β),白细胞介素-6(IL-6)表达的调控趋势.方法:RSV滴鼻感染BALB/c小鼠,白藜芦醇灌胃给药进行干预,并于首次滴鼻后24,72,144 h取各组小鼠支气管肺泡灌洗液,ELISA法检测其中TNF-α,IL-1β,IL

  10. The expression of lysophosphatidic acid, its receptors, and IL-6 and IL-8 in breast cancer%溶血磷脂酸及其受体和IL-6 IL-8在乳腺癌进展中的表达变化与意义

    Institute of Scientific and Technical Information of China (English)

    涂福平; 黄莉; 王祥财; 许明君; 王钇力; 衷敬华

    2013-01-01

    Objective:This work aimed to investigate the expression level of lysophosphatidic acid (LPA) and its receptors. The paper also discussed the interrelationship among the LPA, the receptors, and IL-6 and IL-8 in breast cancer tissues. Methods:The ex-pressions of the 3 hypo-types of LPA receptor in the breast cancer and paraneoplastic tissues were detected using semi-quantitative re-verse transcription polymerase chain reaction. The plasma levels of LPA, IL-6 and IL-8 were respectively detected in healthy subjects and in patients with benign breast tumor using the LPA biochemistry and enzyme linked immunosorbent assay kits. Results:The plas-ma LPA level was significantly higher in patients with breast cancer metastasis than in those with local breast cancer (P<0.01), benign breast tumor (P<0.01), and healthy volunteers (P<0.01). In addition, the IL-6 and IL-8 plasma levels were higher in the group with me-tastasis compared with the other three groups, too (P<0.01). LPA1 expression level was higher in breast cancer tissue than in benign breast tumor (P<0.05) and in normal breast tissue (P<0.05). There was a significantly positive correlation between the plasma LPA and the plasma IL-6 in patients with breast cancer (P<0.01), and between the plasma LPA and IL-8 (P<0.01). Conclusion:LPA expressions on the endogenous IL-6 and IL-8 in patients with breast cancer may have an up-regulation. Moreover, the detection of the LPA, IL-6, and IL-8 expression levels may have some predictable effects on metastatic breast cancer, especially bone metastases.%  目的:探讨溶血磷脂酸(lysophosphatidic acid,LPA)及其受体和IL-6与IL-8在乳腺癌进展中的表达及临床意义。方法:采用半定量RT-PCR方法检测乳腺肿瘤组织和瘤旁组织中LPA受体的表达水平。采用LPA生化测定法和酶联免疫吸附(ELISA)法分别检测乳腺肿瘤患者和健康妇女的血浆LPA、IL-6和IL-8水平。结果:术后复发转移乳腺癌患者血浆LPA、IL

  11. Trichuris suis excretory secretory products (ESP) elicit interleukin-6 (IL-6) and IL-10 secretion from intestinal epithelial cells (IPEC-1).

    Science.gov (United States)

    Parthasarathy, G; Mansfield, L S

    2005-08-10

    Immune responses to gastrointestinal helminth infections have received increasing attention due to similarities to allergen-induced responses. In fact, the whipworm parasite of swine, Trichuris suis, has been used in beginning clinical trials as an antidote to inflammatory bowel disease. This strategy was based on this similarity and the recognition that other worms have been documented to induce anti-inflammatory responses in the host. In an effort to understand the basis for this response, we hypothesized that the proteins and peptides secreted by T. suis stimulate local intestinal epithelial cells to produce anti-inflammatory cytokines. To test this hypothesis in a correlate system of the natural swine host, T. suis excretory secretory products (ESP) were used to treat both differentiated and undifferentiated intestinal pig epithelial cells (IPEC-1) in vitro as a model for the effect on villus tip and crypt epithelial cells in the vicinity of the worms. IPEC-1 were exposed to low-level doses (0.3mg/ml) of T. suis ESP, and IL-4, IL-6 and IL-10 cytokine responses were measured by an enzyme-linked immunosorbant assay (ELISA). IL-6 was the predominant cytokine produced, accompanied by moderate IL-10 secretion from both differentiated and undifferentiated cells. As expected, IL-4 was not produced by IPEC-1. Additionally, IL-6 and IL-10 cytokines were produced within 24h, suggesting that these two cytokines form part of the primary host response to T. suis infections. These data suggest that T. suis ESP could enhance host immune responses and modulation through the induction of enteric IL-6 and IL-10.

  12. Resveratrol reduces IL-6 and VEGF secretion from co-cultured A549 lung cancer cells and adipose-derived mesenchymal stem cells.

    Science.gov (United States)

    Sahin, Erhan; Baycu, Cengiz; Koparal, Ayse Tansu; Burukoglu Donmez, Dilek; Bektur, Ezgi

    2016-06-01

    Stem cell therapies are important treatment methodologies used in many areas of experimental or clinical medicine. In recent studies of cancer models, Mesenchymal stem cells (MSCs) suppressed the growth of cancer cells. However, also in some studies, stem cell treatments have been shown to induce cancer formation, increase tumor volume, induce the formation of new vessels, and lead to cancer invasion. The presence of MSC-secreted cytokines and their effects on cancer cells limits the reliability of MSC-based treatments. Resveratrol (trans-3,5,4'-trihydroxystilbene), an antioxidant found in red wine, has been shown to have therapeutic effects against several cancers. The aim of this study was to co-culture MSCs with A549 cancer cells to suppress the release of cancer-promoting cytokines from MSCs and to increase the applicability and reliability of stem cell therapies with resveratrol. MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and neutral red cell viability assays were used to find safety dose of resveratrol. The MSCs secreted the cytokines IL-6 and VEGF, and the effect of resveratrol on these cytokines was analyzed by ELISA and western blot analysis of conditioned medium. One μM of resveratrol was found to be the safety dose for the A549 cancer cells and MSCs. We observed the highest release of IL-6 and VEGF from the co-cultured A549 cells and MSCs, and resveratrol was found to significantly decrease the release of these cytokines. Our study suggests that resveratrol exerts a positive effect on the release of cytokines. The safety dose of resveratrol can be administered together with stem cells during stem cell treatment.

  13. IL-6, IL-12, IL-33 expression in patients with hepatitis C and their clinical significance%IL-6、IL-12、IL-33在丙型肝炎患者中的表达及其临床意义

    Institute of Scientific and Technical Information of China (English)

    何敬远

    2014-01-01

    Objecitve To investigates the change of IL-6, IL-12 and IL-33 in serum of patients with hepatitis C and its clinical significance. Methods The expression of IL-6, IL-12 and IL-33 in serum were detected in 30 cases of patients with hepatitis C, 30 cases of hepatitis C virus carriers and 30 cases of healthy control group by ELISA. Results Compared with the hepatitis C virus carriers and healthy control group, the expression level of IL-6, IL-12 and IL-33 in the serum of patients with hepatitis C was significantly elevated(P<0.01), and the expression level of IL-6, IL-12 and IL-33 in the serum of hepatitis C patients were significantly higher than that of hepatitis C virus carriers(P < 0.01); The content of IL-6, IL-12 and IL-33 in the serum of patients with hepatitis C were decreased significantly after treatment(P<0.01). Conclusion IL-6, IL-12 and IL-33-mediated immune responses involved in the pathogenesis of hepatitis C infection, and have certain clinical value in the pathogenesis of HCV infection.%目的:探讨丙型肝炎患者血清中IL-6、IL-12及IL-33含量的变化及其临床意义。方法ELISA法检测30例丙型肝炎患者、30例丙型肝炎病毒携带者及30例健康对照者血清中IL-6、IL-12及IL-33的表达水平。结果相比丙型肝炎病毒携带者及健康对照者,丙型肝炎患者血清中IL-6、IL-12及IL-33的表达水平显著升高(P<0.01),且丙型肝炎患者血清中IL-6、IL-12及IL-33的含量显著高于丙型肝炎病毒携带者(P<0.01);经治疗后丙型肝炎患者血清中IL-6、IL-12及IL-33的含量显著降低(P<0.01)。结论IL-6、IL-12及IL-33介导的免疫应答参与了丙型肝炎的发病,在丙型肝炎病毒感染的致病机制中有一定的临床价值。

  14. IL-6 Overexpression in ERG-Positive Prostate Cancer Is Mediated by Prostaglandin Receptor EP2.

    Science.gov (United States)

    Merz, Constanze; von Mässenhausen, Anne; Queisser, Angela; Vogel, Wenzel; Andrén, Ove; Kirfel, Jutta; Duensing, Stefan; Perner, Sven; Nowak, Michael

    2016-04-01

    Prostate cancer is the most diagnosed cancer in men and multiple risk factors and genetic alterations have been described. The TMPRSS2-ERG fusion event and the overexpression of the transcription factor ERG are present in approximately 50% of all prostate cancer patients, however, the clinical outcome is still controversial. Prostate tumors produce various soluble factors, including the pleiotropic cytokine IL-6, regulating cellular processes such as proliferation and metastatic segregation. Here, we used prostatectomy samples in a tissue microarray format and analyzed the co-expression and the clinicopathologic data of ERG and IL-6 using immunohistochemical double staining and correlated the read-out with clinicopathologic data. Expression of ERG and IL-6 correlated strongly in prostate tissue samples. Forced expression of ERG in prostate tumor cell lines resulted in significantly increased secretion of IL-6, whereas the down-regulation of ERG decreased IL-6 secretion. By dissecting the underlying mechanism in prostate tumor cell lines we show the ERG-mediated up-regulation of the prostanoid receptors EP2 and EP3. The prostanoid receptor EP2 was overexpressed in human prostate cancer tissue. Furthermore, the proliferation rate and IL-6 secretion in DU145 cells was reduced after treatment with EP2-receptor antagonist. Collectively, our study shows that the expression of ERG in prostate cancer is linked to the expression of IL-6 mediated by the prostanoid receptor EP2.

  15. 水飞蓟素对急性肺损伤小鼠肺组织IL-1β、IL-6、趋化因子fractalkine表达的影响%The effects of silymarin on IL-1β, IL-6, fractalkine gene expression in lung tissue rats with acute lung injury

    Institute of Scientific and Technical Information of China (English)

    张晓鸣; 顾绍庆

    2012-01-01

    Objective:To investigate the effects of silymarin (SIL) on the expressions of IL-lβ, IL-6,and fractalkine in lung tissue of rat with acute lung injury. Methods; A rat model of acute lung injury (ALI) was induced by lipopolysaecharide (LPS). All rats were randomly divided into SIL group, LPS group and normal saline control group. SIL(200 mg/kg) was dropped into airway of rats in SIL group 6,4,and 2 h before treated with LPS. After LPS was given for 6,12 and 24 h,IL-lβ,IL-6,chemotatic factor fractalkine protein levels in lung tissue homogenate were detected by ELISA. Results:At all time point,IL-lβ,IL-6,fractalkine protein levels of SIL group were all significantly lower than thoBe in LPS group (P < 0.05). Conclusion:SIL could significantly inhibit the expression of IL-lβ,IL-6,fractalkine in lung tissue of rat with acute lung injury.%目的:探讨水飞蓟素(silymarin,SIL)对急性肺损伤小鼠肺组织中白细胞介素(interleukin,IL)-1β、IL-6、趋化因子fractalkine表达的影响与意义.方法:利用内毒素(lipopolysaccharide,LPs)气管内滴入制备小鼠急性肺损伤的模型;设立SIL治疗组(S组)、LPS组(I组)、生理盐水对照组(N组),S组在气管内滴入LPS前6、4、2h以200 mg/kg水飞蓟素灌胃,分别在LPS处理后6、12、24 h取肺组织匀浆,用ELISA法分别测定各组IL-1β、IL-6、fractalkine蛋白水平.结果:在各时间点,S组肺组织中IL-1β、IL-6、fractalkine蛋白表达水平均显著低于L组.结论:SIL能有效抑制小鼠急性肺损伤时肺组织中IL-1β、IL-6、趋化因子fractalkine的表达.

  16. Maleylated-BSA suppresses lipopolysaccharide-induced IL-6 production by activating the ERK-signaling pathway in murine RAW264.7 cells.

    Science.gov (United States)

    Tada, Rui; Koide, Yusuke; Yamamuro, Mitsuaki; Tanaka, Riki; Hidaka, Akira; Nagao, Koichiro; Aramaki, Yukihiko

    2014-03-01

    Macrophages are well known for their ability to induce diverse beneficial immune responses, especially in the defense against pathogens. However, an excessive activation of macrophages may cause harmful inflammation. In this context, the suppression of excessive macrophage activation would be a promising therapeutic strategy for treating inflammatory diseases. We have previously found that maleylated-bovine serum albumin (maleylated-BSA) suppresses the production of inflammatory mediators in murine macrophages. However, the immunosuppressive effects and underlying mechanism(s) of maleylated-BSA remain unclear. Here, we report that pretreatment with maleylated-BSA strongly inhibited the production of interleukin 6 (IL-6) induced by bacterial lipopolysaccharide (LPS) in murine RAW264.7 cells. This inhibitory effect of maleylated-BSA on LPS-induced IL-6 production was eliminated by treatment with an extracellular signal-regulated kinase (ERK) inhibitor, U0126, indicating the involvement of ERK pathways. Taken together, we have shown that maleylated-BSA suppresses LPS-induced production of IL-6 via the activation of an ERK signaling pathway in murine macrophages. The findings of this study imply the possibility of a novel therapeutic strategy for inflammatory diseases.

  17. Sporothrix schenckii yeasts induce ERK pathway activation and secretion of IL-6 and TNF-α in rat mast cells, but no degranulation.

    Science.gov (United States)

    Romo-Lozano, Yolanda; Hernández-Hernández, Francisca; Salinas, Eva

    2014-11-01

    Sporothrix schenckii is a dimorphic fungus that causes sporotrichosis, a subcutaneous mycosis found throughout the world in humans and other mammals. After contact with conidia, transition to the yeast stage is required for establishment of infection. Mast cells are one of the first components of the immune system to make contact with invading pathogens. They release potent mediators that are decisive in initiating and directing the course of immune and inflammatory responses in the host. It remains unknown whether or not yeast cells of S. schenckii activate mast cells. Our aim in this study was to evaluate the in vitro response of mast cells to S. schenckii yeasts cells. Mast cells became activated after interaction with the yeasts, although exocytosis of preformed mediators was not stimulated. Sporothrix schenckii yeasts induced the release of early response cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 and activation of the extracellular signal-regulated kinase (ERK) signaling pathway in mast cells. As TNF-α and IL-6 are considered crucial mediators in the defense of the host against fungal disease, the release of both mediators from mast cells may contribute to the overall response of the host immune system during S. schenckii infection.

  18. Effects of Traditional Chinese Medicine Qingre Lishi Yin on Expressions of IL-6mRNA and IL-8mRNA and IL-10mRNA and Secretion of IL-8 and IL-10 in HaCaT Cells%中药清热利湿饮对HaCaT细胞表达IL-6mRNA、IL-8mRNA、IL-10mRNA及分泌IL-8、IL-10的影响

    Institute of Scientific and Technical Information of China (English)

    范玉; 杜锡贤; 张春红

    2014-01-01

    目的:揭示中药清热利湿饮对人永生化角质形成细胞HaCaT细胞表达IL-6mRNA、IL-8mRNA、IL-10mRNA和分泌IL-8、IL-10的作用机制.方法:以HaCaT细胞为研究对象,分别采用RT-PCR技术及ELISA方法观察中药清热利湿饮提取液对经TNF-α诱导活化的HaCaT细胞表达IL-6mRNA、IL-8mRNA、IL-10mRNA和分泌IL-8、IL-10的影响.结果:清热利湿饮对经TNF-α诱导活化的HaCaT细胞IL-6mRNA和IL-8mRNA的表达有下调作用,在药物浓度为10g/L和12.5g/L时,HaCaT细胞IL-10mRNA的表达量增强较为明显,与TNF-α诱导活化组相比,有显著性差异(P<0.05或P<0.01).清热利湿饮对经TNF-α诱导活化的HaCaT细胞IL-8的分泌有不同程度的抑制作用,但对IL-10的影响不明显.结论:清热利湿饮可下调IL-6mRNA、IL-8mRNA的表达,上调IL-10mRNA的表达,且此作用随药物浓度的升高而增强;同时可降低细胞IL-8的分泌,但对IL-10的分泌无明显的作用.

  19. Effects of hypoxia on secretion of IL-1β, IL-6 and TNF-α in cerebral cortex cells of rats%低氧对大鼠大脑皮质细胞分泌IL-1β、IL-6和TNF-α的影响

    Institute of Scientific and Technical Information of China (English)

    李华华; 娄淑杰

    2012-01-01

    目的 观察低氧环境对大鼠大脑皮质细胞分泌IL-1β、IL-6和TNF-α的影响.方法 原代培养新生SD大鼠大脑皮质细胞,设1%、4%两个低氧浓度和3h、6h两个低氧处理时间,处理结束后采用ELISA方法检测各组细胞培养液中IL-1β、IL-6和TNF-α的含量.结果 与相应的常氧(20%氧)对照组相比,1%氧浓度环境处理细胞3h和6h,IL-6含量均下降(P<0.01,P<0.05),IL-1β和TNF-α含量变化无统计学意义(P>0.05).与相应的常氧(20%氧)对照组相比,4%氧浓度环境处理细胞3h,IL-1β、IL-6和TNF-α含量变化均无统计学意义(P>0.05);处理细胞6h时,IL-1β (P<0.01)和IL-6 (P<0.05)均显著下降,TNF-α含量变化无统计学意义(P>0.05).结论 1%氧浓度环境虽对大脑皮质细胞分泌IL-1β和TNF-α无影响,但可抑制细胞分泌IL-6. 4%氧浓度环境虽对细胞分泌TNF-α无影响,但对细胞分泌IL-1β和IL-6具有抑制作用.%Objective To investigate the effects of different hypoxia treatments on secretion of IL-1|3, IL-6 and TNF-a in the cerebral cortex cells of rats. Methods Primary cultured cerebral cortex cells were subjected to hypoxia treatments (1% and 4% oxygen) for 3 h or 6 h. Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of IL-1β, IL-6 and TNF-a protein in cultural supernatants. Results (1) Compared with the corresponding normoxia (20% oxygen) controls, IL-6 level was significantly decreased after treatment with 1% oxygen for 3 h and 6 h (P0. 05) ; the levels of IL-1β and IL-6 were significantly decreased in cells treated with 4% oxygen for 6 h (P0. 05). Conclusion Oxygen at 1% has no influence on IL-l(3 or TNF-a secretion in cerebral cortex cells of rats, and it can inhibit the production of IL-6. Oxygen at 4% has inhibitory effect on IL-1β and IL-6 production, and it has no effect on TNF-a production.

  20. CYP19A1 single nucleotide polymorphism associations with CYP19A1, NFκB1, and IL6 gene expression in human normal colon and normal liver samples

    Directory of Open Access Journals (Sweden)

    Penney RB

    2014-07-01

    Full Text Available Rosalind B Penney,1 Abbie Lundgreen,2 Aiwei Yao-Borengasser,3 Vineetha K Edavana,3 Suzanne Williams,3 Ishwori Dhakal,4 Roger K Wolff,2 Susan Kadlubar,3 Martha L Slattery2 1Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR, 2Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, 3Division of Medical Genetics, University of Arkansas for Medical Sciences, Little Rock, AR, 4Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR, USA Background: Estrogen is known to decrease the risk of colon cancer in postmenopausal women, and may exert its actions by decreasing interleukin-6 (IL6 production via stabilization of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB. Estrogens are biosynthesized by CYP19A1 (aromatase, so it is possible that genetic variations in CYP19A1 influences the risk of colon cancer by altering expression of CYP19A1. Further, studies on gene-gene interactions suggest that single nucleotide polymorphisms in one gene may affect expression of other genes. The current study aims to explore the role of CYP19A1 single nucleotide polymorphisms on CYP19A1, NFκB1 and IL6 gene expression. Methods: Phenotype–genotype associations, cross-associations between genes, and haplotype analyses were performed in both normal human colon (n=82 and liver (n=238 samples. Results: CYP19A1 rs10459592, rs1961177, and rs6493497 were associated with CYP19A1 expression in colon samples (P=0.042, P=0.041, and P=0.013, respectively. CYP19A1 single nucleotide polymorphisms (rs12908960, rs730154, rs8025191, and rs17523880 were correlated with NFκB1 expression (P=0.047, P=0.04, P=0.05, and P=0.03, respectively, and CYP19A1 rs11856927, rs2470152, and rs2470144 (P=0.049, P=0.025, P=0.047, respectively were associated with IL6 expression in the colon. While rs730154 and rs17523880

  1. The Regulatory Mechanism of Hepcidin Expression by Interleukin 6(IL-6) in Exercise%运动引起的白细胞介素6的改变与铁调素的调控

    Institute of Scientific and Technical Information of China (English)

    闫芬; 李颖; 刘树欣; 刘玉倩

    2011-01-01

    运动可改变机体铁状态,过度运动会引起机体铁缺乏,甚至导致机体出现运动性贫血,影响运动员成绩.近几年研究表明铁调素(Hepcidin)是调控机体铁代谢的关键因素,而运动中产生的白细胞介素6(IL-6)是影响Hepcidin表达变化的重要原因之一.介绍了IL-6对Hepcidin表达的影响、运动对IL-6表达调控的研究进展,综合分析了运动引起的IL-6的改变及其对Hepcidin的调控机制.%The iron status can be changed during exercise. Excessive exercise can lead to iron deficiency, even sports anemia. Accordingly athletes performance is greatly affected by iron status. The researches on the regulatory mechanism of iron metabolism show that hepcidin plays an important role in iron metabolism,and IL -6 is one of the important reasons for the expression of hepcidin in exercise. This review reveals the regulaory mechanism of IL-6 on hepcidin expression in exercise.

  2. Deletion of gp130 in myeloid cells modulates IL-6-release and is associated with more severe liver injury of Con A hepatitis.

    Science.gov (United States)

    Lutz, H H; Sackett, S D; Kroy, D C; Gassler, N; Trautwein, C

    2012-01-01

    IL-6/gp130 dependent signaling plays an important role in modulating inflammation in acute and chronic diseases. The course of Concanavalin A- (Con A) induced hepatitis can be modulated by different immune-mediated mechanisms. IL-6/gp130-dependent signaling has been shown to be protective in hepatocytes. However, the role of this pathway in myeloid cells has not yet been studied. In our present study we used macrophage/neutrophil-specific gp130 knockout (gp130(ΔLys), KO) animals and analyzed its relevance in modulating Con A-induced hepatitis. Additionally, we performed in vitro studies with gp130(ΔLys)-macrophages. We demonstrate that gp130(ΔLys) animals are more susceptible to Con A-induced hepatitis. This is reflected by higher transaminases, higher lethality and more severe liver injury as shown by histological staining. Using flow cytometry analysis we further could show that increased liver injury of gp130(ΔLys) animals is associated with a stronger infiltration of CD11b/F4/80 double-positive cells compared to wild-type (gp130(flox/flox), WT) controls. To further characterize our observations we studied thioglycolate-elicited peritoneal macrophages from gp130(ΔLys) animals. Interestingly, the LPS-dependent IL-6 release in gp130(ΔLys) macrophages is significantly reduced (pCon A injection were significantly lower in gp130(ΔLys) animals compared to WT animals (pCon A-induced hepatitis.

  3. Myeloid-Derived Suppressor Cells Endow Stem-like Qualities to Breast Cancer Cells through IL6/STAT3 and NO/NOTCH Cross-talk Signaling.

    Science.gov (United States)

    Peng, Dongjun; Tanikawa, Takashi; Li, Wei; Zhao, Lili; Vatan, Linda; Szeliga, Wojciech; Wan, Shanshan; Wei, Shuang; Wang, Yin; Liu, Yan; Staroslawska, Elzbieta; Szubstarski, Franciszek; Rolinski, Jacek; Grywalska, Ewelina; Stanisławek, Andrzej; Polkowski, Wojciech; Kurylcio, Andrzej; Kleer, Celina; Chang, Alfred E; Wicha, Max; Sabel, Michael; Zou, Weiping; Kryczek, Ilona

    2016-06-01

    Myeloid-derived suppressor cells (MDSC) contribute to immune suppression in cancer, but the mechanisms through which they drive metastatic progression are not fully understood. In this study, we show how MDSC convey stem-like qualities to breast cancer cells that coordinately help enable immune suppression and escape. We found that MDSC promoted tumor formation by enhancing breast cancer cell stem-like properties as well as by suppressing T-cell activation. Mechanistic investigations indicated that these effects relied upon cross-talk between the STAT3 and NOTCH pathways in cancer cells, with MDSC inducing IL6-dependent phosphorylation of STAT3 and activating NOTCH through nitric oxide leading to prolonged STAT3 activation. In clinical specimens of breast cancer, the presence of MDSC correlated with the presence of cancer stem-like cells (CSC) and independently predicted poor survival outcomes. Collectively, our work revealed an immune-associated mechanism that extrinsically confers cancer cell stemness properties and affects patient outcome. We suggest that targeting STAT3-NOTCH cross-talk between MDSC and CSC could offer a unique locus to improve cancer treatment, by coordinately targeting a coupled mechanism that enables cancer stemness and immune escape. Cancer Res; 76(11); 3156-65. ©2016 AACR.

  4. Knockout of the c-Jun N-terminal Kinase 2 aggravates the development of mild chronic dextran sulfate sodium colitis independently of expression of intestinal cytokines TNFα, TGFB1, and IL-6

    Directory of Open Access Journals (Sweden)

    Kersting S

    2013-02-01

    Full Text Available Sabine Kersting,1 Kirstin Reinecke,2 Christoph Hilgert,1 Monika S Janot,1 Elisabeth Haarmann,1 Martin Albrecht,1 Annette M Müller,3 Thomas Herdegen,2 Ulrich Mittelkötter,1 Waldemar Uhl,1 Ansgar M Chromik11Department of General and Visceral Surgery, St Josef Hospital, Ruhr-University of Bochum, Bochum, Germany; 2Institute of Experimental and Clinical Pharmacology, University Hospital of Schleswig-Holstein, Campus Kiel, Germany; 3Department of Pediatric Pathology, Rheinische Friedrich-Wilhems-University of Bonn, Bonn, GermanyIntroduction: The c-Jun N-terminal kinases (JNKs are involved in signal transduction of inflammatory bowel diseases. The aim of this study was to examine the function of JNKs by using a low-dose dextran sulfate sodium (DSS model in JNK1 knockout mice (Mapk8–/–, JNK2 knockout mice (Mapk9–/–, and wild-type controls (WT1, WT2.Methods: The animals were evaluated daily using a disease activity index. After 30 days, the intestine was evaluated histologically with a crypt damage score. CD4+ and CD8+ cells were quantified using immunofluorescence. Analysis of tumor necrosis factor-a (TNFα, interleukin-6 (IL-6, and transforming growth factor ß1 (TGFB1 expression was carried out using LightCycler® real-time polymerase chain reaction.Results: Cyclic administration of low-dose DSS (1% was not able to induce features of chronic colitis in Mapk8–/– WT2 mice. By contrast, DSS administration significantly increased the disease activity index in WT1 and Mapk9–/– mice. In Mapk9–/– mice, the crypt damage score and the number of CD4+ and CD8+ cells as features of chronic colitis/inflammation were also significantly elevated. Expression of TNFα, IL-6, and TGFB1 was not altered by the JNK knockout.Conclusion: Administering DSS at a defined low concentration that is unable to induce colitis in WT animals leads to clinically and histologically detectable chronic colitis in Mapk9–/– mice. The reason for this disease

  5. 帕瑞昔布超前镇痛对烧伤患者术后疼痛及血清IL-6和IL-1O表达的影响%Preemptive analgesia and effects of parecoxib on IL-6 and IL-10 expressions in burned patients

    Institute of Scientific and Technical Information of China (English)

    华海峰; 邹俊; 张中军

    2012-01-01

    目的 探讨帕瑞昔布超前镇痛对术后镇痛及血清IL-6和IL-10水平的影响.方法 36例烧伤患者随机均分为两组:A组术毕前50 min缓慢静注帕瑞昔布40 mg;B组不施行超前镇痛.术后不行自控镇痛,在患者主诉疼痛难忍时肌注哌替啶75 mg/次.记录术后4、8、12、24 h静息VAS疼痛评分,并用放射免疫分析方法测定血清IL-6和IL-10浓度.结果 A组术后4、8、12h的VAS评分均显著低于B组(P<0.01),血清IL-6水平低于B组,而IL-10水平高于B组(P<0.05).结论 术毕前预用帕瑞昔布可明显减少烧伤术后疼痛和炎性反应.%Objective To study the preemptive analgesia and effects of parecoxib on IL-6 and IL-10 expressions in burned patients. Methods Thirty-six burned patients were equally randomized to two groups of A( injected parecoxib 40 rag at 30 min before the end of operation) and B( without parecoxib as the control). Intramuscular injection of pethidine 75 mg was performed after operation if necessary. Postoperative pain was scored by VAS at 4, 8, 12, and 24 h after operation and the expressions of serum IL-6 and IL-10 were detected by radioimmunoassay. Results At 4,8 and 12 h after operation, the VAS scores were significantly less in group A than those in group B(P<0. 01), serum IL-6 was lower,but IL-10 was higher,in group A than those in group B(P<0. 05). Conclusion Preemptive analgesia with parecoxib 40 mg can effectively attenuate postoperative pain and inflammatory cytokine response after surgery for bum.

  6. 热化疗治疗非小细胞肺癌对IL-2、IL-6、IL-8、IL-10及TNF的影响%Effect of thermochemotherapy on levels of IL-2 ,IL-6 ,IL-8 ,IL-10 and TNF in non-small cell lung cancer

    Institute of Scientific and Technical Information of China (English)

    李新民; 尉继伟; 刘治邦; 刘建国

    2014-01-01

    目的 探讨热化疗治疗非小细胞肺癌(NSCLC)对白细胞介素-2(IL-2)、白细胞介素-6(IL-6)、白细胞介素-8(IL-8)、白细胞介素-10(IL-10)及肿瘤坏死因子(TNF)的影响.方法 回顾性分析大同大学附属医院2004年10月至2013年1月收治的134例NSCLC患者,进行热疗联合NP方案化疗(NVB+ DDP),并分别在治疗前、治疗3个周期后、治疗6个周期后、治疗结束后3个月对患者血清中IL-2、IL-6、IL-8、IL-10及TNF的变化进行监测.结果 热化疗3个周期后,IL-2、TNF水平逐渐增高,明显高于治疗前;IL-6、IL-8和IL-10水平明显低于化疗前.热化疗6个周期后,血IL-6、IL-8、IL-10、IL-2和TNF都有所下降,其中IL-2、TNF浓度显著低于化疗3个周期后的水平.热化疗结束后3个月,血IL-6、IL-8、IL-10水平继续下降;而IL-2、TNF浓度逐渐增高,低于化疗3个周期后的水平,但高于治疗前水平.结论 热化疗治疗NSCLC对IL-2、TNF水平有明显的增高作用,而对IL-6、IL-8、IL-10有降低作用.%Objective To investigate the effect of hot therapy on interleukin-2 (IL-2),interleukin-6 (IL-6),interlerukin-8 (IL-8),interleukin-10 (IL-10) and tumor necrosis factor (TNF) in nonsmall cell lung cancer(NSCLC).Methods One hundred and thirty-four patients with NSCLC,admitted to our hospital from October 2004 to January 2013,received hot therapy and vinorelbine plus cisplatin (NP) chemotherapy.The IL-6,IL-8,IL-10 and TNF level before therapy,after 3 cycles,after 6 cycles and 3 months after chemotherapy were observed.Results IL-2 and TNF levels increased gradually after 3 cycles of hot therapy,and were significant higher than those before therapy.Compared to before therapy,IL-6,IL-8 and IL-10 levels significantly decreased.IL-6,IL-8,IL-10,IL-2 and TNF levels all decreased at 6 months after hot therapy.IL-2 and TNF levels were significant lowered than those of 3 cycles after chemotherapy.IL-6,IL-8 and IL-10 continued to decrease 3 months after the end of

  7. Induction of IL-6 and inhibition of IL-8 secretion in the human airway cell line Calu-3 by urban particulate matter collected with a modified method of PM sampling

    Energy Technology Data Exchange (ETDEWEB)

    Alfaro-Moreno, Ernesto, E-mail: ealfaro.incan@gmail.com [Lung Toxicology Unit, Pneumology Section, K.U. Leuven (Belgium); Subdireccion de Investigacion Basica, Instituto Nacional de Cancerologia, Avenida San Fernando 22, C.P. 14080, Mexico D.F. (Mexico); Torres, Victor [Departamento Farmacologia, Facultad de Medicina, U.N.A.M. (Mexico); Miranda, Javier [Departamento de Fisica Experimental, Instituto de Fisca, U.N.A.M. (Mexico); Martinez, Leticia [Deparatmento de Aerobiologia, Centro de Ciencias de la Atmosfera - Facultad de Medicina, U.N.A.M. (Mexico); Garcia-Cuellar, Claudia [Subdireccion de Investigacion Basica, Instituto Nacional de Cancerologia, Avenida San Fernando 22, C.P. 14080, Mexico D.F. (Mexico); Nawrot, Tim S.; Vanaudenaerde, Bart; Hoet, Peter [Lung Toxicology Unit, Pneumology Section, K.U. Leuven (Belgium); Ramirez-Lopez, Pavel [Escuela Superior de Ingenieria Quimica e Industrias Extractivas, I.P.N. (Mexico); Rosas, Irma [Deparatmento de Aerobiologia, Centro de Ciencias de la Atmosfera - Facultad de Medicina, U.N.A.M. (Mexico); Nemery, Benoit [Lung Toxicology Unit, Pneumology Section, K.U. Leuven (Belgium); Osornio-Vargas, Alvaro Roman [Subdireccion de Investigacion Basica, Instituto Nacional de Cancerologia, Avenida San Fernando 22, C.P. 14080, Mexico D.F. (Mexico)

    2009-07-15

    Exposure to particulate matter (PM) induces inflammatory cytokines. In the present study, we evaluated the secretion of IL-6 and IL-8 by an airway cell line exposed to PM with a mean aerodynamic size equal to or less than 10 or 2.5 {mu}m (PM{sub 10} and PM{sub 2.5}, respectively) collected in Mexico City, using a modified high-volume sampling method avoiding the use of solvents or introducing membrane components into the samples. PM was collected on cellulose-nitrate (CN) membranes modified for collection on high-volume samplers. Composition of the particles was evaluated by particle-induced X-ray emission (PIXE) and scanning electron microscopy. The particles (10-160 {mu}g/cm{sup 2}) were tested on Calu-3 cells. Control cultures were exposed to LPS (10 ng/mL to 100 {mu}g/mL) or silica (10-160 {mu}g/cm{sup 2}). IL-6 and IL-8 secretions were evaluated by ELISA. An average of 10 mg of PM was recovered form each cellulose-nitrate filter. No evidence of contamination from the filter was found. Cells exposed to PM{sub 10} presented an increase in the secretion of IL-6 (up to 400%), while IL-8 decreased (from 40% to levels below the detection limit). A similar but weaker effect was observed with PM{sub 2.5}. In conclusion, our modified sampling method provides a large amount of urban PM free of membrane contamination. The urban particles induce a decrease in IL-8 secretion that contrasts with the LPS and silica effects. These results suggest that the regulation of IL-8 expression is different for urban particles (complex mixture containing combustion-related particles, soil and biologic components) than for biogenic compounds or pure mineral particles.

  8. Doxorubicin-Hyaluronan Conjugated Super-Paramagnetic Iron Oxide Nanoparticles (DOX-HA-SPION) Enhanced Cytoplasmic Uptake of Doxorubicin and Modulated Apoptosis, IL-6 Release and NF-kappaB Activity in Human MDA-MB-231 Breast Cancer Cells.

    Science.gov (United States)

    Vyas, Dinesh; Lopez-Hisijos, Nicolas; Gandhi, Sulakshana; El-Dakdouki, M; Basson, Marc D; Walsh, Mary F; Huang, X; Vyas, Arpita K; Chaturvedi, Lakshmi S

    2015-09-01

    Triple negative breast cancer exhibit increased IL-6 expression compared with matched healthy breast tissue and a strong link between inflammation and cancer progression and metastasis has been reported. We investigated whether doxorubicin-hyaluronan-super-paramagnetic iron oxide nanoparticles (DOX-HA-SPION) would show greater therapeutic efficacy in human triple negative breast cancer cells (TNBC) MDA-MB-231, as was recently shown in drug-sensitive and multi-drug-resistant ovarian cancer cells. Therefore, we measured cellular DOX uptake via confocal microscopy; observed morphologic changes: mitochondrial and nuclear changes with electron microscopy, and quantitated apoptosis using FACS analysis after Annexin V and PI staining in MDA-MB-231 cells treated with either DOX alone or DOX-HA-SPION. We also measured both proinflammatory and anti-inflammatory cytokines; IL-6, IL-10 respectively and also measured nitrate levels in the conditioned medium by ELISA. Inaddition, NF-κB activity was measured by luciferase assay. Confocal microscopy demonstrated greater cytoplasmic uptake of DOX-HA-SPION than free DOX. We also demonstrated reduction of Vimentin with DOX-HA-SPION which is significantly less than both control and DOX. DOX-HA-SPION enhanced apoptosis and significantly down regulated both pro-inflammatory mediators IL-6 and NF-κB in comparison to DOX alone. The secretion levels of anti-inflammatory mediators IL-10 and nitrate was not decreased in the DOX or DOX-HA-SPION treatment groups. Our data suggest that DOX-HA-SPION nanomedicine-based drug delivery could have promising potential in treating metastasized and chemoresistant breast cancer by enhancing the drug efficacy and minimizing off-target effects.

  9. 姜黄素对戊四氮致癫大鼠海马区 IL-2和IL-6表达水平的影响%Effect of the curcumin on expression of IL-2 and IL-6 of hippocampus in pentyle-netetrazol-induced epilepsy in rats

    Institute of Scientific and Technical Information of China (English)

    董伟; 严建维; 谈巧玲; 叶森

    2016-01-01

    Objective To investigate the mechanism of anti-epileptic effect of the curcumin .Methods The SD rats were injected intraperitoneally with pentylenetetrazol kindling 25 .0 mg/kg to induce a rat epilepsy model .All of the treatments were performed once a day continuously for 28 days .The rats in blank group and model group received 5 ml of normal saline .The rats in the high and low curcumin group were given 200 mg/kg and 100 mg/kg of curcumin once a day ,respectively .The rats in the sodium valproate (VPA) group were given 400 mg/kg of VPA once a day by gavage .After treatment ,the seizures level was recorded by using the Racine′s six point grading scale ,and the expression of IL-2 and IL-6 of hippocampus were detected by the enzyme linked immunoassay (ELISA) .Results The seizures level was reduced by curcumin in epileptic rats .The ex-pressions of IL-2 and IL-6 of the model group were significantly higher than those of the blank group (P0 .05) . Conclusion The curcumin can reduce the seizure level in rats ,it shows some anti-epileptic effets and dose-dependently ,which may be through down-regulating the expression of IL-2 and IL-6 in hippocampus .%目的:探讨姜黄素抗癫的作用机制。方法取健康成年雄性SD大鼠,连续腹腔注射戊四氮,诱发大鼠点燃致癫模型。空白组和模型组灌予生理盐水5 ml ,1次/d ,连续28 d。低剂量和高剂量姜黄素组分别灌予姜黄素100 mg/kg和200 mg/kg ,1次/d ,连续28 d;丙戊酸钠组灌予丙戊酸钠400 mg/kg ,1次/d ,连续28 d。治疗结束后,按照Racine的6级评分标准,观察癫大鼠发作等级变化,用酶联免疫法(ELISA)检测海马区IL-2和IL-6表达水平的变化。结果姜黄素组的癫大鼠惊厥发作等级降低。模型组IL-2和IL-6高表达,比空白组呈显著升高(P<0.05)。与模型组比较,姜黄素组大鼠海马区IL-2和IL-6的表达明显降低( P<0.05);与低剂量姜黄素组

  10. Blocking IL-6 trans-signaling prevents high-fat diet-induced adipose tissue macrophage recruitment but does not improve insulin resistance.

    Science.gov (United States)

    Kraakman, Michael J; Kammoun, Helene L; Allen, Tamara L; Deswaerte, Virginie; Henstridge, Darren C; Estevez, Emma; Matthews, Vance B; Neill, Bronwyn; White, David A; Murphy, Andrew J; Peijs, Lone; Yang, Christine; Risis, Steve; Bruce, Clinton R; Du, Xiao-Jun; Bobik, Alex; Lee-Young, Robert S; Kingwell, Bronwyn A; Vasanthakumar, Ajithkumar; Shi, Wei; Kallies, Axel; Lancaster, Graeme I; Rose-John, Stefan; Febbraio, Mark A

    2015-03-01

    Interleukin-6 (IL-6) plays a paradoxical role in inflammation and metabolism. The pro-inflammatory effects of IL-6 are mediated via IL-6 "trans-signaling," a process where the soluble form of the IL-6 receptor (sIL-6R) binds IL-6 and activates signaling in inflammatory cells that express the gp130 but not the IL-6 receptor. Here we show that trans-signaling recruits macrophages into adipose tissue (ATM). Moreover, blocking trans-signaling with soluble gp130Fc protein prevents high-fat diet (HFD)-induced ATM accumulation, but does not improve insulin action. Importantly, however, blockade of IL-6 trans-signaling, unlike complete ablation of IL-6 signaling, does not exacerbate obesity-induced weight gain, liver steatosis, or insulin resistance. Our data identify the sIL-6R as a critical chemotactic signal for ATM recruitment and suggest that selectively blocking IL-6 trans-signaling may be a more favorable treatment option for inflammatory diseases, compared with current treatments that completely block the action of IL-6 and negatively impact upon metabolic homeostasis.

  11. In-vitro suppression of IL-6 and IL-8 release from human pulmonary epithelial cells by non-anticoagulant fraction of enoxaparin.

    Directory of Open Access Journals (Sweden)

    Madhur D Shastri

    Full Text Available Enoxaparin, a mixture of anticoagulant and non-anticoagulant fractions, is widely used as an anticoagulant agent. However, it is also reported to possess anti-inflammatory properties. Our study indicated that enoxaparin inhibits the release of IL-6 and IL-8 from A549 pulmonary epithelial cells. Their release causes extensive lung tissue damage. The use of enoxaparin as an anti-inflammatory agent is hampered due to the risk of bleeding associated with its anticoagulant fractions. Therefore, we aimed to identify the fraction responsible for the observed anti-inflammatory effect of enoxaparin and to determine the relationship between its structure and biological activities.A549 pulmonary epithelial cells were pre-treated in the presence of enoxaparin and its fractions. The levels of IL-6 and IL-8 released from the trypsin-stimulated cells were measured by ELISA. The anticoagulant activity of the fraction responsible for the effect of enoxaparin was determined using an anti-factor-Xa assay. The fraction was structurally characterised using nuclear magnetic resonance. The fraction was 2-O, 6-O or N-desulfated to determine the position of sulfate groups required for the inhibition of interleukins. High-performance size-exclusion chromatography was performed to rule out that the observed effect was due to the interaction between the fraction and trypsin or interleukins.Enoxaparin (60 μg/mL inhibited the release of IL-6 and IL-8 by >30%. The fraction responsible for this effect of enoxaparin was found to be a disaccharide composed of α-L-iduronic-acid and α-D-glucosamine-6-sulfate. It (15 μg/mL inhibited the release of interleukins by >70%. The 6-O sulphate groups were responsible for its anti-inflammatory effect. The fraction did not bind to trypsin or interleukins, suggesting the effect was not due to an artefact of the experimental model.The identified disaccharide has no anticoagulant activity and therefore eliminates the risk of bleeding

  12. 肥胖对PCOS血清白介素-6表达的影响%Effect of obesity on the expression of serum IL-6 in PCOS

    Institute of Scientific and Technical Information of China (English)

    夏宇东

    2010-01-01

    目的:研究IL-6在肥胖与PCOS发病机制中的作用.方法:分别选择20例PCOS肥胖患者、非肥胖PCOS患者、肥胖对照患者及非肥胖对照患者,记录临床特征,检测血清生殖激素及血清IL-6.结果:IL-6浓度在不肥胖且非PCOS、肥胖但非PCOS、PCOS非肥胖、PCOS且肥胖女性的血清中依次显著升高.结论:肥胖和PCOS都与血清高水平IL-6相关,IL-6既能够参与肥胖的病理生理过程,也能够参与PCOS的病理生理过程.肥胖加重PCOS血清白介素-6的表达.

  13. Macrophage-associated mesenchymal stem cells assume an activated, migratory, pro-inflammatory phenotype with increased IL-6 and CXCL10 secretion.

    Directory of Open Access Journals (Sweden)

    Kevin Anton

    Full Text Available Mesenchymal stem cells (MSCs exhibit tropism for sites of tissue injury and tumors. However, the influence of the microenvironment on MSC phenotype and localization remains incompletely characterized. In this study, we begin to define a macrophage-induced MSC phenotype. These MSCs secrete interleukin-6 (IL-6, CCL5, and interferon gamma-induced protein-10 (CXCL10 and exhibit increased mobility in response to multiple soluble factors produced by macrophages including IL-8, CCL2, and CCL5. The pro-migratory phenotype is dependent on activation of a c-Jun N-terminal kinase (JNK pathway. This work begins to identify the influence of macrophages on MSC biology. These interactions are likely to play an important role in the tissue inflammatory response and may provide insight into the migratory potential of MSCs in inflammation and tissue injury.

  14. NF-κB,IL-6 and PGE2 expression in periodontal tissue of rats with periodontitis under chronic intermittent hypoxia%间歇性低氧对牙周炎大鼠牙周组织中 NF-κB、IL-6及 PGE2含量的影响

    Institute of Scientific and Technical Information of China (English)

    王月昊; 王小琴; 苗伟; 柴晶; 程宇钊; 马小雯

    2016-01-01

    Objective:To examine the effects of chronic intermittent hypoxia(CIH)on the NF-κB,IL-6 and PGE2 level in rats with periodontitis.Methods:32 male SD rats(6 weeks old)were randomly divided into 4 groups(n =8),group A(normoxic control),B (normoxic periodontitis),C(CIH)and D(periodontitis +CIH).Periodontitis model was established in the upper second molars by liga-tion technique and high-glucose diet in the rats of group B and D.The rats in the group C and D were subjected to CIH in a cycle of al-ternative nitrogen and oxygen in a closed chamber.The chamber was filled with nadir and zenith ambient oxygen every 1 20 seconds per cycle for 8 hours per day.The rats were sacrificed and the gingival tissues were examined for the detection of IL-6 and PGE2 expression by ELISA,and NF-κB expression by immunohistochemistry.Results:Histology revealed apical migration of junctional epithetlium and crestal alveolar bone resorption in group B and D,and in the above phenomena of group D was the severest.The content of NF-κB,IL-6 and PGE2 in group B,C,D was higher than that in group A(P <0.05),and in group D was the highest(P <0.05).Conclusion:Chro-nic intermittent hypoxia can aggravate the inflammation of periodontitis.%目的:建立慢性间歇性低氧(CIH)及牙周炎大鼠模型,研究 NF-κB、IL-6及 PGE2水平的变化。方法:将32只普通级6周龄雄性 SD 大鼠随机分为4组(n =8):A:常氧空白组、B:常氧牙周炎组、C:CIH 组、D:CIH 合并牙周炎组。B、D 组大鼠上颌第二磨牙进行结扎处理,辅以高糖饮食;A、C 组正常饮食。C、D 组置于低氧舱8 h/d。8周后处死,HE 染色,免疫组化检测牙周组织 NF-κB 含量,ELISA 检测牙龈组织 IL-6、PGE2。结果:HE 染色:8周后 B 组、D 组牙周炎症表现明显。免疫组化:B、C、D 组 NF-κB 表达均高于 A 组(P <0.05);ELISA 检测:B、C、D 组 IL-6、PGE2含量高于 A 组(P <0.05),且 D 组 IL-6

  15. Selection of the In Vitro Culture Media Influences mRNA Expression of Hedgehog Genes, Il-6, and Important Genes regarding Reactive Oxygen Species in Single Murine Preimplantation Embryos

    Directory of Open Access Journals (Sweden)

    N. Pfeifer

    2012-01-01

    Full Text Available Background. The aim of this paper was to determine the influence of different in vitro culture media on mRNA expression of Hedgehog genes, il-6, and important genes regarding reactive oxygen species in single mouse embryos. Methods. Reverse transcription of single embryos either cultured in vitro from day 0.5 until 3.5 (COOK’s Cleavage medium or Vitrolife’s G-1 PLUS medium or in vivo until day 3.5 post coitum. PCR was carried out for β-actin followed by nested-PCR for shh, ihh, il-6, nox, gpx4, gpx1, and prdx2. Results. The number of murine blastocysts cultured in COOK medium which expressed il-6, gpx4, gpx1, and prdx2 mRNA differed significantly compared to the in vivo group. Except for nox, the mRNA profile of the Vitrolife media group embryos varied significantly from the in vivo ones regarding the number of blastocysts expressing the mRNA of shh, ihh, il-6, gpx4, gpx1 and prdx2. Conclusions. The present study shows that different in vitro culture media lead to different mRNA expression profiles during early development. Even the newly developed in vitro culture media are not able to mimic the female reproductive tract. The question of long-term consequences for children due to assisted reproduction techniques needs to be addressed in larger studies.

  16. Comparative effects of low-level laser therapy pre- and post-injury on mRNA expression of MyoD, myogenin, and IL-6 during the skeletal muscle repair.

    Science.gov (United States)

    Alves, Agnelo Neves; Ribeiro, Beatriz Guimarães; Fernandes, Kristianne Porta Santos; Souza, Nadhia Helena Costa; Rocha, Lília Alves; Nunes, Fabio Daumas; Bussadori, Sandra Kalil; Mesquita-Ferrari, Raquel Agnelli

    2016-05-01

    This study analyzed the effect of pre-injury and post-injury irradiation with low-level laser therapy (LLLT) on the mRNA expression of myogenic regulatory factors and interleukin 6 (IL-6) during the skeletal muscle repair. Male rats were divided into six groups: control group, sham group, LLLT group, injury group; pre-injury LLLT group, and post-injury LLLT group. LLLT was performed with a diode laser (wavelength 780 nm; output power 40 mW' and total energy 3.2 J). Cryoinjury was induced by two applications of a metal probe cooled in liquid nitrogen directly onto the belly of the tibialis anterior (TA) muscle. After euthanasia, the TA muscle was removed for the isolation of total RNA and analysis of MyoD, myogenin, and IL-6 using real-time quantitative PCR. Significant increases were found in the expression of MyoD mRNA at 3 and 7 days as well as the expression of myogenin mRNA at 14 days in the post-injury LLLT group in comparison to injury group. A significant reduction was found in the expression of IL-6 mRNA at 3 and 7 days in the pre-injury LLLT and post-injury LLLT groups. A significant increase in IL-6 mRNA was found at 14 days in the post-injury LLLT group in comparison to the injury group. LLLT administered following muscle injury modulates the mRNA expression of MyoD and myogenin. Moreover, the both forms of LLLT administration were able to modulate the mRNA expression of IL-6 during the muscle repair process.

  17. Metallothionein treatment reduces proinflammatory cytokines IL-6 and TNF-alpha and apoptotic cell death during experimental autoimmune encephalomyelitis (EAE)

    DEFF Research Database (Denmark)

    Penkowa, M; Hidalgo, J

    2001-01-01

    , which is characterized by significant inflammation and neuroglial damage. We have recently shown that the exogenous administration of the antioxidant protein zinc-metallothionein-II (Zn-MT-II) significantly decreased the clinical symptoms, mortality, and leukocyte infiltration of the CNS during EAE...... apoptotic cell death of neurons and oligodendrocytes during EAE, as judged by using TUNEL and immunoreactivity for cytochrome c and caspases 1 and 3. In contrast, the number of apoptotic lymphocytes and macrophages was less affected by Zn-MT-II treatment. The Zn-MT-II-induced decrease in proinflammatory...

  18. Suppressor of cytokine signaling 3 inhibits LPS-induced IL-6 expression in osteoblasts by suppressing CCAAT/enhancer-binding protein ß activity

    Science.gov (United States)

    Suppressors of cytokine signaling 3 (SOCS3) is an important intracellular regulator of TLR4 signaling and has been implicated in several inflammatory diseases. Although SOCS3 seems to contribute to the balance between the pro-inflammatory effects of IL-6 and antiinflammatory signaling of IL-10 by ne...

  19. The prognostic value of the hypoxia markers CA IX and GLUT 1 and the cytokines VEGF and IL 6 in head and neck squamous cell carcinoma treated by radiotherapy ± chemotherapy

    Directory of Open Access Journals (Sweden)

    Goethals Laurence

    2005-04-01

    Full Text Available Abstract Background Several parameters of the tumor microenvironment, such as hypoxia, inflammation and angiogenesis, play a critical role in tumor aggressiveness and treatment response. A major question remains if these markers can be used to stratify patients to certain treatment protocols. The purpose of this study was to investigate the inter-relationship and the prognostic significance of several biological and clinicopathological parameters in patients with head and neck squamous cell carcinoma (HNSCC treated by radiotherapy ± chemotherapy. Methods We used two subgroups of a retrospective series for which CT-determined tumoral perfusion correlated with local control. In the first subgroup (n = 67, immunohistochemistry for carbonic anhydrase IX (CA IX and glucose transporter-1 (GLUT-1 was performed on the pretreatment tumor biopsy. In the second subgroup (n = 34, enzyme linked immunosorbent assay (ELISA was used to determine pretreatment levels of the cytokines vascular endothelial growth factor (VEGF and interleukin-6 (IL-6 in serum. Correlation was investigated between tumoral perfusion and each of these biological markers, as well as between the markers mutually. The prognostic value of these microenvironmental parameters was also evaluated. Results For CA IX and GLUT-1, the combined assessment of patients with both markers expressed above the median showed an independent correlation with local control (p = 0.02 and disease-free survival (p = 0.04 with a trend for regional control (p = 0.06. In the second subgroup, IL-6 pretreatment serum level above the median was the only independent predictor of local control (p = 0.009, disease-free survival (p = 0.02 and overall survival (p = 0.005. Conclusion To our knowledge, we are the first to report a link in HNSCC between IL-6 pretreatment serum levels and radioresistance in vivo. This link is supported by the strong prognostic association of pretreatment IL-6 with local control, known to be

  20. TGF-{beta}1 increases invasiveness of SW1990 cells through Rac1/ROS/NF-{kappa}B/IL-6/MMP-2

    Energy Technology Data Exchange (ETDEWEB)

    Binker, Marcelo G. [Departments of Medicine and Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8 (Canada); CBRHC Research Center, Buenos Aires (Argentina); Binker-Cosen, Andres A. [CBRHC Research Center, Buenos Aires (Argentina); Gaisano, Herbert Y. [Departments of Medicine and Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8 (Canada); Cosen, Rodica H. de [CBRHC Research Center, Buenos Aires (Argentina); Cosen-Binker, Laura I., E-mail: laura.cosen.binker@utoronto.ca [Departments of Medicine and Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8 (Canada); CBRHC Research Center, Buenos Aires (Argentina)

    2011-02-04

    Research highlights: {yields} Rac1 mediates TGF-{beta}1-induced SW1990 invasion through MMP-2 secretion and activation. {yields} NADPH-generated ROS act downstream of Rac1 in TGF-{beta}1-challenged SW1990 cells. {yields} TGF-{beta}1-stimulated ROS activate NF-{kappa}B in SW1990 cells. {yields} NF{kappa}B-induced IL-6 release is required for secretion and activation of MMP-2 in SW1990 cells. -- Abstract: Human pancreatic cancer invasion and metastasis have been found to correlate with increased levels of active matrix metalloproteinase 2 (MMP-2). The multifunctional cytokine transforming growth factor beta 1 (TGF-{beta}1) has been shown to increase both secretion of MMP-2 and invasion by several pancreatic cancer cell types. In the present study, we investigated the signaling pathway involved in TGF-{beta}1-promoted MMP-2 secretion and invasion by human pancreatic cancer cells SW1990. Using specific inhibitors, we found that stimulation of these tumor cells with TGF-{beta}1 induced secretion and activation of the collagenase MMP-2, which was required for TGF-{beta}1-stimulated invasion. Our results also indicate that signaling events involved in TGF-{beta}1-enhanced SW1990 invasiveness comprehend activation of Rac1 followed by generation of reactive oxygen species through nicotinamide adenine dinucleotide phosphate-oxidase, activation of nuclear factor-kappa beta, release of interleukin-6, and secretion and activation of MMP-2.

  1. The MEK-Inhibitor Selumetinib Attenuates Tumor Growth and Reduces IL-6 Expression but Does Not Protect against Muscle Wasting in Lewis Lung Cancer Cachexia

    Science.gov (United States)

    Au, Ernie D.; Desai, Aditya P.; Koniaris, Leonidas G.; Zimmers, Teresa A.

    2017-01-01

    Cachexia, or wasting of skeletal muscle and fat, afflicts many patients with chronic diseases including cancer, organ failure, and AIDS. Muscle wasting reduces quality of life and decreases response to therapy. Cachexia is caused partly by elevated inflammatory cytokines, including interleukin-6 (IL-6). Others and we have shown that IL-6 alone is sufficient to induce cachexia both in vitro and in vivo. The mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitor Selumetinib has been tested in clinical trials for various cancers. Moreover, Selumetinib has also been shown to inhibit the production of IL-6. In a retrospective analysis of a phase II clinical trial in advanced cholangiocarcinoma, patients treated with Selumetinib experienced significant gains in skeletal muscle vs. patients receiving standard therapy. However, the use of Selumetinib as a treatment for cachexia has yet to be investigated mechanistically. We sought to determine whether MEK inhibition could protect against cancer-induced cachexia in mice. In vitro, Selumetinib induced C2C12 myotube hypertrophy and nuclear accretion. Next we tested Selumetinib in the Lewis lung carcinoma (LLC) model of cancer cachexia. Treatment with Selumetinib reduced tumor mass and reduced circulating and tumor IL-6; however MEK inhibition did not preserve muscle mass. Similar wasting was seen in limb muscles of Selumetinib and vehicle-treated LLC mice, while greater fat and carcass weight loss was observed with Selumetinib treatment. As well, Selumetinib did not block wasting in C2C12 myotubes treated with LLC serum. Taken together, out results suggest that this MEK inhibitor is not protective in LLC cancer cachexia despite lowering IL-6 levels, and further that it might exacerbate tumor-induced weight loss. Differences from other studies might be disease, species or model-specific. PMID:28149280

  2. Male IL-6 gene knock out mice developed more advanced osteoarthritis upon aging.

    NARCIS (Netherlands)

    Hooge, A.S.K. de; Loo, F.A.J. van de; Bennink, M.B.; Arntz, O.J.; Hooge, P. de; Berg, W.B. van den

    2005-01-01

    OBJECTIVE: Interleukin-6 (IL-6) is expressed in osteoarthritic joints but its function in osteoarthritis (OA) is unknown. To study this, spontaneous and experimental OA were evaluated in IL-6 deficient (IL-6(-/-)) mice. DESIGN: Histology of knees of 18-23-month-old wild type (wt) and IL-6(-/-) mice

  3. Effect of astrocyte-targeted production of IL-6 on traumatic brain injury and its impact on the cortical transcriptome

    DEFF Research Database (Denmark)

    Quintana, Albert; Molinero, Amalia; Borup, Rehannah

    2008-01-01

    (freeze) injury in the cortex, increasing healing and decreasing oxidative stress and apoptosis. To determine the transcriptional basis for these responses here we analyzed the global gene expression profile of the cortex, at 0 (unlesioned), 1 or 4 days post lesion (dpl), in both GFAP-IL6 mice...... stress (Atf4). Furthermore, the presence of IL-6 altered the expression of genes involved in hemostasis (Vwf), cell migration and proliferation (Cap2), and synaptic activity (Vamp2). All these changes in gene expression could underlie the phenotype of the GFAP-IL6 mice after injury, but many other...

  4. Excretory/secretory products of the carcinogenic liver fluke are endocytosed by human cholangiocytes and drive cell proliferation and IL6 production.

    Science.gov (United States)

    Chaiyadet, Sujittra; Smout, Michael; Johnson, Michael; Whitchurch, Cynthia; Turnbull, Lynne; Kaewkes, Sasithorn; Sotillo, Javier; Loukas, Alex; Sripa, Banchob

    2015-10-01

    Liver fluke infection caused by Opisthorchis viverrini remains a major public health problem in many parts of Asia including Thailand, Lao PDR, Vietnam and Cambodia, where there is a strikingly high incidence of cholangiocarcinoma (CCA - hepatic cancer of the bile duct epithelium). Among other factors, uptake of O. viverrini excretory/secretory products (OvES) by biliary epithelial cells has been postulated to be responsible for chronic inflammation and proliferation of cholangiocytes, but the mechanisms by which cells internalise O. viverrini excretory/secretory products are still unknown. Herein we incubated normal human cholangiocytes (H69), human cholangiocarcinoma cells (KKU-100, KKU-M156) and human colon cancer (Caco-2) cells with O. viverrini excretory/secretory products and analysed the effects of different endocytic inhibitors to address the mechanism of cellular uptake of ES proteins. Opisthorchis viverrini excretory/secretory products was internalised preferentially by liver cell lines, and most efficiently/rapidly by H69 cells. There was no evidence for trafficking of ES proteins to cholangiocyte organelles, and most of the fluorescence was detected in the cytoplasm. Pretreatment with clathrin inhibitors significantly reduced the uptake of O. viverrini excretory/secretory products, particularly by H69 cells. Opisthorchis viverrini excretory/secretory products induced proliferation of liver cells (H69 and CCA lines) but not intestinal (Caco-2) cells, and proliferation was blocked using inhibitors of the classical endocytic pathways (clathrin and caveolae). Opisthorchis viverrini excretory/secretory products drove IL6 secretion by H69 cells but not Caco-2 cells, and cytokine secretion was significantly reduced by endocytosis inhibitors. This the first known study to address the endocytosis of helminth ES proteins by host epithelial cells and sheds light on the pathways by which this parasite causes one of the most devastating forms of cancer in south

  5. MiR-26 down-regulates TNF-α/NF-κB signalling and IL-6 expression by silencing HMGA1 and MALT1.

    Science.gov (United States)

    Chen, Chyi-Ying A; Chang, Jeffrey T; Ho, Yi-Fang; Shyu, Ann-Bin

    2016-05-05

    MiR-26 has emerged as a key tumour suppressor in various cancers. Accumulating evidence supports that miR-26 regulates inflammation and tumourigenicity largely through down-regulating IL-6 production, but the underlying mechanism remains obscure. Here, combining a transcriptome-wide approach with manipulation of cellular miR-26 levels, we showed that instead of directly targeting IL-6 mRNA for gene silencing, miR-26 diminishes IL-6 transcription activated by TNF-α through silencing NF-κB signalling related factors HMGA1 and MALT1. We demonstrated that miR-26 extensively dampens the induction of many inflammation-related cytokine, chemokine and tissue-remodelling genes that are activated via NF-κB signalling pathway. Knocking down both HMGA1 and MALT1 by RNAi had a silencing effect on NF-κB-responsive genes similar to that caused by miR-26. Moreover, we discovered that poor patient prognosis in human lung adenocarcinoma is associated with low miR-26 and high HMGA1 or MALT1 levels and not with levels of any of them individually. These new findings not only unravel a novel mechanism by which miR-26 dampens IL-6 production transcriptionally but also demonstrate a direct role of miR-26 in down-regulating NF-κB signalling pathway, thereby revealing a more critical and broader role of miR-26 in inflammation and cancer than previously realized.

  6. Recent advances in neutralizing the IL-6 pathway in arthritis

    Directory of Open Access Journals (Sweden)

    Charles J Malemud

    2009-10-01

    Full Text Available Charles J MalemudDivision of Rheumatic Diseases, Case Western Reserve University, School of Medicine and University Hospitals Case Medical Center, Cleveland, Ohio, USAAbstract: Recent advances in understanding the mechanism(s of how IL-6 trans-signaling regulates immune cell function and promotes inflammation in autoimmune arthritis are critically reviewed. Serum and/or synovial fluid (SF IL-6 is markedly elevated in adult and juvenile rheumatoid arthritis (RA, psoriatic arthritis (PsA, ankylosing spondylitis (AS and osteoarthritis (OA. IL-6, in concert with IL-17, determines the fate of CD4+ lymphocytes and therefore TH17 cell differentiation. IL-6 also plays a critical role in modulating B-lymphocyte activity. The recognition that IL-6 trans-signaling regulates inflammation resulted in the development of tocilizumab, a fully humanized monoclonal antibody that neutralizes the biological activity of the IL-6-receptor (IL-6R. Significant clinical benefit was demonstrated as well as reduced serum IL-6 levels with suppression of X-ray progression of disease in several clinical trials in which juvenile or adult RA patients were treated with tocilizumab monotherapy or tocilizumab plus methotrexate. However, levels of serum and/or SF IL-6 cytokine protein superfamily members, adiponectin, oncostatin M, pre-B-cell colony enhancing factor/visfatin and leukemia inhibitory factor are also elevated in RA. Additional studies will be required to determine if anti-IL-6 trans-signaling inhibition strategies with tocilizumab or recombinant soluble IL-6R reduce the level of these cytokines.Keywords: interleukin-6, interleukin-6/interleukin-6 receptor/glycoprotein 130, JAK/STAT pathway, SAP/MAPK pathway, osteoarthritis, rheumatoid arthritis

  7. Expression of interleukin-6 is downregulated by 17-(allylamino)-17-demethoxygeldanamycin in human prostatic carcinoma cells

    Institute of Scientific and Technical Information of China (English)

    Ke-hung TSUI; Tsui-hsia FENG; Wen-chi HSIEH; Phei-lang CHANG; Horng-heng JUANG

    2008-01-01

    Aim: Interleukin-6 (IL-6) is a pleiotropic cytokine that is associated with tumor metastasis and prostate cancer. We evaluated the mechanism and effect of 17-(allylamino)-17-demethoxygeldanamycin (17AAG), a novel inhibitor of heat shock protein 90 (Hsp90), on the IL-6 gene expression in human prostatic carcinoma (PC-3) cells. Methods: Quantitative IL-6 and IL-6 receptor (IL-6R) expressions were assessed using RT-PCR. The deregulation of 17AAG and phor-bol 12-myristate 13-acetate (PMA) on the IL-6 gene was determined by ELISA and transient gene expression assays using an IL-6 reporter vector. Results: Although the IL-6R is ubiquitously expressed by prostatic epithelium cells, the IL-6 expression is only found in advanced prostatic carcinoma cells, such as PC-3 and DU145. Further studies using RT-PCR indicated that 17AAG downregulated the gene expression of IL-6. ELISA and the transient gene expression assay revealed that 17AAG blocked the stimulation of PMA of IL-6 gene expression in PC-3 cells. The PMA-induced IL-6 gene expression is dependent on the NF-κB response element. However, the effect of 17AAG appears to be mediated via a region located at -149 to +8 bp upstream of the transcriptional starting site of the IL-6 gene, and might not be through the NF-κB signaling pathway. Conclusion: The present study reveals that IL-6 is transcriptionally downregulated in human prostatic carcinoma cells in response to 17AAG. This result suggests the presence of a novel Hsp90 mediation pathway that is involved in the deregulation on the transcription of the human IL-6 gene in human prostate cancer.

  8. Chronic IL-6 Administration Desensitizes IL-6 Response in Liver, Causes Hyperleptinemia and Aggravates Steatosis in Diet-Induced-Obese Mice

    Science.gov (United States)

    Gavito, Ana Luisa; Bautista, Dolores; Suarez, Juan; Badran, Samir; Arco, Rocío; Pavón, Francisco Javier; Serrano, Antonia; Rivera, Patricia; Decara, Juan; Cuesta, Antonio Luis; Rodríguez-de-Fonseca, Fernando

    2016-01-01

    High-fat diet-induced obesity (DIO) is associated with fatty liver and elevated IL-6 circulating levels. IL-6 administration in rodents has yielded contradictory results regarding its effects on steatosis progression. In some models of fatty liver disease, high doses of human IL-6 ameliorate the liver steatosis, whereas restoration of IL-6 in DIO IL-6-/- mice up-regulates hepatic lipogenic enzymes and aggravates steatosis. We further examined the effects of chronic low doses of murine IL-6 on hepatic lipid metabolism in WT mice in DIO. IL-6 was delivered twice daily in C57BL/6J DIO mice for 15 days. The status and expression of IL-6-signalling mediators and targets were investigated in relation to the steatosis and lipid content in blood and in liver. IL-6 administration in DIO mice markedly raised circulating levels of lipids, glucose and leptin, elevated fat liver content and aggravated steatosis. Under IL-6 treatment there was hepatic Stat3 activation and increased gene expression of Socs3 and Tnf-alpha whereas the gene expression of endogenous IL-6, IL-6-receptor, Stat3, Cpt1 and the enzymes involved in lipogenesis was suppressed. These data further implicate IL-6 in fatty liver disease modulation in the context of DIO, and indicate that continuous stimulation with IL-6 attenuates the IL-6-receptor response, which is associated with high serum levels of leptin, glucose and lipids, the lowering levels of lipogenic and Cpt1 hepatic enzymes and with increased Tnf-alpha hepatic expression, a scenario evoking that observed in IL-6-/- mice exposed to DIO and in obese Zucker rats. PMID:27333268

  9. B-cell exposure to self-antigen induces IL-10 producing B cells as well as IL-6- and TNF-α-producing B-cell subsets in healthy humans

    DEFF Research Database (Denmark)

    Langkjær, Anina; Kristensen, Birte; Hansen, Bjarke E

    2012-01-01

    of IL-10 and TGF-β, in addition to TNF-α and IL-6. Pulsing with foreign antigen, tetanus toxoid (TT), induced a Th1-response with minimal IL-10 production. After thyroglobulin-pulsing, 1.10±0.50% of B cells and 1.00±0.20% of CD4(+) T cells produced IL-10, compared to 0.29±0.19% of B cells (P=0.01) and 0...... cells mediate self-antigen-specific IL-10, TNF-α and IL-6 production in co-cultures with T cells and contribute actively to these cytokine secretions.......Human B cells are able to secrete IL-10 after stimulation with mitogens, but their ability to produce IL-10 and regulate T-cell responses after stimulation with self-antigens is unclear. We co-cultured thyroglobulin-pulsed B cells from healthy donors with autologous T cells and observed production...

  10. Effects of nicotine on LPS-induced microglia activation and cytokine IL-6 expression in rats%尼古丁对脂多糖诱导的大鼠小胶质细胞激活和白细胞介素6表达的影响

    Institute of Scientific and Technical Information of China (English)

    李治华; 赵青赞; 张华; 任秀花; 周明付; 臧卫东

    2011-01-01

    目的:观察尼古丁对脂多糖(LPS)诱导的原代大鼠脑皮层小胶质细胞激活的影响及对细胞因子白细胞介素6(IL-6)表达的影响,探讨尼古丁在PD中的可能作用机制.方法:培养原代大鼠脑皮质胶质细胞,纯化小胶质细胞,用尼古丁预处理30 min,再加入LPS,采用ELISA检测小胶质细胞不同时间点分泌IL-6的水平及免疫细胞化学检测小胶质细胞特异的离子钙结合蛋白(Ibal)的阳性细胞数.结果:激活的小胶质细胞胞体增大,活化标记物Ibal表达上调;ELISA方法测定显示10μg/L LPS致小胶质细胞在4、8和24 h分泌细胞因子IL-6的量与对照组比较均增加(t=14.115、23.530和32.076,P均=13.418,P:0.006),且在4 h分泌IL-6的量减少(F=92.569,P<0.001).结论:尼古丁可能对LPS引起的炎症反应具有保护作用.%Aim :To observe the effects of nicotine on LPS-induced primary rat cortical microglia activation and cytokine IL-6 expression and to explore the possible mechanism of nicotine in PD. Methods:Primary rat cortical glial cells were cultured and microglial cells were purified,with or without nicotine and/or LPS. The IL-6 secretion concentration of microglia at different time was detected by ELISA and the activation of microglia( Ibal positive cells) was detected by immunocytochemical staining. Results: LPS induced activation of microglia, activated microglia increased the expression of activation marker lbal. 10 μg/L LPS induced the amount of cytokine IL-6 secretion of microglia at 4,8 and 24 h respectively were significantly higher than those of the control group ( t = 14. I 15,23. 530, and 32.076,P < 0.05 ). The secretion of IL-6 had no significant difference between the amount at 4 and 8 h in microglia, which reached a peak; but pretreatment of cells with nicotine significantly inhibited microglia activation ( F = 13. 418, P = 0. 006 ) and the LPS-induced IL-6 production ( F =92. 569 ,P <0. 001 ). Conclusion: Nicotine may has protective

  11. Chikusetsusaponin IVa Methyl Ester Isolated from the Roots of Achyranthes japonica Suppresses LPS-Induced iNOS, TNF-α, IL-6, and IL-1β Expression by NF-κB and AP-1 Inactivation.

    Science.gov (United States)

    Lee, Hae-Jun; Shin, Ji-Sun; Lee, Woo-Seok; Shim, Heon-Yong; Park, Ji-Min; Jang, Dae-Sik; Lee, Kyung-Tae

    2016-01-01

    We investigated the effect of chikusetsusaponin IVa (CS) and chikusetsusaponin IVa methyl ester (CS-ME) from the roots of Achyranthes japonica NAKAI on lipopolysaccharide (LPS)-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production in RAW264.7 macrophages. CS-ME more potently inhibited LPS-induced NO and PGE2 production than CS. CS-ME concentration-dependently inhibited LPS-induced tumor necrosis factor (TNF)-α and interleukin (IL)-6 and IL-1β production in RAW264.7 macrophages and mouse peritoneal macrophages. Consistent with these findings, CS-ME suppressed LPS-induced expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 at protein level as well as iNOS, COX-2, TNF-α, IL-6, and IL-1β at mRNA level. In addition, CS-ME suppressed LPS-induced transcriptional activity of nuclear factor (NF)-κB and activator protein (AP)-1. The anti-inflammatory properties of CS-ME might result from suppression of iNOS, COX-2, TNF-α, IL-6, and IL-1β expression through downregulation of NF-κB and AP-1 in macrophages.

  12. ICAM-1 triggers liver regeneration through leukocyte recruitment and Kupffer cell-dependent release of TNF-alpha/IL-6 in mice.

    NARCIS (Netherlands)

    Selzner, N; Selzner, M; Odermatt, B; Tian, Y; Rooijen, van N.; Clavien, PA

    2003-01-01

    AIMS: Tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 mediate hepatocyte proliferation in vivo, suggesting that local and systemic inflammatory reactions may trigger hepatic regeneration after major tissue loss. METHODS: Wild-type, intercellular adhesion molecule (ICAM)-1-/-, and neutropeni

  13. Activation of GPER suppresses migration and angiogenesis of triple negative breast cancer via inhibition of NF-κB/IL-6 signals.

    Science.gov (United States)

    Liang, Shuwei; Chen, Zhuojia; Jiang, Guanmin; Zhou, Yan; Liu, Qiao; Su, Qiao; Wei, Weidong; Du, Jun; Wang, Hongsheng

    2017-02-01

    Triple-negative breast cancer (TNBC) is characterized by high vascularity and frequent metastasis. Here, we found that activation of G protein-coupled estrogen receptor (GPER) by its specific agonist G-1 can significantly inhibit interleukin 6 (IL-6) and vascular endothelial growth factor A (VEGF-A). TNBC tissue microarrays from 100 TNBC patients revealed GPER is negatively associated with IL-6 levels and higher grade and stage. Activation of GPER or anti-IL-6 antibody can inhibit both in vitro tube formation of human umbilical vein endothelial cells (HUVECs) and migration of TNBC cells. While recombinant IL-6 supplementary can significantly reverse the inhibitory effects of G-1, suggesting the essential role of IL-6 in G-1 induced suppression of angiogenesis and invasiveness of TNBC cells. G-1 treatment decreased the phosphorylation, nuclear localization, transcriptional activities of NF-κB and suppressed its binding with IL-6 promoter. BAY11-7028, the inhibitor of NF-κB, can mimic the effect of G-1 to suppression of IL-6 and VEGF-A. While over expression of p65 can attenuate the inhibitory effects of G-1 on IL-6 and VEGF expression. The suppression of IL-6 by G-1 can further inhibit HIF-1α and STAT3 signals in TNBC cells by inhibition their expression, phosphorylation and/or nuclear localization. Moreover, G-1 also inhibited the in vivo NF-κB/IL-6 signals and angiogenesis and metastasis of MDA-MB-231 xenograft tumors. In conclusion, our study demonstrated that activation of GPER can suppress migration and angiogenesis of TNBC via inhibition of NF-κB/IL-6 signals, therefore it maybe act as an important target for TNBC treatment.

  14. The Effects of Yerba Maté (Ilex Paraguariensis) consumption on IL-1, IL-6, TNF-α and IL-10 production by bone marrow cells in wistar rats fed a high-fat diet.

    Science.gov (United States)

    Carmo, Luciana Simão; Rogero, Marcelo Macedo; Cortez, Mayara; Yamada, Monica; Jacob, Patrícia Silva; Bastos, Deborah Helena Markowicz; Borelli, Primavera; Ambrósio Fock, Ricardo

    2013-01-01

    An excessive consumption of a high-fat diet (HFD) results in becoming overweight or obese, which triggers a chronic inflammatory condition that is associated with a high white blood cell count. Because of the potential for yerba maté (Ilex paraguariensis) (YM) to impact obesity, this study aimed to investigate the effects of YM consumption on the hematological response and on the production of interleukin (IL)-1α, IL-6, tumor necrosis factor (TNF)-α, and IL-10 by bone marrow cells from Wistar rats fed a HFD. Male Wistar rats were fed a control (CON) or HFD diet for twelve weeks. At the end of this period, the rats received YM (1 g/kg/day body weight) for 4 weeks. After euthanasia, hemograms and myelograms were evaluated, while the bone marrow cells were cultured in the presence or absence of lipopolysaccharide (LPS) to evaluate the production of IL-1α, IL-6, TNF-α, and IL-10. The consumption of YM reduced the body weight, the body adiposity, and the cholesterol levels in HFD-fed rats. Bone marrow cells from the HFD group produced more IL-1α, IL-6, and TNF-α, and less IL-10, when compared to cells from the control group, and YM consumption reduced the IL-1α, IL-6, and TNF-α production by the cells. However, cells from the HFD rats that were stimulated with LPS increased their IL-1α, IL-6, and TNF-α production, but YM consumption did not change this result. In summary, the consumption of YM affects the production of IL-1α, IL-6, and TNF-α by bone marrow cells, promotes weight loss, decreases the number of white blood cells, and significantly improves serum cholesterol level in HFD-fed rats. However, the bone marrow cells from the HFD+YM-fed rats challenged with LPS did not show improvement in the inflammatory response compared to the cells from animals fed only a HFD that were also challenged with LPS.

  15. Stromal cells positively and negatively modulate the growth of cancer cells: stimulation via the PGE2-TNFα-IL-6 pathway and inhibition via secreted GAPDH-E-cadherin interaction.

    Science.gov (United States)

    Kawada, Manabu; Inoue, Hiroyuki; Ohba, Shun-ichi; Yoshida, Junjiro; Masuda, Tohru; Yamasaki, Manabu; Usami, Ihomi; Sakamoto, Shuichi; Abe, Hikaru; Watanabe, Takumi; Yamori, Takao; Shibasaki, Masakatsu; Nomoto, Akio

    2015-01-01

    Fibroblast-like stromal cells modulate cancer cells through secreted factors and adhesion, but those factors are not fully understood. Here, we have identified critical stromal factors that modulate cancer growth positively and negatively. Using a cell co-culture system, we found that gastric stromal cells secreted IL-6 as a growth and survival factor for gastric cancer cells. Moreover, gastric cancer cells secreted PGE2 and TNFα that stimulated IL-6 secretion by the stromal cells. Furthermore, we found that stromal cells secreted glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Extracellular GAPDH, or its N-terminal domain, inhibited gastric cancer cell growth, a finding confirmed in other cell systems. GAPDH bound to E-cadherin and downregulated the mTOR-p70S6 kinase pathway. These results demonstrate that stromal cells could regulate cancer cell growth through the balance of these secreted factors. We propose that negative regulation of cancer growth using GAPDH could be a new anti-cancer strategy.

  16. Early Secreted Antigenic Target of 6-kDa of Mycobacterium tuberculosis Stimulates IL-6 Production by Macrophages through Activation of STAT3

    Science.gov (United States)

    Jung, Bock-Gie; Wang, Xisheng; Yi, Na; Ma, Justin; Turner, Joanne; Samten, Buka

    2017-01-01

    As early secreted antigenic target of 6 kDa (ESAT-6) of Mycobacterium tuberculosis (Mtb) is an essential virulence factor and macrophages are critical for tuberculosis infection and immunity, we studied ESAT-6 stimulated IL-6 production by macrophages. ESAT-6 stimulated significantly higher IL-6 secretion by murine bone marrow derived macrophages (BMDM) compared to culture filtrate protein 10 kDa (CFP10) and antigen 85A. Polymyxin B, an LPS blocker, did not affect ESAT-6 stimulated macrophage IL-6 production. ESAT-6 but not Pam3CSK4 induced IL-6 by TLR2 knockout BMDM. ESAT-6 induced phosphorylation and DNA binding of STAT3 and this was blocked by STAT3 inhibitors but not by rapamycin. STAT3 inhibitors suppressed ESAT-6-induced IL-6 transcription and secretion without affecting cell viability. This was confirmed by silencing STAT3 in macrophages. Blocking neither IL-6Rα/IL-6 nor IL-10 affected ESAT-6-induced STAT3 activation and IL-6 production. Infection of BMDM and human macrophages with Mtb with esat-6 deletion induced diminished STAT3 activation and reduced IL-6 production compared to wild type and esat-6 complemented Mtb strains. Administration of ESAT-6 but not CFP10 induced STAT3 phosphorylation and IL-6 expression in the mouse lungs, consistent with expression of ESAT-6, IL-6 and phosphorylated-STAT3 in Mtb-infected mouse lungs. We conclude that ESAT-6 stimulates macrophage IL-6 production through STAT3 activation. PMID:28106119

  17. Sequential signaling cascade of IL-6 and PGC-1α is involved in high glucose-induced podocyte loss and growth arrest

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Dong Il; Park, Soo Hyun, E-mail: parksh@chonnam.ac.kr

    2013-06-14

    Highlights: •The pathophysiological role of IL-6 in high glucose-induced podocyte loss. •The novel role of PGC-1α in the development of diabetic nephropathy. •Signaling of IL-6 and PGC-1α in high glucose-induced dysfunction of podocyte. -- Abstract: Podocyte loss, which is mediated by podocyte apoptosis, is implicated in the onset of diabetic nephropathy. In this study, we investigated the involvement of interleukin (IL)-6 in high glucose-induced apoptosis of rat podocytes. We also examined the pathophysiological role of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) in this system. High glucose treatment induced not only podocyte apoptosis but also podocyte growth arrest. High glucose treatment also increased IL-6 secretion and activated IL-6 signaling. The high glucose-induced podocyte apoptosis was blocked by IL-6 neutralizing antibody. IL-6 treatment or overexpression induced podocyte apoptosis and growth arrest, and IL-6 siRNA transfection blocked high glucose-induced podocyte apoptosis and growth arrest. Furthermore, high glucose or IL-6 treatment increased PGC-1α expression, and PGC-1α overexpression also induced podocyte apoptosis and growth arrest. PGC-1α siRNA transfection blocked high glucose-induced podocyte apoptosis and growth arrest. Collectively, these findings showed that high glucose promoted apoptosis and cell growth arrest in podocytes via IL-6 signaling. In addition, PGC-1α is involved in podocyte apoptosis and cell growth arrest. Therefore, blocking IL-6 and its downstream mediators such as IL6Rα, gp130 and PGC-1α may attenuate the progression of diabetic nephropathy.

  18. APE1/Ref-1 siRNA inhibits IL-6 and IL-8 secretion by cultured bone marrow stromal cells isolated from multiple myeloma patients%APE1/Ref-1 siRNA抑制多发性骨髓瘤骨髓基质细胞IL-6及IL-8分泌的体外研究

    Institute of Scientific and Technical Information of China (English)

    谢家印; 王阁; 王东; 李梦侠; 向德兵; 杨镇洲; 杨宇馨; 李增鹏; 曾林立; 仲召阳

    2009-01-01

    目的 体外通过APE1/Ref-1 siRNA敲低多发性骨髓瘤骨髓基质细胞(bone marrow stromal cells,BMSCs)APE1/Ref-1的表达,观察BMSCs的增殖及分泌细胞因子IL-6、IL-8的变化,初步探讨BMSCs APE1/Ref-1表达的功能特点.方法 通过免疫细胞化学染色法定量榆测35例初治、11例复发/难治多发性骨髓瘤患者及10例正常人BMSCsAPE1/Ref-1的表达特点及其差异,经Adv5-APE1/Ref-1 siRNA感染BMSCs后,流式细胞仪检测BMSCs细胞周期的变化;ELISA法检测BMSCs分泌IL-6、IL-8的水平变化情况.结果 多发性骨髓瘤BMSCs的APE1/Ref-1蛋白阳性表达率显著高于正常BMSCs APE1/Ref-1蛋白阳性表达率(P<0.05),且多发性骨髓瘤BMSCs的APE1/Ref-1呈细胞核及核浆共间表达方式.Adv5-APE1/Ref-1 siRNA感染敲低多发性骨髓瘤及正常BMSCs APE1/Ref-1的表达量呈进行性减少(P<0.01),同时发现APE1/Ref-1 siRNA对多发性骨髓瘤BMSCs抑制作用更明显.Adv5-APE1/Ref-1 siRNA感染BMSCs后对正常人及骨髓瘤患者BMSCs分泌细胞因子IL-6、IL-8的量有显著的抑制作用,特别是感染72 h后,骨髓瘤患者及正常人的BMSCs分泌IL-6[初治患者(246.29±46.51)pg/ml,复发/难治患者(365.09±75.25)pg/ml]、IL-8[初治患者(118.77±18.08)pg/ml,复发/难治患者(188.71±33.76)pg/ml]的量最低,与其他时段比较差异有统计学意义(P<0.01).结论 多发性骨髓瘤BMscs APE1/Ref-1的表达特点不同于正常BMSCs,可能导致其功能差异;APE1/Ref-1 siRNA敲低了MM BMSCsAPE1/Ref-1的表达,同时明显抑制了其IL-6、IL-8的分泌,减少了对骨髓瘤细胞的促增殖和凋亡作用.

  19. The Pathological and Physiological Roles of IL-6 Amplifier Activation

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    Masaaki Murakami, Toshio Hirano

    2012-01-01

    Full Text Available The NFκB-triggered positive feedback loop for IL-6 signaling in type 1 collagen+ non-immune cells (IL-6 amplifier was first discovered to be a synergistic signal that is activated following IL-17A and IL-6 stimulation in type 1 collagen+ non-immune cells. Subsequent disease models have shown that it can also be stimulated by the simultaneous activation of NFκB and STAT3, functions as a local chemokine inducer, and acts as a mechanism for local inflammation, particularly chronic ones like rheumatoid arthritis and a multiple sclerosis. Moreover, we have recently shown that hyper activation of the IL-6 amplifier via regional neural activation establishes a gateway for immune cells including autoreactive T cells to pass the blood-brain barrier at dorsal vessels in 5th lumbar cord. Here we review how the IL-6 amplifier is activated by neural activation and the physiological relevance of the gateway to the central nervous system. Accumulating evidences continues to suggest that the IL-6 amplifier offers a potential molecular mechanism for the relationship between neural activation and the development of inflammatory diseases, which could establish a new interdisciplinary field that fuses neurology and immunology.

  20. Monocyte chemoattractant protein-1-deficiency impairs the expression of IL-6, IL-1β and G-CSF after transient focal ischemia in mice.

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    Jan-Kolja Strecker

    Full Text Available Monocyte chemoattractant protein-1 (MCP-1, a chemokine secreted by neurons and astrocytes following stroke is known to aggravate ischemia-related damage. Previous studies revealed that MCP-1-deficient mice develop smaller infarcts and have an improved neurological outcome, whereas mice overexpressing MCP-1 show worsened brain damage and impaired neurological function. The aim of the present study was to elucidate the molecular background of the enhanced recovery in MCP-1-deficient mice after stroke. For this purpose, we (1 performed expression analyses on crucial post-stroke related inflammatory genes in MCP-1-deficient mice compared to wildtype controls, (2 analyzed a possible impact of MCP-1 on astrocyte activation (3 investigated the cellular origin of respective inflammatory cytokines and (4 analyzed the impact of MCP-1 secretion on the migration of both neutrophil granulocytes and T-cells. Here we report that MCP-1-deficiency leads to a shift towards a less inflammatory state following experimental occlusion of the middle cerebral artery including an impaired induction of interleukin-6, interleukin-1β and granulocyte-colony stimulating factor expression as well as a subsequent diminished influx of hematogenous cells. Additionally, MCP-1-deficient mice developed smaller infarcts 36 hours after experimental stroke. Investigations revealed no differences in transcription of tumor necrosis factor-α and astrogliosis 12 and 36 hours after onset of ischemia. These novel results help to understand post ischemic, inflammatory mechanisms and might give further arguments towards therapeutical interventions by modulation of MCP-1 expression in post stroke inflammation.

  1. IL-6-deficient Mice Are Susceptible to Ethanol-induced Hepatic Steatosis: IL-6 Protects against Ethanol-induced Oxidative Stress and Mitochondrial Permeability Transition in the Liver

    Institute of Scientific and Technical Information of China (English)

    Osama El-Assal; Feng Hong; Won-Ho Kim; Svetlana Radaeva; Bin Gao

    2004-01-01

    Interleukin-6 (IL-6)-deficient mice are prone to ethanol-induced apoptosis and steatosis in the liver; however, the underlying mechanism is not fully understood. Mitochondrial dysfunction caused by oxidative stress is an early event that plays an important role in the pathogenesis of alcoholic liver disease. Therefore, we hypothesize that the protective role of IL-6 in ethanol-induced liver injury is mediated via suppression of ethanol-induced oxidative stress and mitochondrial dysfunction. To test this hypothesis, we examined the effects of IL-6 on ethanol-induced oxidative stress, mitochondrial injury, and energy depletion in the livers of IL-6 (-/-) mice and hepatocytes from ethanol-fed rats. Ethanol consumption leads to stronger induction of malondialdehyde (MDA) in IL-6 (-/-) mice compared to wild-type control mice, which can be corrected by administration of IL-6. In vitro,IL-6 treatment prevents ethanol-mediated induction of reactive oxygen species (ROS), MDA, mitochondrial permeability transition (MPT), and ethanol-mediated depletion of adenosine triphosphate (ATP) in hepatocytes from ethanol-fed rats. Administration of IL-6 in vivo also reverses ethanol-induced MDA and ATP depletion in hepatocytes. Finally, IL-6 treatment induces metallothionein protein expression, but not superoxide dismutase and glutathione peroxidase in cultured hepatocytes. In conclusion, IL-6 protects against ethanol-induced oxidative stress and mitochondrial dysfunction in hepatocytes via induction of metallothionein protein expression, which may account for the protective role of IL-6 in alcoholic liver disease.

  2. IL-6-deficient Mice Are Susceptible to Ethanol-induced Hepatic Steatosis: IL-6 Protects against Ethanol-induced Oxidative Stress and Mitochondrial Permeability Transition in the Liver

    Institute of Scientific and Technical Information of China (English)

    OsamaEl-Assal; FengHong; Won-HoKim; SvetlanaRadaeva; BinGao

    2004-01-01

    Interleukin-6 (IL-6)-deficient mice are prone to ethanol-induced apoptosis and steatosis in the liver; however,the underlying mechanism is not fully understood. Mitochondrial dysfunction caused by oxidative stress is an early event that plays an important role in the pathogenesis of alcoholic liver disease. Therefore, we hypothesize that the protective role of IL-6 in ethanol-induced liver injury is mediated via suppression of ethanol-induced oxidative stress and mitochondrial dysfunction. To test this hypothesis, we examined the effects of IL-6 on ethanol-induced oxidative stress, mitochondrial injury, and energy depletion in the livers of IL-6 (-/-) mice and hepatocytes from ethanol-fed rats. Ethanol consumption leads to stronger induction of malondialdehyde (MDA) in IL-6 (-/-) mice compared to wild-type control mice, which can be corrected by administration of IL-6. In vitro,IL-6 treatment prevents ethanol-mediated induction of reactive oxygen species (ROS), MDA, mitochondrial permeability transition (MPT), and ethanol-mediated depletion of adenosine triphosphate (ATP) in hepatocytes from ethanol-fed rats. Administration of IL-6 in vivo also reverses ethanol-induced MDA and ATP depletion in hepatocytes. Finally, IL-6 treatment induces metallothionein protein expression, but not superoxide dismutase and glutathione peroxidase in cultured hepatocytes. In conclusion, IL-6 protects against ethanol-induced oxidative stress and mitochondrial dysfunction in hepatocytes v/a induction of metallothionein protein expression, which mav account for the nrotective role of IL-6 in alcoholic liver disease.

  3. Downregulation of IL6 Targeted MiR-376b May Contribute to a Positive IL6 Feedback Loop During Early Liver Regeneration in Mice

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    Shan Lu

    2015-08-01

    Full Text Available Background/Aims: MicroRNAs (miRNAs are a group of endogenous, small, noncoding RNAs implicated in a variety of biological processes, including cell proliferation, apoptosis, differentiation and metabolism. The present study aims to explore the potential role and molecular mechanism of miR-376b during the early phase of liver regeneration. Methods: MiRNA profiling microarrays were used to assess the changes in miRNA expression. For functional analysis, cell proliferation, apoptosis assays, real time quantitative PCR and westernblot analysis were performed. Results: The comprehensive miRNA expression profiling assays on regenerating liver tissues 4 h after partial hepatectomy (PH showed that three miRNAs (miR-127, miR-376b and miR-494 located in the Dlk1-Gtl2 miRNA cluster were significantly downregulated. In vitro functional studies demonstrated that high-level interleukin 6 (IL6 inhibited the expression of miR-376b, and miR-376b mimics treatment decreased cell proliferation and increased apoptosis. Further target analysis showed that miR-376b reduced the mRNA and protein expression levels of NF-kappa-B inhibitor zeta (NFKBIZ and signal transducers and transcription activators 3 (STAT3. Additionally, IL6-induced miR-376b downregulation would, in turn, increase the expression of IL-6 possibly via a feedback loop involving NFKBIZ or/and STAT3. Conclusion: During the early phase of liver regeneration, miR-376b expression was significantly decreased. Our findings reveal that a regulatory circuitry between miR-376b and IL-6 may exist, which trigger the initiation of liver regeneration.

  4. 双歧杆菌四联活菌片联合用药对小儿非感染性腹泻的疗效及血清中IL-6、IL-17表达影响研究%Effect of viable bifidobacterium quadruple combination use in treating children non-infectious diarrhea and its influence on serum IL-6,IL-17 expression

    Institute of Scientific and Technical Information of China (English)

    吴立新; 张声生

    2013-01-01

    目的 探讨双歧杆菌四联活菌片联合用药对小儿非感染性腹泻的疗效及血清中白细胞介素(IL)-6、IL-17表达的影响.方法 选择重庆市开县人民医院儿科收治的非感染性腹泻患儿100例,采用双歧杆菌四联活菌片联合用药治疗50例为观察组;采用常规治疗50例为对照组.比较两组患儿的疗效及血清中IL-6、IL-17表达水平.结果 观察组总有效率与对照组比较,差异有统计学意义(P0.05).结论 双歧杆菌四联活菌片联合用药治疗小儿非感染性腹泻疗效显著,且血清中IL-6、IL-17表达水平恢复正常相对更快,而且服用方便,无明显不良反应,适宜应用于临床.%Objective To investigate the effect of viable bifidobacterium quadruple combination use in treating children non-infectious diarrhea and its influence on serum IL-6,IL-17 expression. Methods 100 children with non-infectious diarrhea in this hospital were selected .The observation group (50 cases) was treated by viable bifidobacterium quadruple combination use and the con -trol group (50 cases) by the conventional therapy .The effects and serum expression levels of IL-6 and IL-17 were compared between the two groups .Results The total effective rates had statistical differences between the two groups (P0 .05) .Conclusion Viable bifidobacterium quadruple combination use has significant effect in treating children non-infectious diarrhea ,serum IL-6 ,IL-17 expression returning to normal rapidly ,which is easy to take without significant adverse reactions and suitable for clinical application .

  5. 脑胶质瘤患者血清IL-6、IL-8、IL-10和TNF-α的表达及临床意义%The Expression of IL-6, IL-8, IL-10 and TNF-α in Serum of Glioma and Clinical Significance

    Institute of Scientific and Technical Information of China (English)

    李春生; 张朋军

    2013-01-01

    [Purpose] To explore the diagnostic value of serum interleukin-6 (IL-6), IL-8, IL-10 and tumor necrosis factor (TNF-α) for glioma. [Materials and methods] The content of IL-6, IL-8, IL-10 and TNF-α in the healthy control group, the low-grade gliomas group and the high-grade gliomas group were detected by Luminex 200. [Results] Compared to the healthy control group, IL-6, IL-8, and TNF-α in the low-grade gliomas group showed significantly different, IL-6, IL-8, IL-10 and TNF-α in the high-level group of glioma showed significantly different. Compared to the low-grade gliomas Group, IL-6, IL-10 and TNF-α in the high-grade gliomas showed significantly different. When we discriminated the low-grade gliomas and high-grade gliomas, the best indicators was IL-10, and the diagnostic sensitivity and specificity were 74.90% and 65.80%, respectively. When the IL-6, IL-10 and TNF-α were combined, the sensitivity and specificity were 92.30% and 93.10%, respectively. [Conclusion] IL-6, IL-10 and TNF-α joint diagnostic value showed significant improvedment when compared to the individual indicators. It may provide a auxiliary method for brain the clinical diagnosis of glioma.%  [目的]探讨血清中白介素6(IL-6)、IL-8、IL-10和肿瘤坏死因子(TNF-α)对于脑胶质瘤的诊断价值。[材料与方法]分别检测健康对照组、低级别脑胶质瘤组和高级别脑胶质瘤组中IL-6、IL-8、IL-10和TNF-α的含量。[结果]与健康对照组比较,低级别脑胶质瘤组的IL-6、IL-8和TNF-α有统计学差异,高级别脑胶质瘤组的IL-6、IL-8、IL-10和TNF-α均具有统计学差异。与低级别脑胶质瘤组相比较,高级别脑胶质瘤组的IL-6、IL-10和TNF-α有统计学差异。其中区分低级别脑胶质瘤和高级别脑胶质瘤的诊断价值最好的指标为IL-10,其诊断灵敏性和特异性分别为74.90%和65.80%。IL-6、IL-10和TNF-α联合检测时其灵敏性和特异性分别为92.30%和93.10%。[结论]证实IL

  6. Production of IL-6 and TNF-α in periodontal ligament cells stimulated by lipopolysaccharides%牙龈卟啉菌和大肠杆菌内毒素对人牙周膜细胞分泌IL-6、TNF-α的影响

    Institute of Scientific and Technical Information of China (English)

    张凤秋; 吴织芬; 万玲; 袁乃梅

    2002-01-01

    目的:研究牙龈卟啉菌、大肠杆菌内毒素对人牙周膜细胞(PDLC) 分泌IL-6、TNF-α的影响.方法:采用细胞培养技术和ELISA方法,检测培养上清中IL-6、TNF-α水平.结果:在孵育6h后,即可在培养上清中检测到IL-6和TNF-α.IL-6在12h、TNF-α在24h内呈时间依赖性方式升高.结论:PDLC在内毒素作用下局部分泌IL-6、TNF-α,参与了牙周炎的发生、发展过程.

  7. ROLE OF IL-6 IN EXPERIMENTAL ARTHRITIS CAUSED BY TRANSFER OF ARTHRITOGENIC ANTIBODIES

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    M. S. Drutskaya

    2016-01-01

    Full Text Available Interleukin-6 (IL-6 exerts important functions on immune regulation. In case of high expression, IL-6 may promote autoimmune disorders, e.g., arthritis. Systemic IL-6 blockers based on monoclonal antibodies against IL-6, or its specific receptor subunit, are already used in clinical settings, adding to a range of known biological drugs, such as, TNF blockers. Rheumatic disorders and their experimental therapy are reproducible in mice. This study revealed systemically increased levels of IL-6 in developing arthritis caused by transfer of pathogenic antibodies, as well as the effects of IL-6 neutralization by monoclonal antibodies against murine IL-6. Our results suggest a pathogenic role of the two cytokines, TNF and IL-6, in experimental arthritis induced by passive transfer of anti-collagen antibodies.

  8. Expressions of IL-6 and IL-8 in normal gastric tissue, gastric ulcer and gastric cancer%IL-6和IL-8在正常胃组织、胃溃疡及胃癌组织中的表达

    Institute of Scientific and Technical Information of China (English)

    赵志威; 朴大勋; 姜涛; 张哲男; 王剑冰; 荆琼优

    2014-01-01

    目的 探讨白细胞介素(IL)-6和IL-8在正常胃组织、胃溃疡及胃癌组织中的表达情况.方法 采用酶联免疫吸附法(ELISA)测定正常对照组(33例)、胃溃疡患者(30例)和准备手术的胃癌患者(52例)血浆中IL-6和IL-8的表达水平,并随访胃癌患者术后1周的IL-6、IL-8表达水平;免疫组织化学法检测胃癌周围正常组织(45例)、胃溃疡组织(35例)和胃癌组织(45例)标本中IL-6和IL-8的表达.结果 胃癌患者(术前和术后)血浆中IL-6、IL-8的表达明显高于胃溃疡和正常对照组(均P<0.0l),胃癌患者术后IL-6和IL-8水平较术前明显降低(P<0.01).癌周正常组织、胃溃疡和胃癌组织中IL-6和IL-8蛋白阳性表达率依次上升,且差异有统计学意义(x2=38.87,P<0.01;x2=42.23,P<0.01).结论 IL-6和IL-8在胃癌患者血浆和胃癌组织中均表达上调,检测患者血浆和病理组织中的IL-6、IL-8水平有助于判断病情和评估预后.

  9. The expression of serum IL-6, IL-10, IL-12 level in gastrointestinal neoplasm and its significance%血清IL-6、IL-10、IL-12在消化道肿瘤中的表达及其意义

    Institute of Scientific and Technical Information of China (English)

    姚琪远; 张群华; 倪泉兴; 张延龄

    2000-01-01

    目的探讨消化道肿瘤患者血清IL-6、IL-10、IL-12的变化及其意义.方法应用酶联免疫法测定了胃癌、结肠癌及健康者血清IL-6、IL-10、IL-12含量,比较其相互间的关系.结果胃癌和结肠癌组IL-10、IL-12含量低于对照组;IL-6含量则高于对照组,且随着肿瘤临床病理分期的进展而不断升高;胃癌血清IL-6、IL-10、IL-12含量与结肠癌接近.结论消化道肿瘤患者血清细胞因子IL-6、IL-10、IL-12的变化可能与肿瘤的生长及机体抗肿瘤免疫功能的受损有关.

  10. Mangiferin suppresses CIA by suppressing the expression of TNF-α, IL-6, IL-1β, and RANKL through inhibiting the activation of NF-κB and ERK1/2.

    Science.gov (United States)

    Tsubaki, Masanobu; Takeda, Tomoya; Kino, Toshiki; Itoh, Tatsuki; Imano, Motohiro; Tanabe, Genzo; Muraoka, Osamu; Satou, Takao; Nishida, Shozo

    2015-01-01

    Rheumatoid arthritis is a systemic autoimmune disease characterized by chronic inflammation of synovial joints, ultimately leading to a progressive and irreversible joint destruction. Activation of nuclear factor-kappa B (NF-κB) promotes production of proinflammatory cytokines in various inflammatory diseases including rheumatoid arthritis. Mangiferin, 1,3,6,7-tetrahydroxyxanthone-C2-β-D-glucoside (C-glucosyl xanthone), is a naturally occurring polyphenol. Our previous results showed that mangiferin suppressed NF-κB activation. However, it is unclear, whether mangiferin can prevent rheumatoid arthritis through suppression of NF-κB activation and expression of various cytokines, such as tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6), which play a critical role in the pathogenesis of rheumatoid arthritis. In the present study, we found that mangiferin suppressed the progression and incidence of CIA in DBA1/J mice. In CIA mice, mangiferin inhibited the mRNA expression of cytokine genes in thymus and spleen of CIA mie and led to decreased serum levels of IL-1β, IL-6, TNF-α, and receptor activator NF-κB ligand (RANKL) via inhibition of NF-κB and activation of extracellular signal-regulated kinase 1/2 (ERK1/2). In addition, mangiferin markedly inhibited not only developing but also clinically evident CIA. These findings suggest that mangiferin has potential clinical applications for the treatment of rheumatoid arthritis.

  11. Loss of p53 attenuates the contribution of IL-6 deletion on suppressed tumor progression and extended survival in Kras-driven murine lung cancer.

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    Xiaohong Tan

    Full Text Available Interleukin-6 (IL-6 is involved in lung cancer tumorigenesis, tumor progression, metastasis, and drug resistance. Previous studies show that blockade of IL-6 signaling can inhibit tumor growth and increase drug sensitivity in mouse models. Clinical trials in non-small cell lung cancer (NSCLC reveal that IL-6 targeted therapy relieves NSCLC-related anemia and cachexia, although other clinical effects require further study. We crossed IL-6(-/- mice with Kras(G12D mutant mice, which develop lung tumors after activation of mutant Kras(G12D, to investigate whether IL-6 inhibition contributes to tumor progression and survival time in vivo. Kras(G12D; IL-6(-/- mice exhibited increased tumorigenesis, but slower tumor growth and longer survival, than Kras(G12D mice. Further, in order to investigate whether IL-6 deletion contributes to suppression of lung cancer metastasis, we generated Kras(G12D; p53(flox/flox; IL-6(-/- mice, which developed lung cancer with a trend for reduced metastases and longer survival than Kras(G12D; p53(flox/flox mice. Tumors from Kras(G12D; IL-6(-/- mice showed increased expression of TNFα and decreased expression of CCL-19, CCL-20 and phosphorylated STAT3(pSTAT3 than Kras(G12D mice; however, these changes were not present between tumors from Kras(G12D; p53(flox/flox; IL-6(-/- and Kras(G12D; p53(flox/flox mice. Upregulation of pSTAT3 and phosphorylated AKT(pAKT were observed in Kras(G12D tumors with p53 deletion. Taken together, these results indicate that IL-6 deletion accelerates tumorigenesis but delays tumor progression and prolongs survival time in a Kras-driven mouse model of lung cancer. However, these effects can be attenuated by p53 deletion.

  12. Determinants of IL-6 levels during HIV infection

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    Álvaro H Borges

    2014-11-01

    Full Text Available Introduction: Elevated IL-6 levels have been linked to increased risk of cardiovascular disease (CVD, cancer and death. Compared to the general population, treated HIV+ persons have 50–100% higher IL-6 levels, but few data on the determinants of IL-6 levels during HIV infection currently exist. Material and Methods: Participants in three international HIV trials (SMART, ESPRIT and SILCAAT with IL-6 plasma levels measured at baseline were included (N=9864. Factors independently associated with log2-transformed IL-6 level were identified by multivariate linear regression; exponentiated estimates corresponding to fold differences (FDs in IL-6 were calculated. Demographics (age, gender, race, BMI and HIV-specific variables (nadir and entry CD4 counts, HIV-RNA, use of different ART regimens were investigated in all three trials. In SMART (N=4498, smoking, comorbidities (CVD, diabetes, hepatitis B/C [HBV/HCV], HDL-cholesterol, renal function (eGFR and educational level were also assessed. Results: Demographics associated with higher IL-6 were older age (FD [95% CI]: 1.09 [1.08–1.11] per 10 yr and higher BMI (1.02 [1.01–1.04] per 5 kg/m2, whereas black race was associated with reduced IL-6 (0.96 [0.93–0.99]. As for HIV variables, patients not receiving ART (1.36 [1.29–1.43] and with higher HIV-RNA (1.24 [1.01–1.52] for >100,000 vs. ≤500 copies/mL had increased IL-6. Participants taking protease inhibitors (PI had higher IL-6 (1.14[1.09–1.19]. Higher nadir CD4 count (0.98 [0.97–0.99]/100 cells/µL was related to lower IL-6. All evaluated comorbidities were related to higher IL-6; FDs in IL-6 were 1.08 [1.04–1.12] for smoking, 1.12 [1.02–1.24] for CVD, 1.07 [1.00–1.16] for diabetes and 1.12 [1.02–1.24] for HBV (1.15 [1.02–1.30] and 1.53 [1.45–1.62] for HCV. IL-6 increased with decreasing eGFR (0.98 [0.97–1.00]/10 mL/min and HDL-cholesterol (0.98 [0.96–0.99]/10 mg/mL. Lower education was related to higher IL-6 (1.09 [1

  13. Interleukin-6 receptor expression and localization after transient global ischemia in gerbil hippocampus.

    Science.gov (United States)

    Vollenweider, Florence; Herrmann, Martina; Otten, Uwe; Nitsch, Cordula

    2003-04-24

    Ischemia results in increased interleukin-6 (IL-6) expression in the brain. To prove a connection between IL-6 upregulation and IL-6 receptor (IL-6R) expression following ischemia, we analyzed cell-type specific expression changes of IL-6R using transient global ischemia in the gerbil as a model. In sham operated animals, IL-6R mRNA and protein were mainly detected in hippocampal pyramidal cells and interneurons. After ischemia, IL-6R was expressed in neurons but there was no increase during the peak IL-6 expression. Neuronal IL-6R mRNA and protein decreased in parallel with pyramidal cell death, starting 2 days after ischemia. Double-labeling experiments revealed that in postischemic hippocampus IL-6R was not present in GFAP-reactive astrocytes but that the surviving parvalbumin containing interneurons expressed IL-6R mRNA.

  14. HIF-α/MIF and NF-κB/IL-6 axes contribute to the recruitment of CD11b+Gr-1+ myeloid cells in hypoxic microenvironment of HNSCC.

    Science.gov (United States)

    Zhu, Guiquan; Tang, Yaling; Geng, Ning; Zheng, Min; Jiang, Jian; Li, Ling; Li, Kaide; Lei, Zhengge; Chen, Wei; Fan, Yunlong; Ma, Xiangrui; Li, Longjiang; Wang, Xiaoyi; Liang, Xinhua

    2014-02-01

    CD11b+Gr-1+ myeloid cells have gained much attention due to their roles in tumor immunity suppression as well as promotion of angiogenesis, invasion, and metastases. However, the mechanisms by which CD11b+Gr-1+ myeloid cells recruit to the tumor site have not been well clarified. In the present study, we showed that hypoxia could stimulate the migration of CD11b+Gr-1+ myeloid cells through increased production of macrophage migration inhibitory factor (MIF) and interleukin-6 (IL-6) by head and neck squamous cell carcinoma (HNSCC) cells. Hypoxia-inducible factor-1α (HIF-1α)- and HIF-2α-dependent MIF regulated chemotaxis, differentiation, and pro-angiogenic function of CD11b+Gr-1+ myeloid cells through binding to CD74/CXCR2, and CD74/CXCR4 complexes, and then activating p38/mitogen-activated protein kinase (MAPK) and phosphatidylinositide 3-kinases (PI3K)/AKT signaling pathways. Knockdown (KD) of HIF-1α and HIF-2α in HNSCC cells decreased MIF level but failed to inhibit the CD11b+Gr-1+ myeloid cell migration, because HIF-1α/2α KD enhanced nuclear factor κB (NF-κB) activity that increased IL-6 secretion. Simultaneously blocking NF-κB and HIF-1α/HIF-2α had better inhibitory effect on CD11b+Gr-1+ myeloid cell recruitment in the hypoxic zone than individually silencing HIF-1α/2α or NF-κB. In conclusion, the interaction between HIF-α/MIF and NF-κB/IL-6 axes plays an important role in the hypoxia-induced accumulation of CD11b+Gr-1+ myeloid cells and tumor growth in HNSCC.

  15. Distinct myeloid suppressor cell subsets correlate with plasma IL-6 and IL-10 and reduced interferon-alpha signaling in CD4⁺ T cells from patients with GI malignancy.

    Science.gov (United States)

    Mundy-Bosse, Bethany L; Young, Gregory S; Bauer, Todd; Binkley, Elaine; Bloomston, Mark; Bill, Matthew A; Bekaii-Saab, Tanios; Carson, William E; Lesinski, Gregory B

    2011-09-01

    Interferon-alpha (IFN-α) promotes anti-tumor immunity through its actions on immune cells. We hypothesized that elevated percentages of myeloid-derived suppressor cells (MDSC) and increased pro-inflammatory cytokines in peripheral blood would be associated with impaired response to IFN-α in patients with gastrointestinal (GI) malignancies. This study evaluated relationships between plasma IL-6, IL-10, circulating MDSC subsets, and IFN-α-induced signal transduction in 40 patients with GI malignancies. Plasma IL-6 and IL-10 were significantly higher in patients versus normal donors. CD33(+)HLADR(-)CD11b(+)CD15(+) and CD33(+)HLADR(-/low)CD14(+) MDSC subsets were also elevated in patients versus normal donors (P normal donors. Exploratory multivariable Cox proportional hazards models revealed that an increased percentage of the CD33(+)HLADR(-)CD15(-) MDSC subset was associated with reduced overall survival (P = 0.049), while an increased percentage of the CD33(+)HLADR(-/low)CD14(+) subset was associated with greater overall survival (P = 0.033). These data provide evidence for a unique relationship between specific cytokines, MDSC subsets, and IFN-α responsiveness in patients with GI malignancies.

  16. Control of IgE responses. III. IL-6 and IFN-alpha are isotype-specific regulators of peak BPO-specific IgE antibody-forming cell responses in mice.

    Science.gov (United States)

    Auci, D L; Kleiner, G I; Chice, S M; Dukor, P; Durkin, H G

    1993-03-01

    The ability of cytokines (IL-4, IL-5, IL-6, IFN-alpha, IFN-gamma, TNF-alpha, GmCSF) to regulate peak benzylpenicilloyl (BPO)-specific IgE antibody-forming cell (AFC) responses was investigated. These responses were induced in BALB/c mice by ip injection of BPO-keyhole limpet hemocyanin (BPO-KLH; 10 micrograms) in aluminum hydroxide gel on Days 0, 21, and 42. On Day 44, or on Days 43, 44, and 45, mice were injected sc with varying doses of cytokine or anti-cytokine antibody. On Day 46, the numbers of BPO-specific AFC (IgM, IgG1, IgE and IgA) in spleen were determined ex vivo in enzyme-linked immunosorbent spot assay. Among the cytokines tested, only IL-6 suppressed BPO-specific IgE AFC responses in an isotype-specific fashion (60-90%). However, treatment of mice with anti-IL-6 also suppressed these responses, suggesting that IL-6 can either suppress or increase peak antigen specific IgE responses, depending upon its concentration. Among the cytokines tested, only IFN-alpha increased BPO-specific IgE AFC responses in an isotype-specific fashion. Since treatment with anti-IFN-alpha suppressed these responses, it appears that IFN-alpha is required to maintain peak antigen-specific IgE AFC responses. IL-4 or IFN-gamma nonspecifically suppressed responses of all isotypes. Treatment with anti-IL-4 also suppressed IgE responses, suggesting that this cytokine is required to maintain peak antigen specific IgE responses. Treatment with anti-IFN-gamma increased IgE responses, indicating that IFN-gamma suppresses peak antigen-specific IgE responses.

  17. 汉族和哈萨克族慢性牙周炎的严重程度与 IL-6和 IL-17相关性分析%The correlation between chronic periodontitis and IL-6 and IL-17 expression in serum and saliva of Kazak and Han subjects

    Institute of Scientific and Technical Information of China (English)

    陈世娟; 钟良军; 宋倩

    2016-01-01

    IL-6 and IL-17 levels in saliva and serum were measured by ELISA in 116 cases of chronic periodontitis(CP)in Mulei district of Xinjiang,including 62 cases of Han and 54 of Kazak.Health controls included 50 subjects of Han and 45 of Kazak.IL-6 and IL-17 levels in serum and saliva were higher in CP groups than in the controls(P <0.05),and correlated with the severity of CP(P <0.05),in Kazak CP group were higher than in Han CP group(P <0.05).%纳入新疆木垒地区慢性牙周炎(CP)患者116例,62例汉族组,54例哈萨克族组。以口腔健康的50例汉族,45例哈萨克族为对照。ELISA 检查血液和唾液中 IL-6、IL-17水平。血清与唾液 IL-6和 IL-17水平病例组高于对照组(P <0.05),随 CP 严重程度而升高(P <0.05),哈萨克族病例高于汉族病例组(P <0.05)。

  18. Effect on the Expression of IL-1β,IL-6 in Hippocampus and Serum of Depressive Rats with Chronic Unpredictable Mild Stress Treated by Different Electro-acupuncture Treatment%不同电针对慢性应激抑郁模型大鼠海马及血清细胞因子 IL-1β、IL-6表达的影响

    Institute of Scientific and Technical Information of China (English)

    莫雨平; 李志刚; 邓晓丰; 纪倩; 滕金艳; 姚海江; 宋洪涛; 唐银杉; 许安萍; 张淑静

    2014-01-01

    Objective:To investigate the effect on the expression of IL -1β, IL-6 in the hippocampus and ser-um of rats with chronic unpredictable mild stress treated by different electro -acupuncture(EA) treatment, to elucidate the possible role of IL -1β, IL-6 in the development of experimental depression and the effect of different EA for them .Methods:Adult male SD rats were randomly divided into normal control group ( n=12 ) , model group ( n=12 ) , pulsed EA group ( n=12 ) , music EA group ( n=12 ) and fluoxetine group ( n=12 ) . Depressive models were established by lonely raising and chronic unpredictable mild stress for 21 days. Open-field test was performed to test the behavior of rats .The expression of hippocampus and serum IL -1β, IL-6 was detected by using immunohistochemistry and enzyme linked immunosorbent assay ( ELISA ) techniques respectively .Results:The cross and rear score of model group was significantly lower than that in normal control group , while pulsed EA group , music EA group and fluoxetine group could reverse it .The ex-pression of hippocampus and serum IL -1β, IL-6 in model group increased significantly .The three kinds of treatment could improve these pathological change , but there was no difference among these effects of treat-ment .Conclusion:The levels of IL-1β, IL-6 in hippocampus and serum of depressive rats are higher than those in the normal group .EA treatment may have antagonism against depression by lowering the levels of IL-1β, IL-6 in hippocampus and serum ,and there is no difference between the effects of pulsed EA treat-ment and music EA treatment for depression .%目的:观察不同电针对慢性应激抑郁模型( chronic unpredictable mild stress ,CUMS)大鼠海马及血清中细胞因子IL-1β、IL-6表达的影响,探讨IL-1β、IL-6在大鼠实验性抑郁症发病过程中的作用机制及不同电针干预对其影响。方法:将雄性清洁健康级SD大鼠60只,随机分为正常组、模型组

  19. 外源性IL-10对小儿牙龈炎组织中IL-6和细胞间黏附分子-1表达的影响研究%Study on the effect of exogenous IL-10 on IL-6 and intercellular adhesion molecule-1 expressions in gingivitis tissue of children

    Institute of Scientific and Technical Information of China (English)

    牛兵; 姜瑞中; 王国芳

    2015-01-01

    目的 研究外源性IL-10对小儿牙龈炎组织中IL-6和细胞间黏附分子-1 (ICAM-1)表达的影响.方法 选取2012年5月~2014年6月在该院接受治疗的80例牙龈炎患儿和正常进行健康检查的儿童40名为研究对象.根据探诊深度及附着丧失实施分组,轻度牙龈炎组简称轻度组、重度牙龈炎组简称重度组,各40例,选取同期在该院进行健康检查的儿童40名为对照组.对比各组IL-6含量水平,各组ICAM-1含量水平,分析外源性IL-10与IL-6及ICAM-1的相关性.结果 重度组IL-6含量水平均高于其他两组,经过治疗后重度组及轻度组的IL-6含量水平均降低,但治疗7天后仍显著高于对照组的水平,差异均有统计学意义(均P<0.05).重度组的ICAM-1含量水平均分别显著高于轻度组和对照组,经过治疗后,重度组及轻度组的ICAM-1含量水平均降低,但治疗7天后仍显著高于对照组的水平,差异均有统计学意义(均P<0.05).通过Spearman法分析相关性可知,外源性IL-10与IL-6及ICAM-1均呈显著负相关.结论 外源性IL-10能够较好地降低小儿牙龈炎组织关于IL-6及ICAM-1的表达,值得临床进一步深入研究.

  20. Vaccination with IL-6 analogues induces autoantibodies to IL-6 and influences experimentally induced inflammation

    DEFF Research Database (Denmark)

    Galle, Pia; Jensen, Lene; Andersson, Christina

    2007-01-01

    ; yet they appear healthy and do not exhibit overt clinical or laboratory abnormalities. We induced comparable levels of aAb-IL-6 in different mouse strains by vaccination with immunogenic IL-6 analogues. We observed that the induced aAb-IL-6 protected against collagen-induced arthritis and experimental...

  1. 双歧杆菌四联活菌片联合用药治疗小儿非感染性腹泻的效果及对血清IL-6、IL-17表达的影响%Effect of combined Bifidobacterium,Lactobacillus,Enterococcus and Bacil-lus cereus tablets,live in the treatment of non-infectious diarrhea in chil-dren and influence study on serum IL-6,IL 17 expression

    Institute of Scientific and Technical Information of China (English)

    周慧恩; 梁斐; 周运南; 黎惠章

    2015-01-01

    Objective To investigate the clinical effect of combined Bifidobacterium,Lactobacillus,Enterococcus and Bacillus cereus tablets,live in the treatment of non-infectious diarrhea in children and influence on serum IL-6,IL 17 expression. Methods 120 children with non-infectious diarrhea in our hospital from February 2013 to June 2014 were selected and randomly divided into observation group and control group,each group of 60 cases.Conventional method was used in control group,combined Bifidobacterium,Lactobacillus,Enterococcus and Bacillus cereus tablets,live were applied in observation group on the basis of control group.Total effective rate,diarrhea stopped time,hospital admission time,level of IL-6 and IL-17 in two groups were compared. Results Total effective rate in observation group was 96.67%,higher than that in control group(85.00%),with statistical difference(P<0.05).Diarrhea stopped time,hospital ad-mission time in observation group was shorter than that in control group respectively,with statistical difference(P<0.05). After treatment of 72 hours,level of IL-6 and IL-17 was lower than that in control group respectively (P<0.05). Con-clusion Combined Bifidobacterium,Lactobacillus,Enterococcus and Bacillus cereus tablets,live in the treatment of non-infectious diarrhea in children can shorten diarrhea stopped time,hospital admission time,reduce level of IL-6 and IL-17,has a substantial clinical curative effect and is worthy of promotion and application.%目的:探讨双歧杆菌四联活菌片治疗小儿非感染性腹泻的临床效果及对血清IL-6、IL-17表达的影响。方法选取2013年2月~2014年6月本院收治的120例非感染性腹泻小儿,将其随机分为观察组和对照组,各60例,对照组采用常规方法治疗,观察组在对照组基础上采用双歧杆菌四联活菌片治疗,比较两组的总有效率、腹泻停止时间、住院时间和IL-6、IL-17水平。结果观察组总有效率为96.67%,

  2. The role of intratumoral and systemic IL-6 in breast cancer

    DEFF Research Database (Denmark)

    Dethlefsen, Christine; Højfeldt, Grith Westergaard; Hojman, Pernille

    2013-01-01

    circulating IL-6 and risk of breast cancer, prognosis for patients with prevalent disease, adverse effects and interventions to control systemic IL-6 levels in patients are discussed. In summary, direct application of IL-6 on breast cancer cells inhibits proliferation in estrogen receptor positive cells......, while high circulating IL-6 levels are correlated with a poor prognosis in breast cancer patients. This discrepancy reflects distinct roles of IL-6, with elevated systemic levels being a biomarker for tumor burden, physical inactivity, and impaired metabolism, while local intratumoral IL-6 signaling......Chronic low-grade inflammation plays an important role in the pathogenesis of several cancer forms including breast cancer. The pleiotropic cytokine IL-6 is a key player in systemic inflammation, regulating both the inflammatory response and tissue metabolism during acute stimulations. Here, we...

  3. Expression and Clinical Traumatic Condition Judgment Value of Serum TNF-α and IL-6 Levels in Patients with Severe Lower Extremity Trauma%下肢严重创伤患者血清TNF-α及IL-6的表达及其临床伤情判断价值

    Institute of Scientific and Technical Information of China (English)

    邓志荣; 连俊峰; 杨乐

    2010-01-01

    目的 探讨下肢严重创伤患者TNF-α及IL-6血清浓度的动态变化及其对下肢严重创伤患者伤情判断的意义.方法 2005年1月至2009年12月下肢严重创伤患者31例,按下肢创伤严重度评分(mangled extremity severity score,MESS)为(6.24 ± 1.45)分,MESS<7分26例,MESS≥7分5例.在伤后第6 h及入院后第1、3、5、7、10、14和21 d分别采集静脉血标本,应用ELISA法测定31例下肢严重创伤患者伤后血清TNF-α和IL-6水平变化,并与20例健康对照比较,以判断PCT水平变化与下肢严重创伤严重程度和预后之间的关系.结果 TNF-α及IL-6血清浓度在下肢严重创伤后均较正常对照组显著增高,TNF-α于2周后恢复正常,而IL-6增高持续至2周后.各下肢创伤严重度评分(MESS)分值区段内的创伤患者TNF-α及IL-6水平有显著差异(P <0.05),二者之间存在正相关性.结论 动态检测下肢严重创伤患者外周血TNF-α和IL-6的水平变化可有助于病情的评估及预后判断.

  4. Effect of psychological nursing on expression levels of serum TNF-α, IL-6 and IL-8 in patients after breast cancer operation%心理护理对乳腺癌术后患者血清中TNF-α、IL-6和IL-8蛋白表达水平的影响

    Institute of Scientific and Technical Information of China (English)

    程光文

    2014-01-01

    目的:观察心理护理对乳腺癌术后患者血清中TNF-α、IL-6和IL-8蛋白表达水平的影响.方法:将70例乳腺癌患者随机分为常规护理组和心理护理组各35例,两组乳腺癌患者均于术后第1天采血及术后第7天采血;选择同期体检健康妇女20例作为正常对照组.采用ELISA方法检测血清中TNF-α、IL-6和IL-8的蛋白含量,采用实时荧光定量法检测TNF-α、IL-6和IL-8 mRNA的表达水平.结果:与术后第1天相比较,术后第7天常规护理组TNF-α、IL-6和IL-8的蛋白含量及mRNA的表达水平均降低,差异有统计学意义(P<0.05),术后第7天心理护理组TNF-α、IL-6和IL-8的蛋白含量及mRNA的表达水平均明显降低,差异有统计学意义(P<0.01);术后第7天常规护理组TNF-α、IL-6和IL-8的蛋白含量及mRNA的表达水平仍高于心理护理组,差异有统计学意义(P<0.05).结论:心理护理能进一步降低乳腺癌患者血清中炎性因子的表达水平,从而增强患者免疫力及提高术后生活质量.

  5. Clone-specific expression, transcriptional regulation, and action of interleukin-6 in human colon carcinoma cells

    Directory of Open Access Journals (Sweden)

    Fabjani Gerhild

    2008-01-01

    Full Text Available Abstract Background Many cancer cells produce interleukin-6 (IL-6, a cytokine that plays a role in growth stimulation, metastasis, and angiogenesis of secondary tumours in a variety of malignancies, including colorectal cancer. Effectiveness of IL-6 in this respect may depend on the quantity of basal and inducible IL-6 expressed as the tumour progresses through stages of malignancy. We therefore have evaluated the effect of IL-6 modulators, i.e. IL-1β, prostaglandin E2, 17β-estradiol, and 1,25-dihydroxyvitamin D3, on expression and synthesis of the cytokine at different stages of tumour progression. Methods We utilized cultures of the human colon carcinoma cell clones Caco-2/AQ, COGA-1A and COGA-13, all of which expressed differentiation and proliferation markers typical of distinct stages of tumour progression. IL-6 mRNA and protein levels were assayed by RT-PCR and ELISA, respectively. DNA sequencing was utilized to detect polymorphisms in the IL-6 gene promoter. Results IL-6 mRNA and protein concentrations were low in well and moderately differentiated Caco-2/AQ and COGA-1A cells, but were high in poorly differentiated COGA-13 cells. Addition of IL-1β (5 ng/ml to a COGA-13 culture raised IL-6 production approximately thousandfold via a prostaglandin-independent mechanism. Addition of 17β-estradiol (10-7 M reduced basal IL-6 production by one-third, but IL-1β-inducible IL-6 was unaffected. Search for polymorphisms in the IL-6 promoter revealed the presence of a single haplotype, i.e., -597A/-572G/-174C, in COGA-13 cells, which is associated with a high degree of transcriptional activity of the IL-6 gene. IL-6 blocked differentiation only in Caco-2/AQ cells and stimulated mitosis through up-regulation of c-myc proto-oncogene expression. These effects were inhibited by 10-8 M 1,25-dihydroxyvitamin D3. Conclusion In human colon carcinoma cells derived from well and moderately differentiated tumours, IL-6 expression is low and only marginally

  6. Krüppel-Like Factor 4 Is a Regulator of Proinflammatory Signaling in Fibroblast-Like Synoviocytes through Increased IL-6 Expression

    Directory of Open Access Journals (Sweden)

    Xinjing Luo

    2016-01-01

    Full Text Available Human fibroblast-like synoviocytes play a vital role in joint synovial inflammation in rheumatoid arthritis (RA. Proinflammatory cytokines induce fibroblast-like synoviocyte activation and dysfunction. The inflammatory mediator Krüppel-like factor 4 is upregulated during inflammation and plays an important role in endothelial and macrophage activation during inflammation. However, the role of Krüppel-like factor 4 in fibroblast-like synoviocyte activation and RA inflammation remains to be defined. In this study, we identify the notion that Krüppel-like factor 4 is higher expressed in synovial tissues and fibroblast-like synoviocytes from RA patients than those from osteoarthritis patients. In vitro, the expression of Krüppel-like factor 4 in RA fibroblast-like synoviocytes is induced by proinflammatory cytokine tumor necrosis factor-α. Overexpression of Krüppel-like factor 4 in RA fibroblast-like synoviocytes robustly induced interleukin-6 production in the presence or absence of tumor necrosis factor-α. Conversely, knockdown of Krüppel-like factor 4 markedly attenuated interleukin-6 production in the presence or absence of tumor necrosis factor-α. Krüppel-like factor 4 not only can bind to and activate the interleukin-6 promoter, but also may interact directly with nuclear factor-kappa B. These results suggest that Krüppel-like factor 4 may act as a transcription factor mediating the activation of fibroblast-like synoviocytes in RA by inducing interleukin-6 expression in response to tumor necrosis factor-α.

  7. Molecular Cloning and Expression of Human Interleukin-6 in Insect Cells

    Institute of Scientific and Technical Information of China (English)

    赵春文; 王嘉玺; 肖定华; 马贤凯

    1994-01-01

    670-bp hIL-6 cDNA fragments have been amplified by polymerase chain reaction(PCR)using recombinant plasmid pBMIL-6A as templates and two synthetic oligonucleotides containing the opti-mired translation initiation sequence/and restriction sites suitable for cloning as primers.The amplified IL-6cDNA fragments have then been recombined with a non-fusion expression baculovirus vector pVL1393.Theresultant recombinant plasmid pVL.IL-6 together with wtAcMNPV DNAs were transferred into culturedlepidopteran insect cells(Sf9)by calcium phosphate coprecipitation procedure.The recombinant baculovirus-es were formed by homologous recombination in vivo between pVL.IL-6 and wtAcMNPV DNAs,screenedfor plaque assay,and identified by means of dot blotting hybridization.The expressed rhIL-6 was secretedinto the culture medium,and its bioactivity was measured through half-maximum H-TdR incorporation intoIL-6-dependent cells 7TD1.As a result,the supernatant collected from recombinant baculovirus rAc.IL-6-infected Sf9 cells showed IL-6 activity of 10~6U/mL.The expression level of rhIL-6 of the supernatant deter-mined by IL-6 ELISA quantitation kit was 1 μg/mL.

  8. An intermediate-risk multiple myeloma subgroup is defined by sIL-6r: levels synergistically increase with incidence of SNP rs2228145 and 1q21 amplification

    OpenAIRE

    Stephens, Owen W.; Zhang, Qing; Qu, Pingping; Zhou, Yiming; Chavan, Shweta; Tian, Erming; David R Williams; Epstein, Joshua; Barlogie, Bart; Shaughnessy, John D.

    2012-01-01

    IL-6 signaling can be enhanced through transsignaling by the soluble IL-6 receptor (sIL-6r), allowing for the pleiotropic cytokine to affect cells it would not ordinarily have an effect on. Serum levels of sIL-6r can be used as an independent prognostic indicator and further stratify the GEP 70-gene low-risk group to identify an intermediate-risk group in multiple myeloma (MM). By analyzing more than 600 MM patients with ELISA, genotyping, and gene expression profiling tools, we show how the ...

  9. Pravastatin inhibits fibrinogen- and FDP-induced inflammatory response via reducing the production of IL-6, TNF-α and iNOS in vascular smooth muscle cells.

    Science.gov (United States)

    Lu, Peipei; Liu, Juntian; Pang, Xiaoming

    2015-10-01

    Atherosclerosis is a chronic inflammatory response of the arterial wall to pro‑atherosclerotic factors. As an inflammatory marker, fibrinogen directly participates in the pathogenesis of atherosclerosis. Our previous study demonstrated that fibrinogen and fibrin degradation products (FDP) produce a pro‑inflammatory effect on vascular smooth muscle cells (VSMCs) through inducing the production of interleukin‑6 (IL‑6), tumor necrosis factor‑α (TNF‑α) and inducible nitric oxide synthase (iNOS). In the present study, the effects of pravastatin on fibrinogen‑ and FDP‑induced expression of IL‑6, TNF‑α and iNOS were observed in VSMCs. The results showed that pravastatin dose‑dependently inhibited fibrinogen‑ and FDP‑stimulated expression of IL‑6, TNF‑α and iNOS in VSMCs at the mRNA and protein level. The maximal inhibition of protein expression of IL‑6, TNF‑α and iNOS was 46.9, 42.7 and 49.2% in fibrinogen‑stimulated VSMCs, and 50.2, 49.8 and 53.6% in FDP‑stimulated VSMCs, respectively. This suggests that pravastatin has the ability to relieve vascular inflammation via inhibiting the generation of IL‑6, TNF‑α and iNOS. The results of the present study may aid in further explaining the beneficial effects of pravastatin on atherosclerosis and related cardiovascular diseases. In addition, they suggest that application of pravastatin may be beneficial for prevention of atherosclerosis formation in hyperfibrinogenemia.

  10. Evaluating Blood Parameters, P53, and IL6 in Personnel of Copper Complex: A Comparison with Control Group

    Directory of Open Access Journals (Sweden)

    Hadis Ahmadiraad

    2016-03-01

    Full Text Available Background & Objectives: Industrial pollution including trace elements is the ability to exert many biological effects such as cancer and inflammatory diseases on humans. Therefore, in this study, some of the inflammation and cancer awareness factors such as P53 and IL6 and some blood indices are examined along with trace elements to which people are normally exposed. Materials & Methods: The population includes 45 workers subjected to trace elements who are studied in comparison with the control group with some biochemical parameters such as WBC, RBC, and CRP. In addition, gene expressions of p53 and IL6 are measured by Real time PCR technique. Results: The results show that the gene expressions of IL6 and P53 increases significantly (P –Value p53=0.00, IL6=0.0037. Furthermore, the number of red and white blood cells demonstrate a substantial upsurge. The level of liver enzymes of ALT and AST grows. Additionally, ALP reduces and CRP is negative in all the subjects. (P = 0.001. Conclusion: The results confirm that industrial pollution is able to induce some changes in gene expressions of P53, IL6, and some blood parameters. It may create serious risks for people who will be exposed to pollution in the future.

  11. 雌激素活化GPER介导的IL-6/STAT3通路促进乳腺癌细胞SKBR-3增殖作用%Estrogen activates GPER mediated IL-6/STAT3 signaling pathway to enhance proliferation in breast cancer SKBR-3 cells

    Institute of Scientific and Technical Information of China (English)

    王健; 徐杰; 安雪青; 吕健东

    2015-01-01

    目的 探讨雌激素活化膜性雌激素受体(G-protein coupled estrogen receptor,GPER)所介导的IL-6/STAT3炎症信号通路对乳腺癌SKBR-3细胞增殖能力的影响.方法 用17-β雌二醇(E2)、GPER特异性激动剂(G1)、GPER特异性拮抗剂(G15)、IL-6中和抗体(Anti-IL-6)及STAT3特异性抑制剂JSI-124(cucurbitacin I)药物处理SKBR-3细胞后,分别得到对照组、E2处理组、G1处理组、E2+G15处理组、G1+G15处理组、E2+ Anti-IL-6处理组、G1+Anti-IL-6处理组、E2+ JSI-124处理组与G1+JSI-124处理组,用ELISA检测细胞培养液上清中IL-6的分泌量,CCK-8法检测细胞增殖能力的变化,Westernblot检测细胞中p-STAT3与STAT3的蛋白表达水平.结果 E2和G1显著促进SKBR-3细胞上清中IL-6的分泌量,G15可显著阻断其分泌(P<0.05).E2及G1药物处理细胞后增殖能力较对照组显著增强,相对细胞数分别为对照组的(1.68±0.13)倍与(1.74±0.21)倍,其促增殖作用被G15及IL-6中和抗体(Anti-IL-6)显著抑制(P<0.05).E2及G1在不同时间点(1、3、6、12 h)均可显著促进细胞中p-STAT3的蛋白表达量,分别于12 h和3h达到表达峰值,其蛋白相对表达量分别为对照组的(2.54±0.23)倍和(3.12±0.24)倍.G15、Anti-IL-6及JSI-124显著阻断以上变化(P<0.05).JSI-124亦可明显抑制E2及G1所引起的促增殖效应(P<0.05).结论 雌激素活化膜性雌激素受体GPER促进乳腺癌SKBR-3细胞自分泌IL-6从而激活细胞中下游STAT3炎症信号通路,同时,GPER/IL-6/STAT3信号通路也介导了雌激素对细胞的增殖作用.

  12. Critical appraisal of four IL-6 immunoassays.

    Directory of Open Access Journals (Sweden)

    Dana K Thompson

    Full Text Available BACKGROUND: Interleukin-6 (IL-6 contributes to numerous inflammatory, metabolic, and physiologic pathways of disease. We evaluated four IL-6 immunoassays in order to identify a reliable assay for studies of metabolic and physical function. Serial plasma samples from intravenous glucose tolerance tests (IVGTTs, with expected rises in IL-6 concentrations, were used to test the face validity of the various assays. METHODS AND FINDINGS: IVGTTs, administered to 14 subjects, were performed with a single infusion of glucose (0.3 g/kg body mass at time zero, a single infusion of insulin (0.025 U/kg body mass at 20 minutes, and frequent blood collection from time zero to 180 minutes for subsequent Il-6 measurement. The performance metrics of four IL-6 detection methods were compared: Meso Scale Discovery immunoassay (MSD, an Invitrogen Luminex bead-based multiplex panel (LX, an Invitrogen Ultrasensitive Luminex bead-based singleplex assay (ULX, and R&D High Sensitivity ELISA (R&D. IL-6 concentrations measured with MSD, R&D and ULX correlated with each other (Pearson Correlation Coefficients r = 0.47-0.94, p<0.0001 but only ULX correlated (r = 0.31, p = 0.0027 with Invitrogen Luminex. MSD, R&D, and ULX, but not LX, detected increases in IL-6 in response to glucose. All plasma samples were measurable by MSD, while 35%, 1%, and 4.3% of samples were out of range when measured by LX, ULX, and R&D, respectively. Based on representative data from the MSD assay, baseline plasma IL-6 (0.90 ± 0.48 pg/mL increased significantly as expected by 90 minutes (1.29 ± 0.59 pg/mL, p = 0.049, and continued rising through 3 hours (4.25 ± 3.67 pg/mL, p = 0.0048. CONCLUSION: This study established the face validity of IL-6 measurement by MSD, R&D, and ULX but not LX, and the superiority of MSD with respect to dynamic range. Plasma IL-6 concentrations increase in response to glucose and insulin, consistent with both an early glucose-dependent response (detectable at 1

  13. TLR4介导汉滩病毒引起血管内皮细胞分泌IL-6和TNF-α%Secretion of IL-6,Il-8 and TNF-α from vascular endothelial cells infected by Hantaan virus may be mediated by TLR4

    Institute of Scientific and Technical Information of China (English)

    姜泓; 王平忠; 王丽梅; 张野; 黄长形; 王九平; 徐哲; 孙利; 白雪帆

    2009-01-01

    目的 检测汉滩病毒感染血管内皮细胞后IL-6,IL-8和TNF-α的分泌变化及其与TLR4的关系.方法 用5Lg TCID50/mL的HTNV76-1180.2 mL感染EVC-304细胞(TLR4+)和EVC-304 TS4(TLR4-)分别为实验组,以病毒未感染为阴性对照组,以LPS(2μg/mL)刺激作为阳性对照.48 h后取细胞培养上清,用人IL-6,IL-8和TNF-α定量EIA试剂盒分别检测IL-6,IL-8和TNF-α在两个细胞系感染前后的分泌水平.结果 IL-8在两个细胞系中感染前后的变化不明显,IL-6和TNF-α在EVC-304细胞系中,HTNV感染后升高,而在TLR4表达阴性的EVC-304细胞中,感染前后变化不明显.结论 在TLR4表达阳性的EVC-304细胞中IL-6和TNF-α分泌增加,血管内皮细胞EVC-304在HTNV感染后的IL-6和TNF-α分泌可能是TLR4介导的.

  14. Effects of IL-10 and IL-4 on LPS-induced transcription factors (AP-1, NF-IL6 and NF-kappa B) which are involved in IL-6 regulation

    NARCIS (Netherlands)

    Dokter, Willem; Koopmans, S.B.; Vellenga, E

    1996-01-01

    Interleukin-10 (IL-10), like IL-4, is known to inhibit cytokine expression in activated human monocytes. We showed that both IL-10 and IL-4 inhibit LPS-induced IL-6 mRNA and protein expression by inhibiting the transcription rate of the IL-6 gene. The strong inhibition of the IL-6 transcription rate

  15. The changes of frequencies of regulatory T cells in peripheral blood and serum levels of IL-1β ,IL-6 and IL-10 in patients with HBV-related liver cirrhosis%乙型肝炎肝硬化患者外周血调节性T细胞频率及血清IL-1β、IL-6和IL-10水平的变化

    Institute of Scientific and Technical Information of China (English)

    李晨; 邢少军; 段学章; 胡瑾华; 柳芳芳; 王慧芬; 万谟彬

    2012-01-01

    目的 检测未抗病毒治疗的乙型肝炎肝硬化患者外周血调节性T细胞(Treg细胞)及其亚群频率和血清IL.1 β、IL-6、IL-10水平,以探讨乙型肝炎肝硬化患者免疫功能的变化.方法 在20例健康对照人群、17例慢性乙型肝炎(CHB)患者和38例乙型肝炎肝硬化(LC)患者,采用流式细胞仪检测外周血CD4+CD25+Foxp3+(Treg)细胞频率、CD4+CD39+Foxp3+(CD39+Freg)细胞和CD4+CTLA-4+Foxp3+(CTLA-4+Freg)细胞频率;采用ELISA法检测血清IL-1β、IL-6和IL-10水平.结果 LC患者Treg细胞频率、CD39+Treg细胞频率、CTLA-4+Treg细胞频率、血清IL-1β、IL-6和IL-10水平均高于正常人(P均<0.01)和CHB患者(P<0.05或P<0.01);失代偿期LC患者Treg细胞频率、CD39+Treg细胞频率、IL-6水平高于代偿期患者(P均<0.01);LC患者Treg细胞频率与CD39+Treg细胞频率(r=0.474,P<0.01)、CTLA-4+Treg细胞频率均呈正相关(r=0.330,P<0.05),Treg细胞频率(r=0.381,P<0.05)、CD39+Treg细胞频率(r=0.333,P<0.05)与TBil呈正相关.Treg细胞频率(r=-0.549,P<0.01)、CD39+Treg细胞频率(r=-0.437,P<0.01)、CTLA-4+Treg细胞频率(r=-0.368,P<0.01)与PTA呈负相关,CD39+Treg细胞频率与AST呈正相关(r=0.406,P<0.05).结论 Treg细胞及其亚群频率和IL-1β、IL-6、IL-10水平的变化可作为临床初始治疗的乙型肝炎肝硬化患者辅助检查指标之一.%Objective To investigate the frequencies of regulatory T cells (Treg cells), its subgroups and serum levels of IL-1 B ,IL-6 and IL-10 in HBV-related liver cirrhosis. Methods In 20 healthy persons, 17 patients with chronic hepatitis B (CHB) and 38 with HBV-related liver cirrhosis (LC),the frequencies of CD4+ CD25+Fox3+ cells (Treg cells ),CD4+CD39+Fox3+cells(CD394Treg cells),and CD4+CTLA-4+ Fox3+cells(CTLA-4+ Treg cells) were detected by flow cytometry. The serum levels of IL-1 B , IL-6 and IL-10 were detected by ELISA. Results The frequencies of Treg cells,CD39+ Treg cells and CTLA-4Treg cells and the serum levels of IL

  16. 小檗碱对白介素-6诱导胰岛素抵抗3T3-L1脂肪细胞脂联素表达的影响%Effect of Berberine on Gene Expression of Adiponectin by IL-6 Induced Insulin Resistance in 3T3-L1 Adipocyte

    Institute of Scientific and Technical Information of China (English)

    章常华; 李冰涛; 屈飞; 魏学鑫; 余日跃; 徐国良

    2012-01-01

    Objective; To explore the effect of berberine on adiponectin gene mRNA expression in 3T3-Ll adipocyte of insulin resistant induced by interleukin-6 (IL-6). Method; To build 3T3-L1 adipocyte model of insulin resistant induced by interleukin-6. 3T3-L1 adipocytes were exposed to 20 μg -L-1 IL-6 for 48 h, the 3T3-L1 adipocytes with insulin resistant were divided into six groups randomly; normal control groups, model groups, pioglitazone (50 (μmol -L-1 ) , and low, middle, hight doses of berberine groups (10, 20, 50 (μmol -L-1) , the amount of glucose consumption was measured by detecting the glucose content in cell culture supernatants with glucose oxidase assay, the effect of berberine on glucose uptake of 3T3-L1 adipocytes was observed, and cell model of insulin resistant was identified. mRNA expression of adiponection gene was determined by real-time quantitative reverse-transcription polymerase chain reaction. Result; There was statistical difference between model group and normal control group in their amount of glucose consumption and gene expression of adiponectin, which was decreased markedly in model group (P < 0. 05 ). Pioglitazone (50 (μmol -L-1 ) , and low, middle, high doses of berberine groups (10, 20, 50 (μmol -L-1 ) markedly increased both amount of glucose consumption and gene expression of adiponectin. Conclusion; Berberine can increase mRNA expression of adiponection gene and improve insulin resistant in 3T3-L1 adipocytes.%目的:观察小檗碱对白介素-6(IL-6)诱导胰岛素抵抗的3T3-L1脂肪细胞脂联素表达的影响.方法:选用IL-6诱导3T3-L1脂肪细胞胰岛素抵抗(IR)模型.以20 μg·L-1IL-6培养48 h,将3T3-L1脂肪细胞随机分为正常对照组、模型组、吡格列酮组(50μmol·L-1)和小檗碱高、中、低剂量组(10,20,50 μmol·L-1),以葡萄糖氧化酶法测定葡萄糖消耗量,观察小檗碱对脂肪细胞葡萄糖摄取的影响,鉴定IR模型;采用实时荧光定量PCR技术测定脂肪细胞脂联

  17. IL-6/STAT3 axis initiated CAFs via up-regulating TIMP-1 which was attenuated by acetylation of STAT3 induced by PCAF in HCC microenvironment.

    Science.gov (United States)

    Zheng, Xin; Xu, Meng; Yao, Bowen; Wang, Cong; Jia, Yuli; Liu, Qingguang

    2016-09-01

    Aberrant tumor microenvironment is involved closely in tumor initiation and progression, in which cancer associated fibroblasts (CAFs) play a pivotal role. Both IL-6/STAT3 signaling and TIMP-1 have been found to modulate the crosstalk between tumor cells and CAFs in tumor microenvironment, however, the underlying mechanism remains unclear. Here, we showed that IL-6/STAT3 signaling was activated aberrantly in HCC tissues and correlated with poor post-surgical outcome. The in vitro experiments confirmed that activation of IL-6/STAT3 pathway enhanced TIMP-1 expression directly via phosphorylated STATs (p-STAT3)-binding with TIMP-1 promoter in Huh7 cells. Furthermore, activation of IL-6/STAT3 pathway in HCC cells was shown to induce the transformation from normal liver fibroblasts (LFs) to CAFs via up-regulating TIMP-1 expression. Co-culture with CAFs promoted the growth of Huh7 cells both in vitro and in vivo. Finally, by co-Immunoprecipitation and immunoblotting assessments, PCAF, a well-known acetyltransferase, was revealed to acetylate cytoplasmic STAT3 protein directly and regulate TIMP-1 expression negatively in Huh7 cells. In summary, this investigation indicated that there was a positive IL-6/TIMP-1 feedback loop controlling the crosstalk between HCC cells and its neighbouring fibroblasts. The data here also identified that PCAF repressed TIMP-1 expression via acetylation of STAT3. In conclusion, this investigation demonstrated that CAFs promoted HCC growth via IL-6/STAT3/AKT pathway and TIMP-1 over-expression driven by IL-6/STAT3 pathway in HCC cells brought in more CAFs through activating LFs. Finally, PCAF could block this positive feedback by acetylating STAT3 in HCC cells.

  18. IL-1β, IL-6 levels and SOCS-3 gene expression in hypothalamus of BALB/c mice with brain asymmetry%脑不对称BALB/c小鼠下丘脑IL-1β、IL-6水平和SOCS-3基因表达

    Institute of Scientific and Technical Information of China (English)

    苏芸; 赵丽纯; 李康生

    2005-01-01

    目的:研究脑不对称性对下丘脑中IL-1β、IL-6及细胞因子信号转导抑制因子-3(SOCS-3)表达的影响,从分子水平探讨脑不对称性在神经内分泌免疫调节网络中的作用.方法:运用伸爪取食法将BALB/c小鼠区分为左利、右利和双利鼠.小鼠分组一周后断头杀死,迅速分离出下丘脑,一部分标本制备匀浆后采用ELISA法测定下丘脑中IL-1β、IL-6的蛋白水平;另一部分标本以RT-PCR法间接测定下丘脑SOCS-3 mRNA水平.结果:(1)下丘脑IL-6蛋白水平:左利鼠水平明显高于右利鼠,差异有统计学意义(P<0.05).(2)下丘脑IL-1β蛋白水平:左利、右利小鼠水平相近,差异无显著性(P>0.05).(3)下丘脑SOCS-3表达:右利鼠下丘脑中SOCS-3的表达显著高于左利鼠(P<0.05).结论:脑不对称BALB/c小鼠下丘脑IL-1β、IL-6及细胞因子信号转导抑制因子SOCS-3的表达存在差异,提示这可能是左、右利人群免疫紊乱性疾病发生率不同原因之一.

  19. Chronic administration of EP4-selective agonist exacerbates albuminuria and fibrosis of the kidney in streptozotocin-induced diabetic mice through IL-6.

    Science.gov (United States)

    Mohamed, Riyaz; Jayakumar, Calpurnia; Ramesh, Ganesan

    2013-08-01

    Diabetic nephropathy is currently the most common cause of end-stage renal disease in the western world. Exacerbated inflammation of the kidney is known to contribute acceleration of nephropathy. Despite increased COX-2-mediated production of prostanoid metabolite PGE2, knowledge on its involvement in the progression of diabetic kidney disease is not complete. Here, we show the cross talk of the PGE2-EP4 pathways and IL-6 in inducing albuminuria and fibrosis in an animal model of type 1 diabetes. Hyperglycemia causes enhanced COX-2 expression and PGE2 production. Administration of PGE2 receptor EP4-selective agonist ONO-AE1-329 for 12 weeks exacerbated fibrosis and albuminuria. Diabetes-induced expression of inflammatory cytokines TNFα and TGFβ1 was enhanced in EP4 agonist-treated mice kidney. In addition, urinary excretion of cytokines (TNFα and IL-6) and chemokines (MCP-1 and IP-10) were significantly more in EP4-treated mice than vehicle-treated diabetes. Diabetes-induced collagen I and CTGF expression were also significantly higher in EP4-treated mice. However, EP4 agonist did not alter macrophage infiltration but increased cytokine and chemokine production in RAW264.7 cells. Interestingly, EP4-induced IL-6 expression in the kidney was localized in proximal and distal tubular epithelial cells. To confirm further whether EP4 agonist increases fibrosis and albuminuria through an increase in IL-6 expression, IL-6-knockout mice were administered with EP4 agonist. IL-6-knockout mice were resistant to EP4-induced exacerbation of albuminuria and diabetes and EP4-induced fibrosis. Our data suggest that EP4 agonist through IL-6 induces glomerulosclerosis and interstitial fibrosis, and IL-6 represents a new factor in the EP4 pathway.

  20. Clinical significance of the Changes of Serum Levels of IL-2,IL-6,IL-10,IL-18 and T cell subset in patients with chronic nephritis%慢性肾炎治疗前后血清IL-2、IL-6、IL-10、IL-18和T淋巴细胞亚群检测意义

    Institute of Scientific and Technical Information of China (English)

    刘薇娜; 鲍培玉; 蒋全

    2010-01-01

    目的 探讨慢性肾炎患者治疗前后血清IL-2、IL-6、IL-10、IL-18和T淋巴细胞亚群的变化.方法 分别应用放免法、ELISA法和单克隆抗体法对30例慢性肾炎患者治疗前后进行了血清IL-2、IL-6、IL-10、IL-18和T淋巴细胞亚群水平的检测,并与35名正常健康人作比较.结果 慢性肾炎患者在治疗前血清IL-2和CD4/CD8比值明显低于正常人组(P<0.05),而IL-6、IL-10和IL-18水平高于正常人组(P<0.01);经半年治疗后血清IL-2、IL-6、IL-10、IL-18和CD4/CD8与治疗前组比较差异有统计学意义(P<0.05).结论 检测慢性肾炎患者血清IL-2、IL-6、IL-10、IL-18和T淋巴细胞亚群水平对判断病情及其预后均具有一定的临床实用价值.

  1. Properdin provides protection from Citrobacter rodentium-induced intestinal inflammation in a C5a/IL-6-dependent manner.

    Science.gov (United States)

    Jain, Umang; Cao, Qi; Thomas, Nikhil A; Woodruff, Trent M; Schwaeble, Wilhelm J; Stover, Cordula M; Stadnyk, Andrew W

    2015-04-01

    Citrobacter rodentium is an attaching and effacing mouse pathogen that models enteropathogenic and enterohemorrhagic Escherichia coli in humans. The complement system is an important innate defense mechanism; however, only scant information is available about the role of complement proteins during enteric infections. In this study, we examined the impact of the lack of properdin, a positive regulator of complement, in C. rodentium-induced colitis. Following infection, properdin knockout (P(KO)) mice had increased diarrhea and exacerbated inflammation combined with defective epithelial cell-derived IL-6 and greater numbers of colonizing bacteria. The defect in the mucosal response was reversed by administering exogenous properdin to P(KO) mice. Then, using in vitro and in vivo approaches, we show that the mechanism behind the exacerbated inflammation of P(KO) mice is due to a failure to increase local C5a levels. We show that C5a directly stimulates IL-6 production from colonic epithelial cells and that inhibiting C5a in infected wild-type mice resulted in defective epithelial IL-6 production and exacerbated inflammation. These outcomes position properdin early in the response to an infectious challenge in the colon, leading to complement activation and C5a, which in turn provides protection through IL-6 expression by the epithelium. Our results unveil a previously unappreciated mechanism of intestinal homeostasis involving complement, C5a, and IL-6 during bacteria-triggered epithelial injury.

  2. Interleukin-6 (IL-6) haplotypes and the response to therapy of chronic hepatitis C virus infection

    OpenAIRE

    2009-01-01

    Chronic hepatitis C virus (HCV) infection affects nearly 170 million individuals worldwide. Treatment of HCV with pegylated interferon-α-2a is successful in eradicating virus from only 30%–80% of those treated. Interleukin-6 (IL-6) is an important cytokine involved in the immune response to infectious agents and in vitro studies suggest that host genetic variation, particularly haplotypes, may affect IL-6 expression. We examined the contribution of haplotypes in the IL-6 gene on sustained vir...

  3. The Inhibitory Effect of Quercetin on IL-6 Production by LPS-Stimulated Neutrophils

    Institute of Scientific and Technical Information of China (English)

    Jiajia Liu; Xin Li; Yang Yue; Juan Li; Tao He; Yanzheng He

    2005-01-01

    Quercetin is a herbal flavonoid derived from various foods of plant origin and plays a role in anti-inflammation. Although a number of researches in the field have been done, the mechanism of anti-inflammatory effect of quercetin should be further clarified. In the present study, we investigated the effects of quercetin on IL-6 production by LPS-stimulated neutrophils in human. Neutrophils were were pre-treated with quercetin at the final concentrations of ranging from 0-80 μM for 30 min, or not treated, and then incubated in the presence or absence of lipopolysaccharide (LPS) at a final concentration of 100 ng/ml for indicated time. The secretion level of IL-6 in the culture supernatants was assayed by ELISA, the intracellular level of IL-6 was detected by flow cytometry and the expression of IL-6 mRNA was analyzed by RT-PCR. The experiment results showed that neutrophils cultured with medium or quercetin alone did not express IL-6, but LPS (100 ng/ml) induced IL-6 expression of neutrophils. However, after pre-treatment of neutrophils with quercetin (40 μM) for 30 min, the inducible effects of LPS on the increase of IL-6 secretion, intracellular IL-6 level and IL-6 mRNA expression by neutrophils were abrogated. IL-6 is one of the important pro-inflammatory factors, especially in early phage of inflammation. Thus, our data suggested that quercetin might exert its anti-inflammatory effect through negatively modulating pro-inflammatory factors, such as IL-6. The inhibitory effects of quercetin on IL-6 production by neutrophils may provide a theoretical basis on future therapy of inflammation.

  4. Different associations of CD45 isoforms with STAT3, PKC and ERK regulate IL-6-induced proliferation in myeloma.

    Directory of Open Access Journals (Sweden)

    Xu Zheng

    Full Text Available In response to interleukin 6 (IL-6 stimulation, both CD45RO and CD45RB, but not CD45RA, translocate to lipid rafts. However, the significance of this distinct translocation and the downstream signals in CD45 isoforms-participated IL-6 signal are not well understood. Using sucrose fractionation, we found that phosphorylated signal transducer and activator of transcription (STAT3 and STAT1 were mainly localized in lipid rafts in response to IL-6 stimulation, despite both STAT3 and STAT1 localizing in raft and non-raft fractions in the presence or absence of IL-6. On the other hand, extracellular signal-regulated kinase (ERK, and phosphorylated ERK were localized in non-raft fractions regardless of the existence of IL-6. The rafts inhibitor significantly impeded the phosphorylation of STAT3 and STAT1 and nuclear translocation, but had little effect on (and only postponing the phosphorylation of ERK. This data suggests that lipid raft-dependent STAT3 and STAT1 pathways are dominant pathways of IL-6 signal in myeloma cells. Interestingly, the phosphorylation level of STAT3 but not STAT1 in CD45+ cells was significantly higher compared to that of CD45- cells, while the phosphorylation level of ERK in CD45+ myeloma cells was relatively low. Furthermore, exogenously expressed CD45RO/RB significantly enhanced STAT3, protein kinase C (PKC and downstream NF-κB activation; however, CD45RA/RB inhibited IL-6-induced ERK phosphorylation. CD45 also enhanced the nuclear localization of STAT3 but not that of STAT1. In response to IL-6 stimulation, CD45RO moved into raft compartments and formed a complex with STAT3 and PKC in raft fraction, while CD45RA remained outside of lipid rafts and formed a complex with ERK in non-raft fraction. This data suggests a different role of CD45 isoforms in IL-6-induced signaling, indicating that while CD45RA/RB seems inhibit the rafts-unrelated ERK pathway, CD45RO/RB may actually work to enhance the rafts-related STAT3 and PKC

  5. Structural characterization and immunomodulatory effects of polysaccharides from Phellinus linteus and Phellinus igniarius on the IL-6/IL-10 cytokine balance of the mouse macrophage cell lines (RAW 264.7).

    Science.gov (United States)

    Suabjakyong, Papawee; Nishimura, Kazuhiro; Toida, Toshihiko; Van Griensven, Leo J L D

    2015-08-01

    Phellinus linteus and igniarius (L.) Quel. have been used in traditional Asian medicine for over two centuries against a variety of diseases. Polysaccharides from their fruiting bodies show strong immunomodulatory activity. In this study we characterized the structure and composition of polysaccharides from Phellinus linteus and Phellinus igniarius by HPLC, GC-MS and NMR (1-H, 13-C, COSY, NOESY and TOCSY). The polysaccharides from P. linteus and P. igniarius mainly contained glucose with minor proportions of mannose, galactose, xylose, arabinose and rhamnose. Methylation analyses showed that the glycosidic linkages were mostly 1 → 3, 1 → 6 or 1 → 3,6. The two-dimensional COSY, NOESY and TOCSY confirmed that these polysaccharides have a main chain of →3)-β-D-Glcp-(1→ with →6)-β-D-Glcp-(1→ side chain. In vitro assays by RT-PCR and ELISA showed that (1 → 3; 1 → 6)-β-D-polysaccharides from P. linteus and P. igniarius decreased TNF-α in RAW 264.7 cells, suggesting an immuno-suppressive activity. Furthermore, these polysaccharides stimulated a high IL-10 response and induced strong suppression of transcription of IL-6. The results suggest that polysaccharides from P. linteus and P. igniarius could possibly find applications in restoring the IL-6/IL-10 balance, the disturbance of which is thought to be related to chronic inflammatory disease, obesity, diabetes type 2, and to mania and depression.

  6. Sex differences in the relationship of IL-6 signaling to cancer cachexia progression.

    Science.gov (United States)

    Hetzler, Kimbell L; Hardee, Justin P; Puppa, Melissa J; Narsale, Aditi A; Sato, Shuichi; Davis, J Mark; Carson, James A

    2015-05-01

    A devastating aspect of cancer cachexia is severe loss of muscle and fat mass. Though cachexia occurs in both sexes, it is not well-defined in the female. The Apc(Min/+) mouse is genetically predisposed to develop intestinal tumors; circulating IL-6 is a critical regulator of cancer cachexia in the male Apc(Min/+) mouse. The purpose of this study was to examine the relationship between IL-6 signaling and cachexia progression in the female Apc(Min/+) mouse. Male and female Apc(Min/+) mice were examined during the initiation and progression of cachexia. Another group of females had IL-6 overexpressed between 12 and 14 weeks or 15-18 weeks of age to determine whether IL-6 could induce cachexia. Cachectic female Apc(Min/+) mice lost body weight, muscle mass, and fat mass; increased muscle IL-6 mRNA expression was associated with these changes, but circulating IL-6 levels were not. Circulating IL-6 levels did not correlate with downstream signaling in muscle in the female. Muscle IL-6r mRNA expression and SOCS3 mRNA expression as well as muscle IL-6r protein and STAT3 phosphorylation increased with severe cachexia in both sexes. Muscle SOCS3 protein increased in cachectic females but decreased in cachectic males. IL-6 overexpression did not affect cachexia progression in female Apc(Min/+) mice. Our results indicate that female Apc(Min/+) mice undergo cachexia progression that is at least initially IL-6-independent. Future studies in the female will need to determine mechanisms underlying regulation of IL-6 response and cachexia induction.

  7. IL-6 Mediates the Intestinal Microvascular Thrombosis Associated with Experimental Colitis.

    Science.gov (United States)

    Hozumi, Hideaki; Russell, Janice; Vital, Shantel; Granger, D Neil

    2016-03-01

    Inflammatory bowel diseases are associated with increased risk for thrombus formation both within the inflamed bowel and at distant sites. Although the increased propensity for distant organ thrombus development has been recapitulated in animal models of colitis and linked to interleukin-6 (IL-6), it remains unclear whether experimental colitis results in accelerated thrombus development within the inflamed bowel and whether IL-6 contributes to a local thrombogenic response. These issues related to thrombus formation within the inflamed bowel were addressed in mice with dextran sodium sulfate-induced colitis. Wild-type (WT) mice, IL-6 deficient (IL-6(-/-)) mice, and bone marrow chimeras (WT→WT and IL-6(-/-)→WT) were used. The effects of treatment with either an IL-6-blocking, IL-6Rα-blocking or gp130-blocking antibody were also evaluated. Disease activity index and colonic weight-to-length ratio (W/L) were used to monitor the development of colitis. Intravital videomicroscopy was used to study thrombus development (induced with the light/dye method) in mucosal vessels of the ascending colon. Thrombus development was significantly enhanced in WT colitic mice. Neither genetic deficiency nor immunoblockade of IL-6 significantly altered the disease activity index and W/L responses to dextran sodium sulfate treatment. However, colitis-induced thrombogenesis was attenuated in IL-6(-/-) mice and in WT mice treated with either the IL-6-blocking, IL-6Rα-blocking or gp130-blocking antibody. IL-6(-/-)→WT, but not WT→WT chimeras, exhibited a blunted thrombosis response to dextran sodium sulfate. These results indicate that experimental colitis is associated with accelerated thrombus development within the inflamed colon and that IL-6, derived from bone marrow-derived blood cells, is largely responsible for this response.

  8. Dietary iron enhances colonic inflammation and IL-6/IL-11-Stat3 signaling promoting colonic tumor development in mice.

    Directory of Open Access Journals (Sweden)

    Anita C G Chua

    Full Text Available Chronic intestinal inflammation and high dietary iron are associated with colorectal cancer development. The role of Stat3 activation in iron-induced colonic inflammation and tumorigenesis was investigated in a mouse model of inflammation-associated colorectal cancer. Mice, fed either an iron-supplemented or control diet, were treated with azoxymethane and dextran sodium sulfate (DSS. Intestinal inflammation and tumor development were assessed by endoscopy and histology, gene expression by real-time PCR, Stat3 phosphorylation by immunoblot, cytokines by ELISA and apoptosis by TUNEL assay. Colonic inflammation was more severe in mice fed an iron-supplemented compared with a control diet one week post-DSS treatment, with enhanced colonic IL-6 and IL-11 release and Stat3 phosphorylation. Both IL-6 and ferritin, the iron storage protein, co-localized with macrophages suggesting iron may act directly on IL-6 producing-macrophages. Iron increased DSS-induced colonic epithelial cell proliferation and apoptosis consistent with enhanced mucosal damage. DSS-treated mice developed anemia that was not alleviated by dietary iron supplementation. Six weeks post-DSS treatment, iron-supplemented mice developed more and larger colonic tumors compared with control mice. Intratumoral IL-6 and IL-11 expression increased in DSS-treated mice and IL-6, and possibly IL-11, were enhanced by dietary iron. Gene expression of iron importers, divalent metal transporter 1 and transferrin receptor 1, increased and iron exporter, ferroportin, decreased in colonic tumors suggesting increased iron uptake. Dietary iron and colonic inflammation synergistically activated colonic IL-6/IL-11-Stat3 signaling promoting tumorigenesis. Oral iron therapy may be detrimental in inflammatory bowel disease since it may exacerbate colonic inflammation and increase colorectal cancer risk.

  9. Effect of ultraviolet ray on expression of IL6 and IL10mRNA in peripheral blood monocytes of systemic lupus erythematosus cases%紫外线对SLE白介素-6和白介素-10mRNA表达的影响

    Institute of Scientific and Technical Information of China (English)

    徐文英; 郭庆

    2012-01-01

    目的 探讨紫外线对系统性红斑狼疮(SLE)患者外周血单个核细胞(PBMC)表达白介素-6(IL-6)、白介素-10(IL-10)mRNA的影响.方法 提取SLE患者及健康对照的PBMC,用不同剂量311nm窄谱中波紫外线(NB-UVB)照射,以实时荧光相对定量聚合酶链反应分析照射前后PBMC IL-6、IL-10mRNA的相对表达.结果 SLE患者中狼疮肾炎(LN)患者PBMC高表达IL-6、IL-10mRNA,与非狼疮肾炎(非LN)患者及正常人差异很大,分别是正常人的(105.44±112.94)倍和(1.82±3.41)倍、(28.41±21.14)倍和(1.17±1.43)倍,其中狼疮肾炎(LN)患者PBMC高表达IL-6、IL-10 mRNA,且与临床中24h尿蛋白定量高度相关(r=0.82,0.87,P<0.05),而非狼疮肾炎系统性红斑狼疮患者与正常人相比,差异无统计学意义(t'=0.43,0.87,P>0.05);在紫外线照射后LN患者PBMC IL-6、IL-10mRNA的表达有升高也有降低,升高组SLE疾病活动指数、抗SSA抗体阳性率以及光敏性发生率明显高于降低组.结论 紫外线可改变SLE患者PBMC表达IL-6、IL-10mRNA,紫外线可能通过此途径影响SLE病情.%Objective To observe the impact of ultraviolet ray on the expression of IL-6, IL-10mRNA of peripheral blood monocytes (PBMC)from systemic lupus erythematosus (SLE). Cases. Methods PBMC were isolated from SLE patients and healthy controls .Then they were irradiated with 311 nm narrow band-ultraviolet ray (NB-UVB)in various dbsages.IL-6,IL-10mRNA expression was measured by real-time quantitative PCR. Results The expression of IL-6, IL-10mRNA in SLE patient was very different. IL-6,IL-10mRNA were highly expressed in PBMC from lupus nephritis (LN),and its expression was highly related with 24-hour urinary protein quantitative (r=0.82,0.87,P0.05). The expression of IL-6,IL-10mRNA in LN could increase or decrease after exposured to ultraviolet ray. But the anti-SSA antibody positive rate, systemic lupus erythematosus activity index (SLEDAI)and photosensitivity in exopression -elevated group

  10. CCR5 Blockade Suppresses Melanoma Development Through Inhibition of IL-6-Stat3 Pathway via Upregulation of SOCS3.

    Science.gov (United States)

    Tang, Qiu; Jiang, Jun; Liu, Jian

    2015-12-01

    In order to understand how tumor cells can escape immune surveillance mechanisms and thus develop antitumor therapies, it is critically important to investigate the mechanisms by which the immune system interacts with the tumor microenvironment. In our current study, we found that chemokine receptor 5 (CCR5) neutralization resulted in reduced melanoma tumor size, decreased percentage of CD11b+ Gr-1(+) myeloid-derived suppressor cells (MDSCs), and increased proportion of cluster of differentiation (CD)3+ T cells in tumor tissues. Suppressive activity of MDSCs on CD4+ T cells and CD8+ T cell proliferation is significantly inhibited by anti-CCR5 antibody. CCR5 blockade also suppresses interleukin (IL)-6 induction, which in turn deactivates signal transducer and activator of transcription 3 (Stat3) in tumors. Furthermore, the suppressed B16 tumor growth induced by CCR5 blockade is abolished with additional administration of recombinant IL-6. CCR5 blockade also induces suppressor of cytokine signaling 3 (SOCS3) upregulations, and anti-CCR5 antibody fails to suppress expression of phospho-Stat3 (p-Stat3), matrix metallopeptidase 9 (MMP9), and IL-6 in cells transfected with SOCS3 short-interfering RNA (SiRNA). All these data suggest that CCR5 blockade suppresses melanoma development through inhibition of IL-6-Stat3 pathway via upregulation of SOCS3.

  11. Cytokines TNF-α, IL-6, IL-17F, and IL-4 differentially affect osteogenic differentiation of human adipose stem cells

    NARCIS (Netherlands)

    A.P. Bastidas-Coral; A.D. Bakker; B. Zandieh-Doulabi; C.J. Kleverlaan; N. Bravenboer; T. Forouzanfar; J. Klein-Nulend

    2016-01-01

    During the initial stages of bone repair, proinflammatory cytokines are released within the injury site, quickly followed by a shift to anti-inflammatory cytokines. The effect of pro- and anti-inflammatory cytokines on osteogenic differentiation of mesenchymal stem cells is controversial. Here, we i

  12. Hydrogen sulfide prevents OGD/R-induced apoptosis by suppressing the phosphorylation of p38 and secretion of IL-6 in PC12 cells.

    Science.gov (United States)

    Li, Chong; Liu, Yue; Tang, Peng; Liu, Peng; Hou, Chen; Zhang, Xin; Chen, Li; Zhang, Lina; Gu, Chaochao

    2016-03-01

    Hydrogen sulfide (H2S), a well-known endogenous mediator, has been shown to exert protective effects against neuronal damage caused by brain ischemia, but the mechanism of its action remains unclear. We have reported the neuroprotective properties of H2S against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury by inhibiting the phosphorylation of p38. The present study evaluates the effect of H2S on OGD/R-induced cell injury or apoptosis and the mechanisms for its action in PC12 cells. Pretreatment of PC12 cells with exogenous sodium hydrosulfide (NaHS) (a H2S donor, 100 or 300 µM) for 12 h before exposure to OGD/R markedly attenuated p38 phosphorylation. Activation of p38 MAPK by transfection of activated p38α, but not p38β, reversed the protective effect of NaHS, as measured by enzyme-linked immunosorbent assay analysis. Importantly, SB203580 (a p38 MAPK inhibitor) also reversed the protective effects of p38α-activated p38 MAPK. Interleukin-6 secretion after OGD/R decreased significantly with NaHS compared with without NaHS. Taken together, we show that the p38 pathway contributes toward OGD/R-induced cell death and p38α plays a key role in OGD/R-induced interleukin-6 secretion.

  13. Effect of Dangguishaoyaosan on the blood lipids and the expression of inflammatory factors, such as IL-6, MCP-1, NF-κB and PPAR-γmRNA in the metaflammatory mice%当归芍药散对代谢性炎性反应小鼠血脂和血清炎性反应因子IL-6、MCP-1及 NF-κB、PPARγmRNA 表达的影响

    Institute of Scientific and Technical Information of China (English)

    贾丽超; 周明学; 张蕾; 刘卫红

    2014-01-01

    目的:研究当归芍药散对代谢性炎性反应小鼠血脂和血清炎性反应因子白细胞介素-6(interleukin-6,IL-6)、单核细胞趋化蛋白-1(monocyte chemotactic protein 1,MCP-1)以及核因子κB (nuclear factor kappa B,NF-κB)和活化的过氧化物酶体增生物激活受体γ(peroxisome proliferator-activated receptor gamma,PPARγ)mRNA 表达的影响。方法60只雄性 C57小鼠,采用数字表法将动物随机分为正常组、模型组、立普妥组、当归芍药散组(n =15)。采用高脂饮食联合脂多糖注射造成小鼠代谢性炎性反应模型。造模5周后,开始灌胃给药,每天2次,当归芍药散2.2 g/ kg,立普妥0.003 g/ kg。正常对照组和模型组灌服等体积蒸馏水。连续灌胃5周。处死后采血和取肝脏,检测各组小鼠血清胆固醇(total cholesterol,TC)、三酰甘油(triglyceride,TG)和低密度脂蛋白胆固醇(low density lipoprotein,LDL-C)浓度,并采用流式细胞术检测血清炎性反应因子 IL-6和 MCP-1浓度。反转录聚合酶链式反应(reverse transcription polymerase chain reaction,RT-PCR)法测定肝脏 NF-κB 和 PPARγmRNA 的表达。结果与模型组相比,当归芍药散组小鼠血清 TC 和 LDL-C 水平明显降低(P<0.01),肝脏组织中 NF-κB mRNA 的表达降低,差异有统计学意义(P<0.05),PPARγmRNA 的表达提高,差异有统计学意义(P<0.05)。结论当归芍药散可降低代谢性炎性反应小鼠血脂和血清炎性反应因子 IL-6和 MCP-1浓度,并可通过调控核转录因子 NF-κB 和 PPARγ受体,抑制小鼠体内代谢性炎性反应,从而可能对早期动脉粥样硬化起到干预作用。%Objective To study the effect of Dangguishaoyaosan on the blood lipids and the expression of inflammatory factors, such as IL-6, MCP-1, NF-κB and PPAR-γ mRNA in the metaflammatory mice. Methods Sixty male C57 mice were randomly divided into normal group, model group, the lipitor group and Dangguishaoyaosan group(n = 15). High

  14. An intermediate-risk multiple myeloma subgroup is defined by sIL-6r: levels synergistically increase with incidence of SNP rs2228145 and 1q21 amplification.

    Science.gov (United States)

    Stephens, Owen W; Zhang, Qing; Qu, Pingping; Zhou, Yiming; Chavan, Shweta; Tian, Erming; Williams, David R; Epstein, Joshua; Barlogie, Bart; Shaughnessy, John D

    2012-01-12

    IL-6 signaling can be enhanced through transsignaling by the soluble IL-6 receptor (sIL-6r), allowing for the pleiotropic cytokine to affect cells it would not ordinarily have an effect on. Serum levels of sIL-6r can be used as an independent prognostic indicator and further stratify the GEP 70-gene low-risk group to identify an intermediate-risk group in multiple myeloma (MM). By analyzing more than 600 MM patients with ELISA, genotyping, and gene expression profiling tools, we show how the combination of 2 independent molecular genetic events is related to synergistic increases in sIL-6r levels. We also show that the rs2228145 minor allele is related to increased expression levels of an IL-6r splice variant that purportedly codes exclusively for a sIL-6r isoform. Together, the SNP rs2228145 minor allele C and amplification of chromosome 1q21 are significantly correlated to an increase in sIL-6r levels, which are associated with lower overall survival in 70-gene low-risk disease, and aid in identification of the intermediate-risk MM group.

  15. Greater expression of TLR2, TLR4, and IL6 due to negative energy balance is associated with lower expression of HLA-DRA and HLA-A in bovine blood neutrophils after intramammary mastitis challenge with Streptococcus uberis

    DEFF Research Database (Denmark)

    Moyes, Kasey; Drackley, James K; Morin, Dawn E;

    2010-01-01

    response and metabolism. A total of 12 genes were differentially expressed in blood PMN in NEB versus PEB cows. Upregulated genes by NEB were ALOX5AP, CPNE3, IL1R2, IL6, TLR2, TLR4, and THY1, and downregulated genes were HLA-DRA, HLA-A, IRAK1, SOD1, and TNF. Network analysis revealed that TNF...... with NEB and the corresponding inhibition of immune response in lactating dairy cows....

  16. Astrocytic IL-6 mediates locomotor activity, exploration, anxiety, learning and social behavior.

    Science.gov (United States)

    Erta, Maria; Giralt, Mercedes; Esposito, Flavia Lorena; Fernandez-Gayol, Olaya; Hidalgo, Juan

    2015-07-01

    Interleukin-6 (IL-6) is a major cytokine in the central nervous system, secreted by different brain cells and with roles in a number of physiological functions. We herewith confirm and expand the importance of astrocytic production of and response to IL-6 by using transgenic mice deficient in astrocytic IL-6 (Ast-IL-6 KO) or in its receptor (Ast-IL-6R KO) in full C57Bl/6 genetic background. A major prosurvival effect of astrocytic IL-6 at early ages was clearly demonstrated. Robust effects were also evident in the control of activity and anxiety in the hole-board and elevated plus-maze, and in spatial learning in the Morris water-maze. The results also suggest an inhibitory role of IL-6 in the mechanism controlling the consolidation of hippocampus-dependent spatial learning. Less robust effects of astrocytic IL-6 system were also observed in despair behavior in the tail suspension test, and social behavior in the dominance and resident-intruder tests. The behavioral phenotype was highly dependent on age and/or sex in some cases. The phenotype of Ast-IL-6R KO mice mimicked only partially that of Ast-IL-6KO mice, which indicates both a role of astrocytes in behavior and the participation of other cells besides astrocytes. No evidences of altered function of the hypothalamic-pituitary-adrenal axis were observed. These results demonstrate that astrocytic IL-6 (acting at least partially in astrocytes) regulates normal behavior in mice.

  17. HIV-1 Tat promotes Kaposi's sarcoma-associated herpesvirus (KSHV vIL-6-induced angiogenesis and tumorigenesis by regulating PI3K/PTEN/AKT/GSK-3β signaling pathway.

    Directory of Open Access Journals (Sweden)

    Feng Zhou

    Full Text Available Kaposi's sarcoma (KS-associated herpesvirus (KSHV is etiologically associated with KS, the most common AIDS-related malignancy. KS is characterized by vast angiogenesis and hyperproliferative spindle cells. We have previously reported that HIV-1 Tat can trigger KSHV reactivation and accelerate Kaposin A-induced tumorigenesis. Here, we explored Tat promotion of KSHV vIL-6-induced angiogenesis and tumorigenesis. Tat promotes vIL-6-induced cell proliferation, cellular transformation, vascular tube formation and VEGF production in culture. Tat enhances vIL-6-induced angiogenesis and tumorigenesis of fibroblasts and human endothelial cells in a chicken chorioallantoic membrane (CAM model. In an allograft model, Tat promotes vIL-6-induced tumorigenesis and expression of CD31, CD34, SMA, VEGF, b-FGF, and cyclin D1. Mechanistic studies indicated Tat activates PI3K and AKT, and inactivates PTEN and GSK-3β in vIL-6 expressing cells. LY294002, a specific inhibitor of PI3K, effectively impaired Tat's promotion of vIL-6-induced tumorigenesis. Together, these results provide the first evidence that Tat might contribute to KS pathogenesis by synergizing with vIL-6, and identify PI3K/AKT pathway as a potential therapeutic target in AIDS-related KS patients.

  18. Pokemon inhibits the apoptosis of gastric cancer cell line BGC823 by suppressing p53 and enhancing IL-6%pokemon通过抑制p53和上调白细胞介素6抑制胃肿瘤细胞BGC823凋亡

    Institute of Scientific and Technical Information of China (English)

    季玉连; 赵树立; 赵光峰; 侯亚义

    2012-01-01

    Objective The proto-oncogene Pokemon is a potent transcriptional repressor highly expressed in many kinds of cancers, but its role in the development and progression of cancer remains to be clarified . In this study, we investigated the role of Pokemon in gastric cancer cell line BGC823 and its mechanism. Methods The coding sequence of Pokemon was constructed in the eukaryotic expression vector pcDNA3.1(+), and a specific siRNA targeting Pokemon was constructed in pSilencer 3.1 Hl-neo. The resultant recombinant plasmids pcDNA3. 1-pokemon and pSilencer 3. 1 Hl-#3 were transfected into the BGC823 cells using Lipo-fectamine 2000. The apoptosis of the cells was evaluated by flow cytometry , and the mRNA and protein expressions of Pokemon detemi -ned by PCR analysis and Western blot , respectively. Results We successfully constructed the gene overexpression and interruption vectors pcDNA3.1-pokemon and pSilencer 3. 1 Hl-#3. Overexpressed Pokemon significantly inhibited p53 and enhanced IL-6, while the interference of the Pokemon expression resulted in an increased transcription of p53. The overexpression of Pokemon suppressed , while knockdown of Pokemon increased the apoptosis of BGC 823 cells. Conclusion Pokemon inhibits the apoptosis of gastric cancer cell line BGC823. p53 and IL-6 are the downstream target genes of Pokemon.%目的 原癌基因pokemon是转录抑制因子,高表达于多种肿瘤细胞中,但其在肿瘤发生发展中的机制仍有待阐明.文中研究pokemon在胃腺癌细胞系BGC823中的作用及机制.方法将pokemon的编码片段构建入真核表达载体pcDNA3.1( + )中.将具有靶向沉默pokemon的siRNA互补的DNA构建到pSilencer 3.1 H1-neo中.将构建的质粒pcDNA3.1-pokemon和pSilencer 3.1 H1-3#用脂质体2000转染BGC823细胞.用流式细胞仪检测细胞凋亡,用RT-PCR分析细胞内mRNA的变化,用Western blot检测pokemon蛋白的表达.结果 成功构建了pokemon过表达/干扰载体pcDNA3.1-pokemon和pSilencer 3

  19. IL-6 amplifies TLR mediated cytokine and chemokine production: implications for the pathogenesis of rheumatic inflammatory diseases.

    Directory of Open Access Journals (Sweden)

    Ivan Caiello

    Full Text Available The role of Interleukin(IL-6 in the pathogenesis of joint and systemic inflammation in rheumatoid arthritis (RA and systemic juvenile idiopathic arthritis (s-JIA has been clearly demonstrated. However, the mechanisms by which IL-6 contributes to the pathogenesis are not completely understood. This study investigates whether IL-6 affects, alone or upon toll like receptor (TLR ligand stimulation, the production of inflammatory cytokines and chemokines in human peripheral blood mononuclear cells (PBMCs, synovial fluid mononuclear cells from JIA patients (SFMCs and fibroblast-like synoviocytes from rheumatoid arthritis patients (RA synoviocytes and signalling pathways involved. PBMCs were pre-treated with IL-6 and soluble IL-6 Receptor (sIL-6R. SFMCs and RA synoviocytes were pre-treated with IL-6/sIL-6R or sIL-6R, alone or in combination with Tocilizumab (TCZ. Cells were stimulated with LPS, S100A8-9, poly(I-C, CpG, Pam2CSK4, MDP, IL-1β. Treatment of PBMCs with IL-6 induced production of TNF-α, CXCL8, and CCL2, but not IL-1β. Addition of IL-6 to the same cells after stimulation with poly(I-C, CpG, Pam2CSK4, and MDP induced a significant increase in IL-1β and CXCL8, but not TNF-α production compared with TLR ligands alone. This enhanced production of IL-1β and CXCL8 paralleled increased p65 NF-κB activation. In contrast, addition of IL-6 to PBMCs stimulated with LPS or S100A8-9 (TLR-4 ligands led to reduction of IL-1β, TNF-α and CXCL8 with reduced p65 NF-κB activation. IL-6/IL-1β co-stimulation increased CXCL8, CCL2 and IL-6 production. Addition of IL-6 to SFMCs stimulated with LPS or S100A8 increased CXCL8, CCL2 and IL-1β production. Treatment of RA synoviocytes with sIL-6R increased IL-6, CXCL8 and CCL2 production, with increased STAT3 and p65 NF-κB phosphorylation. Our results suggest that IL-6 amplifies TLR-induced inflammatory response. This effect may be relevant in the presence of high IL-6 and sIL-6R levels, such as in arthritic

  20. [Role of IL-6 in the development and pathogenesis of CIA and EAE].

    Science.gov (United States)

    Fujimoto, Minoru; Serada, Satoshi; Naka, Tetsuji

    2008-04-01

    Interleukin (IL)-6 is a pleiotropic cytokine that has crucial roles in the regulation of immune response, inflammation and hematopoiesis. Recently, a new inflammatory helper T cell subset which produces IL-17A (IL-17), termed Th17 cells was identified and has been reported to be involved in the development and pathogenesis of collagen induced arthritis (CIA) and experimental autoimmune encephalomyelitis (EAE), which are known as the mouse model of rheumatoid arthritis and multiple sclerosis, respectively. It has been demonstrated that IL-6 together with TGF-beta induces the differentiation of Th17 cells from naive helper T cells in vitro. However, IL-6 independent pathway of Th17 differentiation has also been reported, suggesting that the role of IL-6 in vivo in these diseases remains unclear. With the treatment of anti-IL-6R antibody in CIA and EAE, we could suppress the differentiation of antigen specific Th17 cells and the onset of diseases. These results indicate that IL-6 is involved in the induction of Th17 cells in vivo, and anti-IL-6R antibody might be a promising therapy of Th17-mediated autoimmune diseases.

  1. IL-6、IL-8在不同潮气量单肺通气肺癌根治术中的表达%Effect of One-lung Ventilation of Different Tidal Volume on the Expressions of Interleukin-6 and Interleukin-8 in Lung Cancer Patients during Radical Operation

    Institute of Scientific and Technical Information of China (English)

    林飞; 潘灵辉; 钱卫; 黄宇; 杜学柯; 裴圣林

    2012-01-01

    目的 观察在肺癌根治术中不同潮气量(VT)的单肺通气(OLV)对血IL-6、IL-8表达的影响.方法 30例行肺癌根治术患者,用随机数字表法分为3组.行双腔支气管插管麻醉,术中单肺通气期间在保持分钟通气量不变的情况下,A组VT=10 ml/kg,呼吸频率(f)=12次/min,B组VT=8 ml/kg,f=15次/min,C组VT=6 ml/kg,f=20次/min.在OLV前(T1)、OLV后30 min(T2)、60 min(T3)、OLV结束前(T4)检测血IL-6、IL-8的表达.结果 3组在T2、T3、T4时点的IL-6、IL-8表达均明显高于T1(P<0.05),且随OLV时间延长而逐渐升高;OLV后随设定的潮气量减低,IL-6及IL-8表达逐渐降低; A组的IL-6、IL-8表达显著高于B、C组(P<0.05).结论 在单肺通气的肺癌根治术中,采用小潮气量的通气模式可减少肺内炎症反应.%Objective To study effect of one-lung ventilation( OLV ) of different tidal volume( VT ) on the expressions of serum interleukin-6( IL-6 ) and interleukin-8( IL-8 ) in lung cancer patients during radical operation. Methods Thirty lung cancer patients undergoing radical operation were enrolled in the study. All the patients received double-lumen endobronchial intubation anesthesia, and were randomly divided into three groups after one-lung ventilation during radical operation: Group A( VT = 10 ml/kg, respiratory frequency( f ) = 12/min ), Group B( VT = 8 ml/kg, f = 12/min ), Group C( VT =6 ml/kg,f = 12/min ). The expressions of serum IL-6,IL-8 were detected before OLV( T1 ),30 min after OLV ( T2 ),60 min after OLV ( T3 ),1 min before OLV ending( T4 ). Results Compared with T1 ,the expressions of IL-6,IL-8 on T2 ,T3 ,T4 significantly increased in three groups( P <0. 05 ),and the increase was in a time-dependent manner. The expressions of IL-6, IL-8 gradually decreased with VT reduction during OLV. The expressions of IL-6, IL-8 in Group A were significantly higher than those in Group B, C( P < 0. 05 ). Conclusion The ventilation mode of low tidal volume can reduce the pulmonary

  2. Identification of IL6 as a susceptibility gene for major depressive disorder.

    Science.gov (United States)

    Zhang, Chen; Wu, Zhiguo; Zhao, Guoqing; Wang, Fan; Fang, Yiru

    2016-08-09

    Our previous work implied that interleukin 6 (IL6) may be a biological marker for major depressive disorder (MDD). In this study, we performed a comprehensive genetic study to determine the association between the gene encoding IL6 (IL6) and MDD in Han Chinese. There were 50 drug-naïve MDD patients and 50 healthy controls undergoing an mRNA expression study. A sample of 772 patients with MDD and 759 healthy controls were used for genetic analysis. Next, we performed an eQTL analysis to identify whether risk SNP(s) is associated with IL6 expression in brain. Our results showed that patients with MDD have higher levels of IL6 than healthy controls (P = 0.008). The SNP rs1800797 has a significant association with MDD (P = 0.01) in a dominant model. The eQTL analysis showed a marginally significant association between the rs1800797 and IL6 expression in the frontal cortex (P = 0.087). Our preliminary findings are suggestive of an association between rs1800797 and the risk of MDD. Further investigations are required to evaluate this association in larger samples to increase statistical power, and to examine the correlation between rs1800797 and IL6 methylation patterns.

  3. Epigenetic control of the basal-like gene expression profile via Interleukin-6 in breast cancer cells

    Directory of Open Access Journals (Sweden)

    Mitrugno Valentina

    2010-11-01

    Full Text Available Abstract Background Basal-like carcinoma are aggressive breast cancers that frequently carry p53 inactivating mutations, lack estrogen receptor-α (ERα and express the cancer stem cell markers CD133 and CD44. These tumors also over-express Interleukin 6 (IL-6, a pro-inflammatory cytokine that stimulates the growth of breast cancer stem/progenitor cells. Results Here we show that p53 deficiency in breast cancer cells induces a loss of methylation at IL-6 proximal promoter region, which is maintained by an IL-6 autocrine loop. IL-6 also elicits the loss of methylation at the CD133 promoter region 1 and of CD44 proximal promoter, enhancing CD133 and CD44 gene transcription. In parallel, IL-6 induces the methylation of estrogen receptor (ERα promoter and the loss of ERα mRNA expression. Finally, IL-6 induces the methylation of IL-6 distal promoter and of CD133 promoter region 2, which harbour putative repressor regions. Conclusion We conclude that IL-6, whose methylation-dependent autocrine loop is triggered by the inactivation of p53, induces an epigenetic reprogramming that drives breast carcinoma cells towards a basal-like/stem cell-like gene expression profile.

  4. Interleukin-6, A Cytokine Critical to Mediation of Inflammation, Autoimmunity and Allograft Rejection: Therapeutic Implications of IL-6 Receptor Blockade.

    Science.gov (United States)

    Jordan, Stanley C; Choi, Jua; Kim, Irene; Wu, Gordon; Toyoda, Mieko; Shin, Bonga; Vo, Ashley

    2017-01-01

    The success of kidney transplants is limited by the lack of robust improvements in long-term survival. It is now recognized that alloimmune responses are responsible for the majority of allograft failures. Development of novel therapies to decrease allosensitization is critical. The lack of new drug development in kidney transplantation necessitated repurposing drugs initially developed in oncology and autoimmunity. Among these is tocilizumab (anti-IL-6 receptor [IL-6R]) which holds promise for modulating multiple immune pathways responsible for allograft injury and loss. Interleukin-6 is a cytokine critical to proinflammatory and immune regulatory cascades. Emerging data have identified important roles for IL-6 in innate immune responses and adaptive immunity. Excessive IL-6 production is associated with activation of T-helper 17 cell and inhibition of regulatory T cell with attendant inflammation. Plasmablast production of IL-6 is critical for initiation of T follicular helper cells and production of high-affinity IgG. Tocilizumab is the first-in-class drug developed to treat diseases mediated by IL-6. Data are emerging from animal and human studies indicating a critical role for IL-6 in mediation of cell-mediated rejection, antibody-mediated rejection, and chronic allograft vasculopathy. This suggests that anti-IL-6/IL-6R blockade could be effective in modifying T- and B-cell responses to allografts. Initial data from our group suggest anti-IL-6R therapy is of value in desensitization and prevention and treatment of antibody-mediated rejection. In addition, human trials have shown benefits in treatment of graft versus host disease in matched or mismatched stem cell transplants. Here, we explore the biology of IL-6/IL-6R interactions and the evidence for an important role of IL-6 in mediating allograft rejection.

  5. The Experimental Influences of Baihui - Qubin Acupuncture on Interleukin -6Expression of Rats With Intracerebral Hemorrhage%“百会透曲鬓”针刺法对脑出血模型大鼠脑组织IL-6蛋白表达影响的实验研究

    Institute of Scientific and Technical Information of China (English)

    孔莹; 赵佳辉; 邹伟; 乔胜楠; 王珑; 迟庆斌; 刘鹏; 黄亮; 郭新年; 滕伟

    2012-01-01

    Bin point, which could penetrate three regions of the cupula,forehead and temple. 4. The Berderson neural deficit scores were tested at three time points(6h,2d,7d after hemorrhage model establishment)before the rat models were killed, then the brains were removed and indexes were detected. 5. The average gray scale of Interleukin - 6 protein expressio - n by imtnunohistoc - hemical method were checked, and the morphologic change on light microscope was observed. 6. Statistical treatment was made. Results: 1. The results of the neurologic deficit score of acupuncture group was better than intracerebral hemorrhage group and western medicine group for the first two days. Acupuncture group and western medicine group were better than intracerebral hemorrhage group after seven days. 2. The results of masculine cell in the average gray scale of Interleukin-6 in untreated control group were different from intracerebra -1 hemorrhage group (ICH). In two days,the average gray scale of Interleukin - 6 in acupu - ncture group was lower than that in intracerebral hemorrhage group. There was also difference between acupuncture group and western medicine group. Acupuncture group and western medicine group were lower than those in intracerebral hemorrhage group, and there was a difference between acupuncture group and western medicine group in 7 days. 3. The results of the brain pathological change in acupuncture group and western medicine group were different from those in intracerebral hemorrhage group. Conclusion: 1. BaiHui - QuBin acupuncture can obviously raise the B - erderson neural deficit scores, and have the benefit for improvement of extremity function after intracerebral hemorrhage. 2. Study shows that acute phase of cerebral hemorrhage, BaiHui - QuBin scalp - acupuncture therapy can reduce IL - 6 protein expression, reduce the inflammatory response after cerebral hemorrhage caused by the extent of secondary brain injury, ischemic brain tissue in order to improve status and the

  6. Sonic hedgehog inhibitors prevent colitis-associated cancer via orchestrated mechanisms of IL-6/gp130 inhibition, 15-PGDH induction, Bcl-2 abrogation, and tumorsphere inhibition.

    Science.gov (United States)

    Kangwan, Napapan; Kim, Yoon-Jae; Han, Young Min; Jeong, Migyeong; Park, Jong-Min; Go, Eun-Jin; Hahm, Ki-Baik

    2016-02-16

    Sonic hedgehog (SHH) signaling is essential in normal development of the gastrointestinal (GI) tract, whereas aberrantly activated SHH is implicated in GI cancers because it facilitates carcinogenesis by redirecting stem cells. Since colitis-associated cancer (CAC) is associated with inflammatory bowel diseases, in which SHH and IL-6 signaling, inflammation propagation, and cancer stem cell (CSC) activation have been implicated, we hypothesized that SHH inhibitors may prevent CAC by blocking the above SHH-related carcinogenic pathways. In the intestinal epithelial cells IEC-6 and colon cancer cells HCT-116, IL-6 expression and its signaling were assessed with SHH inhibitors and levels of other inflammatory mediators, proliferation, apoptosis, tumorsphere formation, and tumorigenesis were also measured. CAC was induced in C57BL/6 mice by administration of azoxymethane followed by dextran sodium sulfate administration. SHH inhibitors were administered by oral gavage and the mice were sacrificed at 16 weeks. TNF-α-stimulated IEC-6 cells exhibited increased levels of proinflammatory cytokines and enzymes, whereas SHH inhibitors suppressed TNF-α-induced inflammatory signaling, especially IL-6/IL-6R/gp130 signaling. SHH inhibitors significantly induced apoptosis, inhibited cell proliferation, suppressed tumorsphere formation, and reduced stemness factors. In the mouse model, SHH inhibitors significantly reduced tumor incidence and multiplicity, decreased the expression of IL-6, TNF-α, COX-2, STAT3, and NF-κB, and significantly induced apoptosis. In colosphere xenografts, SHH inhibitor significantly suppressed tumorigenesis by inhibiting tumorsphere formation. Taken together, our data suggest that administration of SHH inhibitors could be an effective strategy to prevent colitis-induced colorectal carcinogenesis, mainly by targeting IL-6 signaling, ablating CSCs, and suppressing oncogenic inflammation, achieving chemoquiescence ultimately.

  7. Identification of IL6 as a susceptibility gene for major depressive disorder

    OpenAIRE

    2016-01-01

    Our previous work implied that interleukin 6 (IL6) may be a biological marker for major depressive disorder (MDD). In this study, we performed a comprehensive genetic study to determine the association between the gene encoding IL6 (IL6) and MDD in Han Chinese. There were 50 drug-naïve MDD patients and 50 healthy controls undergoing an mRNA expression study. A sample of 772 patients with MDD and 759 healthy controls were used for genetic analysis. Next, we performed an eQTL analysis to identi...

  8. Knowledge-based matrix factorization temporally resolves the cellular responses to IL-6 stimulation

    Directory of Open Access Journals (Sweden)

    Gretz Norbert

    2010-11-01

    Full Text Available Abstract Background External stimulations of cells by hormones, cytokines or growth factors activate signal transduction pathways that subsequently induce a re-arrangement of cellular gene expression. The analysis of such changes is complicated, as they consist of multi-layered temporal responses. While classical analyses based on clustering or gene set enrichment only partly reveal this information, matrix factorization techniques are well suited for a detailed temporal analysis. In signal processing, factorization techniques incorporating data properties like spatial and temporal correlation structure have shown to be robust and computationally efficient. However, such correlation-based methods have so far not be applied in bioinformatics, because large scale biological data rarely imply a natural order that allows the definition of a delayed correlation function. Results We therefore develop the concept of graph-decorrelation. We encode prior knowledge like transcriptional regulation, protein interactions or metabolic pathways in a weighted directed graph. By linking features along this underlying graph, we introduce a partial ordering of the features (e.g. genes and are thus able to define a graph-delayed correlation function. Using this framework as constraint to the matrix factorization task allows us to set up the fast and robust graph-decorrelation algorithm (GraDe. To analyze alterations in the gene response in IL-6 stimulated primary mouse hepatocytes, we performed a time-course microarray experiment and applied GraDe. In contrast to standard techniques, the extracted time-resolved gene expression profiles showed that IL-6 activates genes involved in cell cycle progression and cell division. Genes linked to metabolic and apoptotic processes are down-regulated indicating that IL-6 mediated priming renders hepatocytes more responsive towards cell proliferation and reduces expenditures for the energy metabolism. Conclusions GraDe provides

  9. HIF-1α Activation Attenuates IL-6 and TNF-α Pathways in Hippocampus of Rats Following Transient Global Ischemia

    Directory of Open Access Journals (Sweden)

    Jihong Xing

    2016-07-01

    Full Text Available Background/Aims: This study was to examine the role played by hypoxia inducible factor-1 (HIF-1α in regulating pro-inflammatory cytokines (PICs pathway in the rat hippocampus after cardiac arrest (CA induced-transient global ischemia followed by cardiopulmonary resuscitation (CPR. Those PICs include interleukin-1β (IL-1β, interleukin-6 (IL-6 and tumor necrosis factor-α (TNF-α. Methods: A rat model of CA induced by asphyxia was used in the current study. Following CPR, the hippocampus CA1 region was obtained for ELISA to determine the levels of HIF-1α and PICs; and Western Blot analysis to determine the protein levels of PIC receptors. Results: Our data show that IL-1β, IL-6 and TNF-α were significant elevated in the hippocampus after CPR as compared with control group. This was companied with increasing of HIF-1α and the time courses for HIF-1α and PICs were similar. In addition, PIC receptors, namely IL-1R, IL-6R and TNFR1 were upregulated in CA rats. Also, stimulation of HIF-1α by systemic administration of ML228, HIF-1α activator, significantly attenuated the amplified IL-6/IL-6R and TNF-α /TNFR1 pathway in the hippocampus of CA rats, but did not modify IL-1β and its receptor. Moreover, ML228 attenuated upregulated expression of Caspase-3 indicating cell apoptosis evoked by CA. Conclusion: Transient global ischemia induced by CA increases the levels of IL-1β, IL-6 and TNF-α and thereby leads to enhancement in their respective receptor in the rat hippocampus. Stabilization of HIF-1α plays a role in attenuating amplified expression IL-6R, TNFR1 and Caspase-3 in the processing of transient global ischemia. Results of our study suggest that PICs contribute to cerebral injuries evoked by transient global ischemia and in this pathophysiological process activation of HIF-1α improves tissues against ischemic injuries. Our data revealed specific signaling pathways in alleviating CA-evoked global cerebral ischemia by elucidating that

  10. 前胡甲素对缺血再灌注心肌IL-6水平及Fas,bax,bcl-2蛋白表达的影响%Effects of dl-praeruptorin A on interleukin-6 level and Fas,bax, bcl-2 protein expression in ischemia-reperfusion myocardium

    Institute of Scientific and Technical Information of China (English)

    常天辉; 刘晓阳; 章新华; 王怀良

    2002-01-01

    AIM: To investigate the effects of dl-praeruptorin (Pd-Ia) on interleukin-6 (IL-6) level and apoptosis-relatedprotein expression in ischemia-reperfusion myocardium. METHODS: Left anterior descending coronary arterywas subjected to 30 min ischemia followed by 120 min reperfusion in open-chest anesthetized rats. Serum IL-6level was measured by radioimmunoassay. Apoptosis-related protein Fas, bax, and bcl-2 expression was detectedby immunohistochemistry and computer image analysis system. Infiltration of neutrophils was observed usingHematoxylin-Eosin staining under optical microscope. RESULTS: Pd-Ia 2.0 mg.kg -1 iv lowered serum 1L-6 level andFas, bax, bcl-2 expression under conditions with hypotension and without changes on heart rate, but increased theratio of bcl-2/bax. There existed a close linearity and positive correlation between IL-6 level and Fas, bax, bcl-2expression. Whereas, the infiltration of neutrophils was mild. CONCLUSION: Pd-Ia elicits a novel target in thetherapeutic prevention of postischemic cardiomyocyte death. The reason might be associated with modulating theexpression of some immediate-early genes including IL-6, Fas, bax, and bcl-2 in ischemia-reperfusion myocardium.%目的:研究前胡甲素对缺血再灌注心肌IL-6水平及凋亡相关蛋白表达的影响.方法:麻醉开胸大鼠左前降枝冠状动脉蒙受30分钟缺血及120分钟再灌注.放射免疫法测定血清IL-6水平;免疫组化法和计算机图像分析系统检测凋亡相关蛋白Fas,bax及bcl-2的表达:苏木精一依红染色法染色并于光镜下观测嗜中性白细胞的浸润.结果:前胡甲素2.0 mg.kg-1 iv,在降压和不影响心率的情况下,减少IL-6水平及Fas,bax,bcl-2蛋白的表达,但增加bcl-2/bax的比率.IL-6水平及Fas,bax,bcl-2蛋白表达之间有密切的线性正相关,而嗜中性白细胞只有轻微浸润.结论:前胡甲素防治缺血后心肌细胞死亡出现新靶位,可能与机体在心肌缺血再灌注期间调控即早基因IL

  11. Genetic variant modifies the effect of N3 PUFAs on DNA methylation of IL6 in the Genetics of Lipid Lowering Drugs and Diet Network study

    Science.gov (United States)

    N3 polyunsaturated fatty acids (N3 PUFAs) ameliorate inflammation status with specific regulation on interleukin-6 (IL6) expression. However, the molecular mechanism for this regulation is unclear. Using both cell lines data from Encyclopedia of DNA Elements (ENCODE) consortium and population data f...

  12. Evaluation of anti-IL-6 monoclonal antibody therapy using murine type II collagen-induced arthritis

    Directory of Open Access Journals (Sweden)

    Shealy David

    2009-04-01

    Full Text Available Abstract Interleukin-6 is a multifunctional cytokine that is critical for T/B-cell differentiation and maturation, immunoglobulin secretion, acute-phase protein production, and macrophage/monocyte functions. Extensive research into the biology of IL-6 has implicated IL-6 in the pathophysiology and pathogenesis of RA. An anti-murine IL-6 mAb that neutralizes mouse IL-6 activities was tested in animal model of collagen-induced arthritis. Prophylactic treatment with anti-IL-6 mAb significantly reduced the incidence and severity of arthritis compared to control mAb treated mice. The mitogenic response of B and T cells isolated from the lymph nodes of anti-IL-6 treated mice was significantly reduced compared to cells isolated from control mAb treated mice. The overall histopathology score for paws from the anti-IL-6 treated mice was significantly reduced when compared to paws from mice treated with control mAb, including both inflammatory (synovitis and pannus and erosive (erosions and architecture parameters. Reduced loss of cartilage matrix components was also observed in the anti-IL-6 treated mice. Collectively, these data suggest that IL-6 plays a major role in the pathophysiology of rheumatoid arthritis, and thus support the potential benefit of anti-IL-6 mAb treatment in rheumatoid arthritis patients.

  13. Interleukin-6 (IL-6) and receptor (IL6-R) gene haplotypes associate with amniotic fluid protein concentrations in preterm birth.

    Science.gov (United States)

    Velez, Digna R; Fortunato, Stephen J; Williams, Scott M; Menon, Ramkumar

    2008-06-01

    Spontaneous preterm birth (PTB-gestational age rs1800797, rs1800796 and rs1800795; in IL-6R markers rs4075015, rs4601580, rs4645618, rs6687726 and rs7549338 and markers rs4845623, rs4537545 and rs4845625. In conclusion, our results suggest that IL-6 AF concentration, in situations of PTB, result from variation in IL-6 and more importantly IL-6R.

  14. Stress-related hormone norepinephrine induces interleukin-6 expression in GES-1 cells

    Energy Technology Data Exchange (ETDEWEB)

    Yang, R.; Lin, Q.; Gao, H.B.; Zhang, P. [Department of Biochemistry and Molecular Cell Biology, School of Medicine, Shanghai Jiao Tong University, Shanghai, China, Department of Biochemistry and Molecular Cell Biology, School of Medicine, Shanghai Jiao Tong University, Shanghai (China)

    2014-02-17

    In the current literature, there is evidence that psychological factors can affect the incidence and progression of some cancers. Interleukin 6 (IL-6) is known to be elevated in individuals experiencing chronic stress and is also involved in oncogenesis and cancer progression. However, the precise mechanism of IL-6 induction by the stress-related hormone norepinephrine (NE) is not clear, and, furthermore, there are no reports about the effect of NE on IL-6 expression in gastric epithelial cells. In this study, we examined the effect of NE on IL-6 expression in immortalized human gastric epithelial cells (GES-1 cells). Using real-time PCR and enzyme-linked immunoassay, we demonstrated that NE can induce IL-6 mRNA and protein expression in GES-1 cells. The induction is through the β-adrenergic receptor-cAMP-protein kinase A pathway and mainly at the transcriptional level. Progressive 5′-deletions and site-directed mutagenesis of the parental construct show that, although activating-protein-1 (AP-1), cAMP-responsive element binding protein (CREB), CCAAT-enhancer binding protein-β (C/EBP-β), and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) binding sites are all required in the basal transcription of IL-6, only AP-1 and CREB binding sites in the IL-6 promoter are required in NE-induced IL-6 expression. The results suggest that chronic stress may increase IL-6 secretion of human gastric epithelial cells, at least in part, by the stress-associated hormone norepinephrine, and provides basic data on stress and gastric cancer progression.

  15. IL-6, but not TNF-α, increases plasma YKL-40 in human subjects

    DEFF Research Database (Denmark)

    Nielsen, Anders R; Plomgaard, Peter; Krabbe, Karen S

    2011-01-01

    Plasma levels of YKL-40 are elevated in patients with systemic infection, inflammatory disorders and cancer. Both monocytes/macrophages, neutrophils, and cancer cells have the capacity to produce YKL-40, but the regulation during the inflammatory response is unknown. To study the possible role...... of interleukin-6 (IL-6) and tumor necrosis factor (TNF)-a in the regulation of YKL-40 plasma levels, we included healthy men, who received either recombinant human (rh)IL-6 (n=6), rhTNF-a (n=8) or vehicle (n=7) for 3h. The plasma levels of IL-6 and TNF-a reached ~ 150 and ~ 18 pg/ml, respectively, during...

  16. The contribution of the functional IL6R polymorphism rs2228145, eQTLs and other genome-wide SNPs to the heritability of plasma sIL-6R levels.

    Science.gov (United States)

    van Dongen, Jenny; Jansen, Rick; Smit, Dirk; Hottenga, Jouke-Jan; Mbarek, Hamdi; Willemsen, Gonneke; Kluft, Cornelis; Penninx, Brenda W J; Ferreira, Manuel A; Boomsma, Dorret I; de Geus, Eco J C

    2014-07-01

    The non-synonymous SNP rs2228145 in the IL6R gene on chromosome 1q21.3 is associated with a wide range of common diseases, including asthma, rheumatoid arthritis, type 1 diabetes and coronary heart disease. We examined the contribution of this functional IL6R gene polymorphism rs2228145 versus other genome-wide SNPs to the variance of sIL-6R levels in blood plasma in a large population-based sample (N ~5,000), and conducted an expression QTL analysis to identify SNPs associated with IL6R gene expression. Based on data from 2,360 twin families, the broad heritability of sIL-6R was estimated at 72 and 51% of the total variance was explained by the functional SNP rs2228145. Converging findings from GWAS, linkage, and GCTA analyses indicate that additional variance of sIL-6R levels can be explained by other variants in the IL6R region, including variants at the 3'-end of IL6R tagged by rs60760897 that are associated with IL6R RNA expression.

  17. Expression of IL-6, IL-23 and TGF-β1 in the mucosa of the ileum and ascending colon of patients with irritable bowel syndrome: an analysis of 110 cases%肠黏膜细胞因子在肠易激综合征患者回肠及升结肠组织中的表达

    Institute of Scientific and Technical Information of China (English)

    刘修波; 张巍巍; 解祥军; 王青

    2011-01-01

    AIM: To investigate the expression of interleukin (IL)-6, IL-23 and transforming growth factor beta1 (TGF-β1) in the mucosa of the ileum and ascending colon of patients with irritable bowel syndrome (IBS).METHODS: One hundred and ten patients with IBS and 40 healthy volunteers were included in the study. Mucosal samples were taken from the ileum and ascending colon of these subjects to detect the expression of IL-6, IL-23 and TGF-β1 by immunohistochemistry.RESULTS: The expression levels of IL-6 and IL-23 in the mucosa of the ileum and ascending colon were higher in IBS patients than in controls (IL-6:106.45 ± 12.54 vs 82.45 ± 11.52, t = 10.58; 107.48 ± 18.75 vs 91.32 ± 10.45, t = 5.16;IL-23:10.68 ± 3.35 vs 4.78 ± 2.54, t = 10.12; 11.42 ±2.87 vs 5.20 ± 1.85, t = 12.76, all P < 0.05). No significant difference was found in the expression level of TGF-β1 in the mucosa of the ileum and ascending colon between the two groups (t = 1.57,1.69, both P > 0.05).CONCLUSION: High expression of proinflammatory cytokines in the mucosa of the ileum and ascending colon may have a correlation with visceral perception and altered bowel habits in patients with IBS.%目的:研究肠易激综合征(IBS)患者回肠末端及升结肠黏膜组织中炎性因子白介素(IL)-6、IL-23及LTGF-β1的表达,探讨IBS的发病机制.方法:选取110例IBS患者,另选40例健康体检者为对照,内镜下取回肠及升结肠肠黏膜组织各1块,用免疫组织化学法测定回肠末端及升结肠肠黏膜中IL-6、IL-23及TGF-β1水平.结果:IL-6及IL-23在IBS患者回肠末端及升结肠肠黏膜的表达高于对照组(IL-6:106.45±12.54 vs 82.45±11.52,t=10.58;107.48±18.75 vs 91.32±10.45,t=5.16;IL-23:10.68±3.35 vs 4.78±2.54,t=10.12:11.42±2.87vs 5.20±1.85,t=12.76,均P0.05).结论:IBS患者回肠黏膜及升结肠炎性细胞因子表达水平升高,促炎细胞因子与抑炎细胞因子失衡,与IBS内脏感知及排便习惯的改变等症状的发生有一定相关性.

  18. Prediction of disease severity in neuromyelitis optica by the levels of interleukin (IL)-6 produced during remission phase.

    Science.gov (United States)

    Barros, P O; Cassano, T; Hygino, J; Ferreira, T B; Centurião, N; Kasahara, T M; Andrade, R M; Linhares, U C; Andrade, A F B; Vasconcelos, C C F; Alvarenga, R; Marignier, R; Bento, C A M

    2016-03-01

    T helper type 17 (Th17) cytokines have been implicated in the pathogenesis of neuromyelitis optica (NMO). As humanized anti-interleukin (IL)-6R (tocilizumab) immunoglobulin (Ig)G has been used as disease-modifying therapy for NMO, the objective of our study was to investigate the role of endogenous IL-6 on NMO-derived CD4(+) T cell behaviour. High production of IL-6, IL-17 and IL-21 by CD4(+) T-cells was detected in NMO patients. Further, IL-21 and IL-6 levels were related directly to the level of neurological disabilities. The addition of anti-IL-6R IgG not only reduced directly the production of these cytokines, but also almost abolished the ability of activated autologous monocytes in enhancing IL-6, IL-17 and IL-21 release by CD4(+) T cells. In contrast, the production of IL-10 was amplified in those cell cultures. Further, anti-IL-6R monoclonal antibodies (mAb) also potentiated the ability of glucocorticoid in reducing Th17 cytokines. Finally, the in-vivo and in-vitro IL-6 levels were significantly higher among those patients who experienced clinical relapse during 2-year follow-up. In summary, our results suggest a deleterious role of IL-6 in NMO by favouring, at least in part, the expansion of corticoid-resistant Th17 cells.

  19. The contribution of the functional IL6R polymorphism rs2228145, eQTLs and other genome-wide SNPs to the heritability of plasma sIL-6R levels

    OpenAIRE

    van Dongen, Jenny; Jansen, Rick; Smit, Dirk; Hottenga, Jouke-Jan; Mbarek, Hamdi; Willemsen, Gonneke; Kluft, Cornelis; Penninx, Brenda W.J.; Ferreira, Manuel A.; Boomsma, Dorret I.; de Geus, Eco J C

    2014-01-01

    The non-synonymous SNP rs2228145 in the IL6R gene on chromosome 1q21.3 is associated with a wide range of common diseases, including asthma, rheumatoid arthritis, type 1 diabetes and coronary heart disease. We examined the contribution of this functional IL6R gene polymorphism rs2228145 versus other genome-wide SNPs to the variance of sIL-6R levels in blood plasma in a large population-based sample (N∼5000), and conducted an expression QTL (eQTL) analysis to identify SNPs associated with IL6R...

  20. IL-6-STAT3 signaling mediates aortic dissections induced by angiotensin II via the Th17 lymphocyte-IL17 axis in C57BL/6 Mice

    Science.gov (United States)

    Ju, Xiaoxi; Ijaz, Talha; Sun, Hong; Ray, Sutapa; Lejeune, Wanda; Lee, Chang; Recinos, Adrian; Guo, Dong-Chuan; Milewicz, Dianna M.; Tilton, Ronald G.; Brasier, Allan R.

    2013-01-01

    Objective Dysregulated angiotensin II (Ang II) signaling induces local vascular interleukin-6 (IL-6) secretion, producing leukocyte infiltration and life-threatening aortic dissections. Precise mechanism(s) by which IL-6 signaling induces leukocyte recruitment remain(s) unknown. T-helper 17lymphocytes (Th17) have been implicated in vascular pathology, but their role in the development of aortic dissections is poorly understood. Here, we tested the relationship of IL-6-STAT3 signaling with Th17-induced inflammation in the formation of Ang II-induced dissections in C57BL/6 mice. Methods and Results Ang II infusion induced aortic dissections and CD4+-interleukin 17A (IL-17A)-expressing, Th17 cell accumulation in C57BL/6 mice. A blunted local Th17 activation, macrophage recruitment, and reduced incidence of aortic dissections were seen in IL-6−/− mice. To determine pathological roles of Th17 lymphocytes, we treated Ang II infused mice with IL-17A neutralizing antibody (IL17A NAb), or infused Ang II in genetically deficientIL-17A mice, and found decreased aortic chemokine MCP-1 production and macrophage recruitment, leading to a reduction in aortic dissections. This effect was independent of blood pressure in IL17ANAb experiment. Application of a cell-permeable STAT3 inhibitor to downregulate the IL-6 pathway decreased aortic dilation and Th17 cell recruitment. We also observed increased aortic Th17 infiltration and IL-17 mRNA expression in patients with thoracic aortic dissections. Lastly, we found that Ang II mediated aortic dissections occurred independent of blood pressure changes. Conclusions Our results indicate that the IL-6-STAT3 signaling pathway converges on Th17 recruitment and IL-17A signaling upstream of macrophage recruitment, mediating aortic dissections. PMID:23685554

  1. INFLUENCE OF PAZHUWAN ON THE LEVELS OF IL-1, IL-6, TNF-α, TGF-β1 AND THE TGF-β1 mRNA EXPRESSION IN LIVER WITH ALCOHOLIC LIVER DISEASE%藏药帕珠丸对慢性酒精性肝损伤大鼠肝组织IL-1、IL-6、TNF-α、TGF-β1含量及TGF-β1 mRNA表达的影响

    Institute of Scientific and Technical Information of China (English)

    韵海霞; 黄以哲; 穆志龙; 俞科贤; 任世存

    2014-01-01

    目的 观察藏药帕珠丸对酒精性肝损伤大鼠肝组织IL-1、IL-6、TNF-α、TGF-β1含量及TGF-β1mRNA表达的影响.方法 分别给予慢性酒精性肝损伤模型大鼠50、100、200 mg·kg-1帕珠丸混悬液,观察其对肝组织IL-1、IL-6、TNF-α、TGF-β1含量及TGF-β1mRNA表达的影响.结果 藏药帕珠丸低、中、高剂量组肝组织IL-1、IL-6、TNF-α、TGF-β1含量均显著降低(P<0.05),TGF-β1mRNA表达下降(P<0.05).结论 藏药帕珠丸可能是通过降低肝组织中IL-1、IL-6、TNF-α、TGF-β1含量及TGF-β1 mRNA表达,对大鼠慢性酒精性肝损伤发挥保肝作用.

  2. IL-6 regulates exercise and training-induced adaptations in subcutaneous adipose tissue in mice

    DEFF Research Database (Denmark)

    Brandt, Claus; Jakobsen, Anne Hviid; Hassing, Helle Adser

    2012-01-01

    Aim: The aim of this study was to test the hypothesis that IL-6 regulates exercise-induced gene responses in subcutaneous adipose tissue in mice. Methods: Four months old male IL-6 whole body knockout (KO) mice and C57B wild-type (WT) mice performed 1h of treadmill exercise, where subcutaneous...... adipose tissue (AT) was removed either immediately after, 4h or 10h after exercise as well as from mice not running acutely. Moreover, AT was sampled at resting conditions after 5 weeks of exercise training. Results: AT leptin mRNA decreased immediately after a single running exercise bout in both...... in regulating exercise and training-induced leptin and PPAR¿ expression in adipose tissue. In addition, while IL-6 is required for TNF-a mRNA reduction in response to acute exercise, IL-6 does not appear to be mandatory for anti-inflammatory effects of exercise training in adipose tissue....

  3. Higher IL-6 and IL6:IGF Ratio in Patients with Barth Syndrome

    Directory of Open Access Journals (Sweden)

    Wilson Lori D

    2012-06-01

    Full Text Available Abstract Background Barth Syndrome (BTHS is a serious X-linked genetic disorder associated with mutations in the tafazzin gene (TAZ, also called G4.5. The multi-system disorder is primarily characterized by the following pathologies: cardiac and skeletal myopathies, neutropenia, growth delay, and exercise intolerance. Although growth anomalies have been widely reported in BTHS, there is a paucity of research on the role of inflammation and the potential link to alterations in growth factors levels in BTHS patients. Methods Plasma from 36 subjects, 22 patients with Barth Syndrome (0.5 - 24 yrs and 14 healthy control males (8 - 21 yrs was analyzed for two growth factors: IGF-1 (bound and free and Growth Hormone (GH; and two inflammatory cytokines IL-6 and TNF-α using high-sensitivity enzyme-linked immunosorbent assays. Results The average IL-6 and IL6:IGF ratio levels were significantly higher in the BTHS (p = 0.046 and 0.02 respectively. As for GH, there was a significant group by age interaction (p = 0.01, such that GH was lower for BTHS patients under the age of 14.4 years and higher than controls after age 14.4 years. TNF-α levels were not significantly different, however, the TNF-α:GH was lower in BTHS patients than controls (p = 0.01. Conclusions Comparison of two anabolic growth mediators, IGF and GH, and two catabolic cytokines, IL-6 and TNF-α, in BTHS patients and healthy age-matched controls demonstrated a potential imbalance in inflammatory cytokines and anabolic growth factors. Higher rates of IL-6 (all ages and lower GH levels were observed in BTHS patients (under age 14.5 compared to controls. These findings may implicate inflammatory processes in the catabolic nature of Barth Syndrome pathology as well as provide a link to mitochondrial function. Furthermore, interactions between growth factors, testosterone and inflammatory mediators may explain some of the variability in cardiac and skeletal myopathies seen

  4. Prevention of AMI Induced Ventricular Remodeling: Inhibitory Effects of Heart-Protecting Musk Pill on IL-6 and TNF-Alpha

    Science.gov (United States)

    Chen, Zhiliang; Hoppe, Ralph

    2017-01-01

    Heart-Protecting Musk Pill (HMP) is a Traditional Chinese Medicine (TCM) that has been used for the prevention and treatment of coronary heart disease in clinic. The current study investigated the effect of HMP on the concentrations of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) and observed the relationship between level changes of inflammatory cytokines and ventricular remodeling in rats with acute myocardial infarction (AMI). Animal models of AMI were made by coronary artery ligation in Sprague-Dawley (SD) rats. AMI rats showed increased levels of IL-6 and TNF-α. Treatment with HMP decreases IL-6 and TNF-α concentrations in rats with AMI. Histopathological and transmission electron microscopic findings were also essentially in agreement with biochemical findings. The results of our study revealed that inflammatory cytokines IL-6 and TNF-α induce cardiac remodeling in rats after AMI; HMP improves cardiac function and ameliorates ventricular remodeling by downregulating the expression of IL-6 and TNF-α and further suppressing the ultrastructural changes of myocardial cells. PMID:28373886

  5. Liposomal Nanoparticles Carrying anti-IL6R Antibody to the Tumour Microenvironment Inhibit Metastasis in Two Molecular Subtypes of Breast Cancer Mouse Models

    Science.gov (United States)

    Guo, Chunlei; Chen, Yanan; Gao, Wenjuan; Chang, Antao; Ye, Yujie; Shen, Wenzhi; Luo, Yunping; Yang, Shengyong; Sun, Peiqing; Xiang, Rong; Li, Na

    2017-01-01

    Tumour microenvironment (TME) contributes significantly towards potentiating the stemness and metastasis properties of cancer cells. IL6-Stat3 is one of the important cell signaling pathways in mediating the communication between tumour and immune cells. Here, we have systematically developed a novel anti-CD44 antibody-mediated liposomal nanoparticle delivery system loaded with anti-IL6R antibody, which could specifically target the TME of CD44+ breast cancer cells in different mouse models for triple negative and luminal breast cancer. This nanoparticle had an enhanced and specific tumour targeting efficacy with dramatic anti-tumour metastasis effects in syngeneic BALB/c mice bearing 4T1 cells as was in the syngeneic MMTV-PyMT mice. It inhibited IL6R-Stat3 signaling and moderated the TME, characterized by the reduced expression of genes encoding Stat3, Sox2, VEGFA, MMP-9 and CD206 in the breast tissues. Furthermore, this nanoparticle reduced the subgroups of Sox2+ and CD206+ cells in the lung metastatic foci, demonstrating its inhibitory effect on the lung metastatic niche for breast cancer stem cells. Taken together, the CD44 targeted liposomal nanoparticles encapsulating anti-IL6R antibody achieved a significant effect to inhibit the metastasis of breast cancer in different molecular subtypes of breast cancer mouse models. Our results shed light on the application of nanoparticle mediated cancer immune-therapy through targeting TME. PMID:28255366

  6. Macrolide antibiotics promote the LPS-induced upregulation of prostaglandin E receptor EP2 and thus attenuate macrolide suppression of IL-6 production.

    Science.gov (United States)

    Sato, Yoshinori; Kaneko, Kenichi; Inoue, Matsuhisa

    2007-03-01

    We studied the influence of the inhibitory effect of clarithromycin (CAM) and erythromycin (EM) on the production of macrophage inflammatory protein (MIP)-2, interleukin-6 (IL-6), and prostaglandin E(2) (PGE(2)), as well as PGE(2) receptor (EP(2)) expression, by LPS-stimulated RAW264.7 cells. Production of IL-6 was significantly decreased by treatment with CAM or EM in a dose-dependent manner, but the inhibitory effect of CAM was significantly weaker than that of EM. In contrast, the production of MIP-2 and PGE(2) was inhibited to the same extent by CAM and EM. LPS induced the expression of EP(2) mRNA and its expression was promoted further by treatment with CAM or EM. In particular, CAM significantly upregulated EP(2) mRNA expression compared with that after stimulation by LPS alone. After treatment with a nonselective cyclooxygenase (COX) inhibitor (indomethacin), a selective COX-2 inhibitor (NS398), or an EP(2)/EP(4) receptor antagonist (AH6809), the inhibitory effect of CAM and EM on LPS-induced IL-6 production was equalized. These results indicate that macrolide antibiotics upregulate the expression of EP(2), which then attenuates the suppressive effect on IL-6 production of these antibiotics, suggesting that these drugs have a variable anti-inflammatory effect that could influence host defenses.

  7. Statins potently reduce the cytokine-mediated IL-6 release in SMC/MNC cocultures.

    Science.gov (United States)

    Loppnow, Harald; Zhang, Li; Buerke, Michael; Lautenschläger, Michael; Chen, Li; Frister, Adrian; Schlitt, Axel; Luther, Tanja; Song, Nan; Hofmann, Britt; Rose-John, Stefan; Silber, Rolf-Edgar; Müller-Werdan, Ursula; Werdan, Karl

    2011-04-01

    Inflammatory pathways are involved in the development of atherosclerosis. Interaction of vessel wall cells and invading monocytes by cytokines may trigger local inflammatory processes. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are standard medications used in cardiovascular diseases. They are thought to have anti-inflammatory capacities, in addition to their lipid-lowering effects. We investigated the anti-inflammatory effect of statins in the cytokine-mediated-interaction-model of human vascular smooth muscle cells (SMC) and human mononuclear cells (MNC). In this atherosclerosis-related inflammatory model LPS (lipopolysaccharide, endotoxin), as well as high mobility group box 1 stimulation resulted in synergistic (i.e. over-additive) IL-6 (interleukin-6) production as measured in ELISA. Recombinant IL-1, tumour necrosis factor-α and IL-6 mediated the synergistic IL-6 production. The standard anti-inflammatory drugs aspirin and indomethacin (Indo) reduced the synergistic IL-6 production by 60%. Simvastatin, atorvastatin, fluvastatin or pravastatin reduced the IL-6 production by 53%, 50%, 64% and 60%, respectively. The inhibition by the statins was dose dependent. Combination of statins with aspirin and/or Indo resulted in complete inhibition of the synergistic IL-6 production. The same inhibitors blocked STAT3 phosphorylation, providing evidence for an autocrine role of IL-6 in the synergism. MNC from volunteers after 5 day aspirin or simvastatin administration showed no decreased IL-6 production, probably due to drug removal during MNC isolation. Taken together, the data show that anti-inflammatory functions (here shown for statins) can be sensitively and reproducibly determined in this novel SMC/MNC coculture model. These data implicate that statins have the capacity to affect atherosclerosis by regulating cytokine-mediated innate inflammatory pathways in the vessel wall.

  8. RETRACTED: Blockade of TNF-α signaling suppresses the AREG-mediated IL-6 and IL-8 cytokines secretion induced by anti-Ro/SSA autoantibodies.

    Science.gov (United States)

    Sisto, Margherita; Lisi, Sabrina; Lofrumento, Dario Domenico; Cucci, Liana; Mitolo, Vincenzo; D'Amore, Massimo

    2010-09-20

    The aim of this study was to analyze the Furin-TNF-α-converting enzyme (TACE)-amphiregulin (AREG)-IL-6/IL-8 secretion pathway in non-neoplastic human salivary gland epithelial cells (SGECs) stimulated with anti-Ro/SSA autoantibodies (Abs). We examined whether anti-Ro/SSA Abs-mediated TACE activation is responsible for AREG activation. As recent studies have demonstrated that AREG could induce proinflammatory cytokines secretion in epithelial cells, we discuss how TACE-mediated AREG shedding, caused by anti-Ro/SSA Abs treatment, could have a critical role in TNF-α-induced IL-6 and IL-8 secretion by SGEC. Furthermore, the effects of TNF-α blockade on AREG expression and TNF-α-AREG-mediated IL-6 and IL-8 secretion were evaluated. We have discovered that the upregulation of AREG occurs through TNF-α produced after anti-Ro/SSA Abs uptake via Fcγ receptors. Biological drug adalimumab and the gene silencing technique were used to study the AREG-IL-6/IL-8 secretion pathway, demonstrating that (i) adalimumab-mediated TNF-α blocking and TNF-α gene silencing provok