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Sample records for htlv-1 tax-induced nfkappab

  1. HTLV-1 Tax-induced NFκB activation is independent of Lys-63-linked-type polyubiquitination

    International Nuclear Information System (INIS)

    Gohda, Jin; Irisawa, Masato; Tanaka, Yuetsu; Sato, Shintaro; Ohtani, Kiyoshi; Fujisawa, Jun-ichi; Inoue, Jun-ichiro

    2007-01-01

    Human T-cell leukemia virus type 1 (HTLV-1) Tax-induced activation of nuclear factor-κB (NFκB) is thought to play a critical role in T-cell transformation and onset of adult T-cell leukemia. However, the molecular mechanism of the Tax-induced NFκB activation remains unknown. One of the mitogen-activated protein kinase kinase kinses (MAP3Ks) members, TAK1, plays a critical role in cytokine-induced activation of NFκB, which involves lysine 63-linked (K63) polyubiquitination of NEMO, a noncatalytic subunit of the IκB kinase complex. Here we show that Tax induces K63 polyubiquitination of NEMO. However, TAK1 is dispensable for Tax-induced NFκB activation, and deubiquitination of the K63 polyubiquitin chain failed to block Tax-induced NFκB activation. In addition, silencing of other MAP3Ks, including MEKK1, MEKK3, NIK, and TPL-2, did not affect Tax-induced NFκB activation. These results strongly suggest that unlike cytokine signaling, Tax-induced NFκB activation does not involve K63 polyubiquitination-mediated MAP3K activation

  2. Two specific drugs, BMS-345541 and purvalanol A induce apoptosis of HTLV-1 infected cells through inhibition of the NF-kappaB and cell cycle pathways.

    Science.gov (United States)

    Agbottah, Emmanuel; Yeh, Wen-I; Berro, Reem; Klase, Zachary; Pedati, Caitlin; Kehn-Hall, Kyleen; Wu, Weilin; Kashanchi, Fatah

    2008-06-10

    Human T-cell leukemia virus type-1 (HTLV-1) induces adult T-cell leukemia/lymphoma (ATL/L), a fatal lymphoproliferative disorder, and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a chronic progressive disease of the central nervous system after a long period of latent infection. Although the mechanism of transformation and leukemogenesis is not fully elucidated, there is evidence to suggest that the viral oncoprotein Tax plays a crucial role in these processes through the regulation of several pathways including NF-kappaB and the cell cycle pathways. The observation that NF-kappaB, which is strongly induced by Tax, is indispensable for the maintenance of the malignant phenotype of HTLV-1 by regulating the expression of various genes involved in cell cycle regulation and inhibition of apoptosis provides a possible molecular target for these infected cells. To develop potential new therapeutic strategies for HTLV-1 infected cells, in this present study, we initially screened a battery of NF-kappaB and CDK inhibitors (total of 35 compounds) to examine their effects on the growth and survival of infected T-cell lines. Two drugs namely BMS-345541 and Purvalanol A exhibited higher levels of growth inhibition and apoptosis in infected cell as compared to uninfected cells. BMS-345541 inhibited IKKbeta kinase activity from HTLV-1 infected cells with an IC50 (the 50% of inhibitory concentration) value of 50 nM compared to 500 nM from control cells as measured by in vitro kinase assays. The effects of Purvalanol A were associated with suppression of CDK2/cyclin E complex activity as previously shown by us. Combination of both BMS-345541 and Purvalanol A showed a reduced level of HTLV-1 p19 Gag production in cell culture. The apparent apoptosis in these infected cells were associated with increased caspase-3 activity and PARP cleavage. The potent and selective apoptotic effects of these drugs suggest that both BMS-345541 and Purvalanol A, which target

  3. Two specific drugs, BMS-345541 and purvalanol A induce apoptosis of HTLV-1 infected cells through inhibition of the NF-kappaB and cell cycle pathways

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    Wu Weilin

    2008-06-01

    Full Text Available Abstract Human T-cell leukemia virus type-1 (HTLV-1 induces adult T-cell leukemia/lymphoma (ATL/L, a fatal lymphoproliferative disorder, and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP, a chronic progressive disease of the central nervous system after a long period of latent infection. Although the mechanism of transformation and leukemogenesis is not fully elucidated, there is evidence to suggest that the viral oncoprotein Tax plays a crucial role in these processes through the regulation of several pathways including NF-κB and the cell cycle pathways. The observation that NF-κB, which is strongly induced by Tax, is indispensable for the maintenance of the malignant phenotype of HTLV-1 by regulating the expression of various genes involved in cell cycle regulation and inhibition of apoptosis provides a possible molecular target for these infected cells. To develop potential new therapeutic strategies for HTLV-1 infected cells, in this present study, we initially screened a battery of NF-κB and CDK inhibitors (total of 35 compounds to examine their effects on the growth and survival of infected T-cell lines. Two drugs namely BMS-345541 and Purvalanol A exhibited higher levels of growth inhibition and apoptosis in infected cell as compared to uninfected cells. BMS-345541 inhibited IKKβ kinase activity from HTLV-1 infected cells with an IC50 (the 50% of inhibitory concentration value of 50 nM compared to 500 nM from control cells as measured by in vitro kinase assays. The effects of Purvalanol A were associated with suppression of CDK2/cyclin E complex activity as previously shown by us. Combination of both BMS-345541 and Purvalanol A showed a reduced level of HTLV-1 p19 Gag production in cell culture. The apparent apoptosis in these infected cells were associated with increased caspase-3 activity and PARP cleavage. The potent and selective apoptotic effects of these drugs suggest that both BMS-345541 and Purvalanol A

  4. HTLV-1 Tax upregulates early growth response protein 1 through nuclear factor-κB signaling.

    Science.gov (United States)

    Huang, Qingsong; Niu, Zhiguo; Han, Jingxian; Liu, Xihong; Lv, Zhuangwei; Li, Huanhuan; Yuan, Lixiang; Li, Xiangping; Sun, Shuming; Wang, Hui; Huang, Xinxiang

    2017-08-01

    Human T cell leukemia virus type 1 (HTLV-1) is a complex retrovirus that causes adult T cell leukemia (ATL) in susceptible individuals. The HTLV-1-encoded oncoprotein Tax induces persistent activation of the nuclear factor-κB (NF-κB) pathway. Early growth response protein 1 (EGR1) is overexpressed in HTLV-1-infected T cell lines and ATL cells. Here, we showed that both Tax expression and HTLV-1 infection promoted EGR1 overexpression. Loss of the NF-κB binding site in the EGR1 promotor or inhibition of NF-κB activation reduced Tax-induced EGR1 upregulation. Tax mutants unable to activate NF-κB induced only slight EGR1 upregulation as compared with wild-type Tax, confirming NF-κB pathway involvement in EGR1 regulation. Tax also directly interacted with the EGR1 protein and increased endogenous EGR1 stability. Elevated EGR1 in turn promoted p65 nuclear translocation and increased NF-κB activation. These results demonstrate a positive feedback loop between EGR1 expression and NF-κB activation in HTLV-1-infected and Tax-expressing cells. Both NF-κB activation and Tax-induced EGR1 stability upregulated EGR1, which in turn enhanced constitutive NF-κB activation and facilitated ATL progression in HTLV-1-infected cells. These findings suggest EGR1 may be an effective anti-ATL therapeutic target.

  5. HTLV-1, Immune Response and Autoimmunity

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    Juarez A S Quaresma

    2015-12-01

    Full Text Available Human T-lymphotropic virus type-1 (HTLV-1 infection is associated with adult T-cell leukemia/lymphoma (ATL. Tropical spastic paraparesis/HTLV-1-associated myelopathy (PET/HAM is involved in the development of autoimmune diseases including Rheumatoid Arthritis (RA, Systemic Lupus Erythematosus (SLE, and Sjögren’s Syndrome (SS. The development of HTLV-1-driven autoimmunity is hypothesized to rely on molecular mimicry, because virus-like particles can trigger an inflammatory response. However, HTLV-1 modifies the behavior of CD4+ T cells on infection and alters their cytokine production. A previous study showed that in patients infected with HTLV-1, the activity of regulatory CD4+ T cells and their consequent expression of inflammatory and anti-inflammatory cytokines are altered. In this review, we discuss the mechanisms underlying changes in cytokine release leading to the loss of tolerance and development of autoimmunity.

  6. [HTLV-1 in a Mapuche population].

    Science.gov (United States)

    Inostroza, J; Díaz, P; Saunier, C

    1990-12-01

    The seroprevalence of HTLV-1 in 405 serum samples from South American Indians, Mapuches, from the IXth region of Chile was investigated using enzyme linked immunosorbent assay (ELISA). Six samples were positive and only 3 of them were also positive by western blot and radio immuno precipitation assay. This corresponds to a seroprevalence of 0.74% for HTLV-1 in healthy Mapuches, which differs from that observed in other populations throughout the world. Additional studies are necessary to evaluate the real magnitudes of HTLV-1 infection in Chile.

  7. Interaction of HTLV-1 Tax protein with calreticulin: implications for Tax nuclear export and secretion.

    Science.gov (United States)

    Alefantis, Timothy; Flaig, Katherine E; Wigdahl, Brian; Jain, Pooja

    2007-05-01

    Human T cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 transcriptional transactivator protein Tax plays an integral role in virus replication and disease progression. Traditionally, Tax is described as a nuclear protein where it performs its primary role as a transcriptional transactivator. However, recent studies have clearly shown that Tax can also be localized to the cytoplasm where it has been shown to interact with a number of host transcription factors most notably NF-kappaB, constitutive expression of which is directly related to the T cell transforming properties of Tax in ATL patients. The presence of a functional nuclear export signal (NES) within Tax and the secretion of full-length Tax have also been demonstrated previously. Additionally, release of Tax from HTLV-1-infected cells and the presence of cell-free Tax was demonstrated in the CSF of HAM/TSP patients suggesting that the progression to HAM/TSP might be mediated by the ability of Tax to function as an extracellular cytokine. Therefore, in both ATL and HAM/TSP Tax nuclear export and nucleocytoplasmic shuttling may play a critical role, the mechanism of which remains unknown. In this study, we have demonstrated that the calcium binding protein calreticulin interacts with Tax by co-immunoprecipitation. This interaction was found to localize to a region at or near the nuclear membrane. In addition, differential expression of calreticulin was demonstrated in various cell types that correlated with their ability to retain cytoplasmic Tax, particularly in astrocytes. Finally, a comparison of a number of HTLV-1-infected T cell lines to non-infected T cells revealed higher expression of calreticulin in infected cells implicating a direct role for this protein in HTLV-1 infection.

  8. Animal Models Utilized in HTLV-1 Research

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    Amanda R. Panfil

    2013-01-01

    Full Text Available Since the isolation and discovery of human T-cell leukemia virus type 1 (HTLV-1 over 30 years ago, researchers have utilized animal models to study HTLV-1 transmission, viral persistence, virus-elicited immune responses, and HTLV-1-associated disease development (ATL, HAM/TSP. Non-human primates, rabbits, rats, and mice have all been used to help understand HTLV-1 biology and disease progression. Non-human primates offer a model system that is phylogenetically similar to humans for examining viral persistence. Viral transmission, persistence, and immune responses have been widely studied using New Zealand White rabbits. The advent of molecular clones of HTLV-1 has offered the opportunity to assess the importance of various viral genes in rabbits, non-human primates, and mice. Additionally, over-expression of viral genes using transgenic mice has helped uncover the importance of Tax and Hbz in the induction of lymphoma and other lymphocyte-mediated diseases. HTLV-1 inoculation of certain strains of rats results in histopathological features and clinical symptoms similar to that of humans with HAM/TSP. Transplantation of certain types of ATL cell lines in immunocompromised mice results in lymphoma. Recently, “humanized” mice have been used to model ATL development for the first time. Not all HTLV-1 animal models develop disease and those that do vary in consistency depending on the type of monkey, strain of rat, or even type of ATL cell line used. However, the progress made using animal models cannot be understated as it has led to insights into the mechanisms regulating viral replication, viral persistence, disease development, and, most importantly, model systems to test disease treatments.

  9. HIV/HTLV-1 co-infection

    African Journals Online (AJOL)

    result of a lymphoproliferative disorder. In the context of HIV co-infection, lympho- cytosis has been described during early sero- conversion associated with CMV, as well as in HIV/HTLV-1 co-infection where CD4+ lymphocytosis can be caused by both a reactive or clonal expansion. Consequently, patients with untreated ...

  10. Suppression of HTLV-1 transcription by SIRT1 deacetylase

    OpenAIRE

    Tang, HMV; Jin, D; Gao, W; Chan, CP; Iha, H; Yuen, KS

    2015-01-01

    Infection with HTLV-1 causes adult T-cell leukemia and tropical spastic paraparesis in different subsets of infected people. Treatments for HTLV-1-associated diseases are unspecific and unsatisfactory. Prophylactic measures have not been developed. Although HTLV-1 pathogenesis involves multiple stages and factors, high proviral load has been singled out as a major risk factor which predicts disease. HTLV-1 encodes Tax transactivator that potently activates transcription from viral long termin...

  11. HTLV-1 HBZ Viral Protein: A Key Player in HTLV-1 Mediated Diseases

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    Marco Baratella

    2017-12-01

    Full Text Available Human T cell leukemia virus type 1 (HTLV-1 is an oncogenic human retrovirus that has infected 10–15 million people worldwide. After a long latency, 3–5% of infected individuals will develop either a severe malignancy of CD4+ T cells, known as Adult T-cell Leukemia (ATL or a chronic and progressive inflammatory disease of the nervous system designated Tropical Spastic Paraparesis/HTLV-1-Associated Myelopathy (HAM/TSP. The precise mechanism behind HTLV-1 pathogenesis still remains elusive. Two viral regulatory proteins, Tax-1 and HTLV-1 bZIP factor (HBZ are thought to play a critical role in HTLV-1-associated diseases. Tax-1 is mainly involved in the onset of neoplastic transformation and in elicitation of the host’s inflammatory responses; its expression may be lost during cell clonal proliferation and oncogenesis. Conversely, HBZ remains constantly expressed in all patients with ATL, playing a role in the proliferation and maintenance of leukemic cells. Recent studies have shown that the subcellular distribution of HBZ protein differs in the two pathologies: it is nuclear with a speckled-like pattern in leukemic cells and is cytoplasmic in cells from HAM/TSP patients. Thus, HBZ expression and distribution could be critical in the progression of HTLV-1 infection versus the leukemic state or the inflammatory disease. Here, we reviewed recent findings on the role of HBZ in HTLV-1 related diseases, highlighting the new perspectives open by the possibility of studying the physiologic expression of endogenous protein in primary infected cells.

  12. HTLV-1 HBZ Viral Protein: A Key Player in HTLV-1 Mediated Diseases.

    Science.gov (United States)

    Baratella, Marco; Forlani, Greta; Accolla, Roberto S

    2017-01-01

    Human T cell leukemia virus type 1 (HTLV-1) is an oncogenic human retrovirus that has infected 10-15 million people worldwide. After a long latency, 3-5% of infected individuals will develop either a severe malignancy of CD4+ T cells, known as Adult T-cell Leukemia (ATL) or a chronic and progressive inflammatory disease of the nervous system designated Tropical Spastic Paraparesis/HTLV-1-Associated Myelopathy (HAM/TSP). The precise mechanism behind HTLV-1 pathogenesis still remains elusive. Two viral regulatory proteins, Tax-1 and HTLV-1 bZIP factor (HBZ) are thought to play a critical role in HTLV-1-associated diseases. Tax-1 is mainly involved in the onset of neoplastic transformation and in elicitation of the host's inflammatory responses; its expression may be lost during cell clonal proliferation and oncogenesis. Conversely, HBZ remains constantly expressed in all patients with ATL, playing a role in the proliferation and maintenance of leukemic cells. Recent studies have shown that the subcellular distribution of HBZ protein differs in the two pathologies: it is nuclear with a speckled-like pattern in leukemic cells and is cytoplasmic in cells from HAM/TSP patients. Thus, HBZ expression and distribution could be critical in the progression of HTLV-1 infection versus the leukemic state or the inflammatory disease. Here, we reviewed recent findings on the role of HBZ in HTLV-1 related diseases, highlighting the new perspectives open by the possibility of studying the physiologic expression of endogenous protein in primary infected cells.

  13. HTLV-1 Tax-mediated TAK1 activation involves TAB2 adapter protein

    International Nuclear Information System (INIS)

    Yu Qingsheng; Minoda, Yasumasa; Yoshida, Ryoko; Yoshida, Hideyuki; Iha, Hidekatsu; Kobayashi, Takashi; Yoshimura, Akihiko; Takaesu, Giichi

    2008-01-01

    Human T cell leukemia virus type 1 (HTLV-1) Tax is an oncoprotein that plays a crucial role in the proliferation and transformation of HTLV-1-infected T lymphocytes. It has recently been reported that Tax activates a MAPKKK family, TAK1. However, the molecular mechanism of Tax-mediated TAK1 activation is not well understood. In this report, we investigated the role of TAK1-binding protein 2 (TAB2) in Tax-mediated TAK1 activation. We found that TAB2 physically interacts with Tax and augments Tax-induced NF-κB activity. Tax and TAB2 cooperatively activate TAK1 when they are coexpressed. Furthermore, TAK1 activation by Tax requires TAB2 binding as well as ubiquitination of Tax. We also found that the overexpression of TRAF2, 5, or 6 strongly induces Tax ubiquitination. These results suggest that TAB2 may be critically involved in Tax-mediated activation of TAK1 and that NF-κB-activating TRAF family proteins are potential cellular E3 ubiquitin ligases toward Tax

  14. Spontaneous neutrophil activation in HTLV-1 infected patients

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    Jaqueline B. Guerreiro

    Full Text Available Human T cell lymphotropic Virus type-1 (HTLV-1 induces lymphocyte activation and proliferation, but little is known about the innate immune response due to HTLV-1 infection. We evaluated the percentage of neutrophils that metabolize Nitroblue tetrazolium (NBT to formazan in HTLV-1 infected subjects and the association between neutrophil activation and IFN-gamma and TNF-alpha levels. Blood was collected from 35 HTLV-1 carriers, from 8 patients with HAM/TSP (HTLV-1- associated myelopathy; 22 healthy individuals were evaluated for spontaneous and lipopolysaccharide (LPS-stimulated neutrophil activity (reduction of NBT to formazan. The production of IFN-gamma and TNF-alpha by unstimulated mononuclear cells was determined by ELISA. Spontaneous NBT levels, as well as spontaneous IFN-gamma and TNF-alpha production, were significantly higher (p<0.001 in HTLV-1 infected subjects than in healthy individuals. A trend towards a positive correlation was noted, with increasing percentage of NBT positive neutrophils and levels of IFN-gamma. The high IFN-gamma producing HTLV-1 patient group had significantly greater NBT than healthy controls, 43±24% and 17±4.8% respectively (p< 0.001, while no significant difference was observed between healthy controls and the low IFN-gamma-producing HTLV-1 patient group (30±20%. Spontaneous neutrophil activation is another marker of immune perturbation resulting from HTLV-1 infection. In vivo activation of neutrophils observed in HTLV-1 infected subjects is likely to be the same process that causes spontaneous IFN-gamma production, or it may partially result from direct IFN-gamma stimulation.

  15. PDZ binding motif of HTLV-1 Tax promotes virus-mediated T-cell proliferation in vitro and persistence in vivo.

    Science.gov (United States)

    Xie, Li; Yamamoto, Brenda; Haoudi, Abdelali; Semmes, O John; Green, Patrick L

    2006-03-01

    HTLV-1 cellular transformation and disease induction is dependent on expression of the viral Tax oncoprotein. PDZ is a modular protein interaction domain used in organizing signaling complexes in eukaryotic cells through recognition of a specific binding motif in partner proteins. Tax-1, but not Tax-2, contains a PDZ-binding domain motif (PBM) that promotes the interaction with several cellular PDZ proteins. Herein, we investigate the contribution of the Tax-1 PBM in HTLV-induced proliferation and immortalization of primary T cells in vitro and viral survival in an infectious rabbit animal model. We generated several HTLV-1 and HTLV-2 Tax viral mutants, including HTLV-1deltaPBM, HTLV-2+C22(+PBM), and HTLV-2+ C18(deltaPBM). All Tax mutants maintained the ability to significantly activate the CREB/ATF or NFkappaB signaling pathways. Microtiter proliferation assays revealed that the Tax-1 PBM significantly increases both HTLV-1- and HTLV-2-induced primary T-cell proliferation. In addition, Tax-1 PBM was responsible for the micronuclei induction activity of Tax-1 relative to that of Tax-2. Viral infection and persistence were severely attenuated in rabbits inoculated with HTLV-1deltaPBM. Our results provide the first direct evidence suggesting that PBM-mediated associations between Tax-1 and cellular proteins play a key role in HTLV-induced cell proliferation and genetic instability in vitro and facilitate viral persistence in vivo.

  16. HTLV-1 tax stabilizes MCL-1 via TRAF6-dependent K63-linked polyubiquitination to promote cell survival and transformation.

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    Young Bong Choi

    2014-10-01

    Full Text Available The human T-cell leukemia virus type 1 (HTLV-1 Tax protein hijacks the host ubiquitin machinery to activate IκB kinases (IKKs and NF-κB and promote cell survival; however, the key ubiquitinated factors downstream of Tax involved in cell transformation are unknown. Using mass spectrometry, we undertook an unbiased proteome-wide quantitative survey of cellular proteins modified by ubiquitin in the presence of Tax or a Tax mutant impaired in IKK activation. Tax induced the ubiquitination of 22 cellular proteins, including the anti-apoptotic BCL-2 family member MCL-1, in an IKK-dependent manner. Tax was found to promote the nondegradative lysine 63 (K63-linked polyubiquitination of MCL-1 that was dependent on the E3 ubiquitin ligase TRAF6 and the IKK complex. Tax interacted with and activated TRAF6, and triggered its mitochondrial localization, where it conjugated four carboxyl-terminal lysine residues of MCL-1 with K63-linked polyubiquitin chains, which stabilized and protected MCL-1 from genotoxic stress-induced degradation. TRAF6 and MCL-1 played essential roles in the survival of HTLV-1 transformed cells and the immortalization of primary T cells by HTLV-1. Therefore, K63-linked polyubiquitination represents a novel regulatory mechanism controlling MCL-1 stability that has been usurped by a viral oncogene to precipitate cell survival and transformation.

  17. HTLV-1 Tax Stabilizes MCL-1 via TRAF6-Dependent K63-Linked Polyubiquitination to Promote Cell Survival and Transformation

    Science.gov (United States)

    Choi, Young Bong; Harhaj, Edward William

    2014-01-01

    The human T-cell leukemia virus type 1 (HTLV-1) Tax protein hijacks the host ubiquitin machinery to activate IκB kinases (IKKs) and NF-κB and promote cell survival; however, the key ubiquitinated factors downstream of Tax involved in cell transformation are unknown. Using mass spectrometry, we undertook an unbiased proteome-wide quantitative survey of cellular proteins modified by ubiquitin in the presence of Tax or a Tax mutant impaired in IKK activation. Tax induced the ubiquitination of 22 cellular proteins, including the anti-apoptotic BCL-2 family member MCL-1, in an IKK-dependent manner. Tax was found to promote the nondegradative lysine 63 (K63)-linked polyubiquitination of MCL-1 that was dependent on the E3 ubiquitin ligase TRAF6 and the IKK complex. Tax interacted with and activated TRAF6, and triggered its mitochondrial localization, where it conjugated four carboxyl-terminal lysine residues of MCL-1 with K63-linked polyubiquitin chains, which stabilized and protected MCL-1 from genotoxic stress-induced degradation. TRAF6 and MCL-1 played essential roles in the survival of HTLV-1 transformed cells and the immortalization of primary T cells by HTLV-1. Therefore, K63-linked polyubiquitination represents a novel regulatory mechanism controlling MCL-1 stability that has been usurped by a viral oncogene to precipitate cell survival and transformation. PMID:25340740

  18. Transcriptional and Epigenetic Regulatory Mechanisms Affecting HTLV-1 Provirus

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    Paola Miyazato

    2016-06-01

    Full Text Available Human T-cell leukemia virus type 1 (HTLV-1 is a retrovirus associated with human diseases, such as adult T-cell leukemia (ATL and HTLV-1-associated myelopathy/Tropic spastic paraparesis (HAM/TSP. As a retrovirus, its life cycle includes a step where HTLV-1 is integrated into the host genomic DNA and forms proviral DNA. In the chronic phase of the infection, HTLV‑1 is known to proliferate as a provirus via the mitotic division of the infected host cells. There are generally tens of thousands of infected clones within an infected individual. They exist not only in peripheral blood, but also in various lymphoid organs. Viral proteins encoded in HTLV-1 genome play a role in the proliferation and survival of the infected cells. As is the case with other chronic viral infections, HTLV-1 gene expression induces the activation of the host immunity against the virus. Thus, the transcription from HTLV-1 provirus needs to be controlled in order to evade the host immune surveillance. There should be a dynamic and complex regulation in vivo, where an equilibrium between viral antigen expression and host immune surveillance is achieved. The mechanisms regulating viral gene expression from the provirus are a key to understanding the persistent/latent infection with HTLV-1 and its pathogenesis. In this article, we would like to review our current understanding on this topic.

  19. The HBZ gene, a key player in HTLV-1 pathogenesis

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    Green Patrick L

    2009-08-01

    Full Text Available Abstract Human T-cell leukemia virus type 1 (HTLV-1 causes adult T-cell leukemia/lymphoma (ATL and is also associated with a variety of lymphocyte-mediated diseases. The HTLV-1 basic leucine zipper (HBZ gene, found to be consistently expressed in ATL, has recently been the subject of intensive research efforts. In this review, we summarize recent findings about HBZ and discuss its roles and functions not only in the virus life cycle, but also in HTLV-1 disease pathogenesis.

  20. Epidemiological Aspects and World Distribution of HTLV-1 Infection

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    Antoine eGessain

    2012-11-01

    Full Text Available The human T-cell leukemia virus type 1 (HTLV-1, identified as the first human oncogenic retrovirus 30 years ago, is not an ubiquitous virus. HTLV-1 is present throughout the world, with clusters of high endemicity located often nearby areas where the virus is nearly absent. The main HTLV-1 highly endemic regions are the Southwestern part of Japan, sub-Saharan Africa and South America, the Caribbean area and foci in Middle East and Australo-Melanesia. The origin of this puzzling geographical or rather ethnic repartition is probably linked to a founder effect in some groups with the persistence of a high viral transmission rate. Despite different socio-economic and cultural environments, the HTLV-1 prevalence increases gradually with age, especially among women in all highly endemic areas. The three modes of HTLV-1 transmission are mother to child, sexual transmission and transmission with contaminated blood products. Twenty years ago, de Thé and Bomford estimated the total number of HTLV-1 carriers to be 10-20 millions people. At that time, large regions had not been investigated, few population-based studies were available and the assays used for HTLV-1 serology were not enough specific. Despite the fact that there is still a lot of data lacking in large areas of the world and that most of the HTLV-1 studies concern only blood donors, pregnant women or different selected patients or high-risk groups, we shall try based on the most recent data, to revisit the world distribution and the estimates of the number of HTLV-1 infected persons.Our best estimates range from 5-10 millions HTLV-1 infected individuals. However, these results were based on approximately 1.5 billion of individuals originating from known endemic areas with reliable available epidemiological data. Correct estimates in other highly populated regions such as China, India, the Maghreb and East Africa is currently not possible, thus, the current number of HTLV-1 carriers is very

  1. HTLV-1 Tax Functions as a Ubiquitin E3 Ligase for Direct IKK Activation via Synthesis of Mixed-Linkage Polyubiquitin Chains.

    Science.gov (United States)

    Wang, Chong; Long, Wenying; Peng, Chao; Hu, Lin; Zhang, Qiong; Wu, Ailing; Zhang, Xiaoqing; Duan, Xiaotao; Wong, Catherine C L; Tanaka, Yuetsu; Xia, Zongping

    2016-04-01

    The HTLV-1 oncoprotein Tax plays a key role in CD4+ T cell transformation by promoting cell proliferation and survival, mainly through permanent activation of the NK-κB pathway and induction of many NF-κB target genes. Elucidating the underlying molecular mechanism is therefore critical in understanding HTLV-1-mediated transformation. Current studies have suggested multiple but controversial mechanisms regarding Tax-induced IKK activation mainly due to blending of primary Tax-induced IKK activation events and secondary IKK activation events induced by cytokines secreted by the primary Tax-induced IKK-NF-κB activation events. We reconstituted Tax-stimulated IKK activation in a cell-free system to dissect the essential cellular components for primary IKK activation by Tax and studied the underlying biochemical mechanism. We found that Tax is a putative E3 ubiquitin ligase, which, together with UbcH2, UhcH5c, or UbcH7, catalyzes the assembly of free mixed-linkage polyubiquitin chains. These free mixed-linkage polyubiquitin chains are then responsible for direct IKK activation by binding to the NEMO subunit of IKK. Our studies revealed the biochemical function of Tax in the process of IKK activation, which utilizes the minimal cellular ubiquitination components for NF-κB activation.

  2. HTLV-1 Tax Functions as a Ubiquitin E3 Ligase for Direct IKK Activation via Synthesis of Mixed-Linkage Polyubiquitin Chains.

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    Chong Wang

    2016-04-01

    Full Text Available The HTLV-1 oncoprotein Tax plays a key role in CD4+ T cell transformation by promoting cell proliferation and survival, mainly through permanent activation of the NK-κB pathway and induction of many NF-κB target genes. Elucidating the underlying molecular mechanism is therefore critical in understanding HTLV-1-mediated transformation. Current studies have suggested multiple but controversial mechanisms regarding Tax-induced IKK activation mainly due to blending of primary Tax-induced IKK activation events and secondary IKK activation events induced by cytokines secreted by the primary Tax-induced IKK-NF-κB activation events. We reconstituted Tax-stimulated IKK activation in a cell-free system to dissect the essential cellular components for primary IKK activation by Tax and studied the underlying biochemical mechanism. We found that Tax is a putative E3 ubiquitin ligase, which, together with UbcH2, UhcH5c, or UbcH7, catalyzes the assembly of free mixed-linkage polyubiquitin chains. These free mixed-linkage polyubiquitin chains are then responsible for direct IKK activation by binding to the NEMO subunit of IKK. Our studies revealed the biochemical function of Tax in the process of IKK activation, which utilizes the minimal cellular ubiquitination components for NF-κB activation.

  3. HBZ and its roles in HTLV-1 oncogenesis

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    Tiejun eZhao

    2012-07-01

    Full Text Available Human T-cell leukemia virus type 1 (HTLV-1 causes adult T-cell leukemia (ATL. The minus strand of HTLV-1 provirus encodes a bZIP protein donated as HTLV-1 bZIP factor (HBZ. Among the HTLV-1 regulatory and accessory genes, the tax and HBZ genes were thought to play critical roles in oncogenesis. However, HBZ is the only gene that remains intact and is consistently expressed in all ATL cases, while the tax gene is frequently inactivated by epigenetic modifications or deletion of the 5’LTR. HBZ gene promotes the proliferation of ATL cells through its mRNA form. Moreover, HBZ induces T-cell lymphoma and systemic inflammation in vivo. HBZ fulfills its functions mainly through regulating HTLV-1 5’LTR transcription and modulating a variety of cellular signaling pathways which are related with cell growth, immune response and T-cell differentiation. Taken together, the multiple functions of HBZ render its predominant function in leukemogenesis of ATL.

  4. Four regulatory elements in the human c-fos promoter mediate transactivation by HTLV-1 Tax protein.

    Science.gov (United States)

    Alexandre, C; Verrier, B

    1991-04-01

    Expression of the human c-fos proto-oncogene is activated in trans by the Tax protein encoded by human T-cell leukemia virus type-1 (HTLV-1). Indeed, we show here that a HeLa clone stably transfected by Tax expresses Fos at a high level. We also show that multiple elements of the human c-fos promoter, i.e. the v-sis conditioned medium inducible element (SIE), the dyad symmetry element (DSE) necessary for growth factor induction, the octanucleotide direct repeat element (DR), and the cyclic AMP response element (CRE) centred at -60, can all mediate Tax transactivation. In the DSE, the 10bp central core that binds the serum response factor (SRF) is, by itself, sufficient to mediate Tax transactivation. Moreover, a CRE-binding protein is involved in Tax activation through the CRE-60 element. Since Fos is a transregulator of cellular genes, our results suggest that the oncoprotein plays a crucial role in T-cell transformation by HTLV-1 in conjunction with other Tax-inducible genes.

  5. TRANSMISIÓN VERTICAL DE HTLV-1 EN EL PERÚ

    Science.gov (United States)

    Villaverde, Jorge Alarcón; Romaní, Franco Romaní; Torres, Silvia Montano; Zunt, Joseph R.

    2012-01-01

    La infección por el virus linfotrópico humano de células T tipo 1 (HTLV-1) ha sido descrita en muchas áreas del mundo, como en los países del Caribe, Japón, África, Oceanía y en Sudamérica. En la presente revisión definimos la endemicidad del HTLV-1 en el país, planteando cuatro criterios epidemiológicos. Luego discutimos el tema central de la revisión: la transmisión vertical del HTLV-1, que en nuestro país sería uno de los principales mecanismos de transmisión. Dentro del desarrollo de este aspecto en particular, presentamos una estimación de la tasa de transmisión vertical y los factores de riesgo asociados con la transmisión vertical sobre la base de una revisión exhaustiva de estudios nacionales y extranjeros. Con esta revisión pretendemos dar una primera aproximación al estudio de la trasmisión vertical de HTLV-1, un aspecto poco estudiado en nuestro medio. PMID:21537777

  6. HTLV-1 induced molecular mimicry in neurological disease.

    Science.gov (United States)

    Lee, S M; Morcos, Y; Jang, H; Stuart, J M; Levin, M C

    2005-01-01

    As a model for molecular mimicry, we study patients infected with human T-lymphotropic virus type 1 (HTLV-1) who develop a neurological disease called HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a disease with important biological similarities to multiple sclerosis (MS) (Khan et al. 2001; Levin et al. 1998, 2002a; Levin and Jacobson 1997). The study of HAM/TSP, a disease associated with a known environmental agent (HTLV-1), allows for the direct comparison of the infecting agent with host antigens. Neurological disease in HAM/TSP patients is associated with immune responses to HTLV-1-tax (a regulatory and immunodominant protein) and human histocompatibility leukocyte antigen (HLA) DRB1*0101 (Bangham 2000; Jacobson et al. 1990; Jeffery et al. 1999; Lal 1996). Recently, we showed that HAM/TSP patients make antibodies to heterogeneous nuclear ribonuclear protein A1 (hnRNP A1), a neuron-specific autoantigen (Levin et al. 2002a). Monoclonal antibodies to tax cross-reacted with hnRNP A1, indicating molecular mimicry between the two proteins. Infusion of cross-reactive antibodies with an ex vivo system completely inhibited neuronal firing indicative of their pathogenic nature (Kalume et al. 2004; Levin et al. 2002a). These data demonstrate a clear link between chronic viral infection and autoimmune disease of the central nervous system (CNS) in humans and, we believe, in turn will give insight into the pathogenesis of MS.

  7. Characteristic expression of HTLV-1 basic zipper factor (HBZ transcripts in HTLV-1 provirus-positive cells

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    Yamada Yasuaki

    2008-04-01

    Full Text Available Abstract Background HTLV-1 causes adult T-cell leukemia (ATL. Although there have been many studies on the oncogenesis of the viral protein Tax, the precise oncogenic mechanism remains to be elucidated. Recently, a new viral factor, HTLV-1 basic Zip factor (HBZ, encoded from the minus strand mRNA was discovered and the current models of Tax-centered ATL cell pathogenesis are in conflict with this discovery. HBZs consisting of non-spliced and spliced isoforms (HBZ-SI are thought to be implicated in viral replication and T-cell proliferation but there is little evidence on the HBZ expression profile on a large scale. Results To investigate the role of HBZ-SI in HTLV-1 provirus-positive cells, the HBZ-SI and Tax mRNA loads in samples with a mixture of infected and non-infected cells were measured and then adjusted by dividing by the HTLV-I proviral load. We show here that the HBZ-SI mRNA level is 4-fold higher than non-spliced HBZ and is expressed by almost all cells harboring HTLV-1 provirus with variable intensity. The proviral-adjusted HBZ-SI and Tax quantification revealed a characteristic imbalanced expression feature of high HBZ and low Tax expression levels in primary ATL cells or high HBZ and very high Tax levels in HTLV-1-related cell lines (cell lines compared with a standard expression profile of low HBZ and low Tax in infected cells. Interestingly, according to the mutual Tax and HBZ expression status, HTLV-1-related cell lines were subcategorized into two groups, an ATL cell type with high HBZ and low Tax levels and another type with high Tax and either high or low HBZ, which was closely related to its cell origin. Conclusion This is the first comprehensive study to evaluate the mutual expression profile of HBZ and Tax in provirus-positive cells, revealing that there are quantitative and relative characteristic features among infected cells, primary ATL cells, and cell lines.

  8. HTLV-1 Alters T Cells for Viral Persistence and Transmission

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    Azusa Tanaka

    2018-03-01

    Full Text Available Human T-cell leukemia virus type 1 (HTLV-1 was the first retrovirus to be discovered as a causative agent of adult T-cell leukemia-lymphoma (ATL and chronic inflammatory diseases. Two viral factors, Tax and HTLV-1 bZIP factor (HBZ, are thought to be involved in the leukemogenesis of ATL. Tax expression is frequently lost due to DNA methylation in the promoter region, genetic changes to the tax gene, and deletion of the 5′ long terminal repeat (LTR in approximately half of all ATL cases. On the other hand, HBZ is expressed in all ATL cases. HBZ is known to function in both protein form and mRNA form, and both forms play an important role in the oncogenic process of HTLV-1. HBZ protein has a variety of functions, including the suppression of apoptosis, the promotion of proliferation, and the impairment of anti-viral activity, through the interaction with several host cellular proteins including p300/CBP, Foxp3, and Foxo3a. These functions dramatically modify the transcriptional profiling of host T cells. HBZ mRNA also promotes T cell proliferation and viability. HBZ changes infected T cells to CCR4+TIGIT+CD4+ effector/memory T cells. This unique immunophenotype enables T cells to migrate into various organs and tissues and to survive in vivo. In this review, we summarize how HBZ hijacks the transcriptional networks and immune systems of host T cells to contribute to HTLV-1 pathogenesis on the basis of recent new findings about HBZ and tax.

  9. Pulmonary malakoplakia associated with immunodeficiency by HTLV-1 and HIV

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    Manuela Madruga

    2014-08-01

    Full Text Available Malakoplakia is a rare chronic inflammatory disease often confused with neoplasia. In this paper we report two cases of pulmonary Malakoplakia, both with typical clinical diagnosis of tuberculosis and lung cancer. A patient with human T-lymphotropic virus type I (HTLV-1 and diagnosis of adult T-cell leukemia/lymphoma, and another patient with human immunodeficiency virus (HIV, which was treated for tuberculosis, but, after pulmonary lobectomy, was evidenced Rodococosis equi, progressed to death.

  10. HTLV-1 infection is associated with a history of active tuberculosis among family members of HTLV-1-infected patients in Peru.

    Science.gov (United States)

    Verdonck, K; González, E; Schrooten, W; Vanham, G; Gotuzzo, E

    2008-08-01

    The purpose of this study was to assess the association between human T-lymphotropic virus 1 (HTLV-1) and a lifetime history of active tuberculosis (TB) among relatives of HTLV-1-infected patients. We reviewed clinical charts of all relatives of HTLV-1-infected index cases who attended our institute in Lima from 1990-2004. The data of 1233 relatives was analysed; 394 (32.0%) were HTLV-1 positive. Eighty-one subjects (6.6%) had a history of active TB, including 45/394 (11.4%) HTLV-1-positive and 36/839 (4.3%) HTLV-1-negative relatives (Phistory: HTLV-1 infection (adjusted OR 2.5, 95% CI 1.6-3.9), age (adjusted OR 1.3, 95% CI 1.1-1.5 per 10-year age increase) and relation to the index case (adjusted OR 2.6, 95% CI 1.3-5.1, for siblings vs. spouses of index cases). In conclusion, HTLV-1 infection may increase the susceptibility to active TB. In populations where both infections are frequent, such an association could affect the dynamics of TB.

  11. Tax Protein-induced Expression of Antiapoptotic Bfl-1 Protein Contributes to Survival of Human T-cell Leukemia Virus Type 1 (HTLV-1)-infected T-cells*♦

    Science.gov (United States)

    Macaire, Héloïse; Riquet, Aurélien; Moncollin, Vincent; Biémont-Trescol, Marie-Claude; Duc Dodon, Madeleine; Hermine, Olivier; Debaud, Anne-Laure; Mahieux, Renaud; Mesnard, Jean-Michel; Pierre, Marlène; Gazzolo, Louis; Bonnefoy, Nathalie; Valentin, Hélène

    2012-01-01

    Human T lymphotropic virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia/lymphoma (ATLL). ATLL is a severe malignancy with no effective treatment. HTLV-1 regulatory proteins Tax and HTLV-1 basic leucine zipper factor (HBZ) play a major role in ATLL development, by interfering with cellular functions such as CD4+ T-cell survival. In this study, we observed that the expression of Bfl-1, an antiapoptotic protein of the Bcl-2 family, is restricted to HTLV-1-infected T-cell lines and to T-cells expressing both Tax and HBZ proteins. We showed that Tax-induced bfl-1 transcription through the canonical NF-κB pathway. Moreover, we demonstrated that Tax cooperated with c-Jun or JunD, but not JunB, transcription factors of the AP-1 family to stimulate bfl-1 gene activation. By contrast, HBZ inhibited c-Jun-induced bfl-1 gene activation, whereas it increased JunD-induced bfl-1 gene activation. We identified one NF-κB, targeted by RelA, c-Rel, RelB, p105/p50, and p100/p52, and two AP-1, targeted by both c-Jun and JunD, binding sites in the bfl-1 promoter of T-cells expressing both Tax and HBZ. Analyzing the potential role of antiapoptotic Bcl-2 proteins in HTLV-1-infected T-cell survival, we demonstrated that these cells are differentially sensitive to silencing of Bfl-1, Bcl-xL, and Bcl-2. Indeed, both Bfl-1 and Bcl-xL knockdowns decreased the survival of HTLV-1-infected T-cell lines, although no cell death was observed after Bcl-2 knockdown. Furthermore, we demonstrated that Bfl-1 knockdown sensitizes HTLV-1-infected T-cells to ABT-737 or etoposide treatment. Our results directly implicate Bfl-1 and Bcl-xL in HTLV-1-infected T-cell survival and suggest that both Bfl-1 and Bcl-xL represent potential therapeutic targets for ATLL treatment. PMID:22553204

  12. New Insights into HTLV-1 Particle Structure, Assembly, and Gag-Gag Interactions in Living Cells

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    Jolene L. Johnson

    2011-06-01

    Full Text Available Human T-cell leukemia virus type 1 (HTLV-1 has a reputation for being extremely difficult to study in cell culture. The challenges in propagating HTLV-1 has prevented a rigorous analysis of how these viruses replicate in cells, including the detailed steps involved in virus assembly. The details for how retrovirus particle assembly occurs are poorly understood, even for other more tractable retroviral systems. Recent studies on HTLV-1 using state-of-the-art cryo-electron microscopy and fluorescence-based biophysical approaches explored questions related to HTLV-1 particle size, Gag stoichiometry in virions, and Gag-Gag interactions in living cells. These results provided new and exciting insights into fundamental aspects of HTLV-1 particle assembly—which are distinct from those of other retroviruses, including HIV-1. The application of these and other novel biophysical approaches promise to provide exciting new insights into HTLV-1 replication.

  13. Interaction of HTLV-1 Tax protein with the calreticulin: Implications for Tax nuclear export and secretion

    OpenAIRE

    Alefantis, Timothy; Flaig, Katherine E.; Wigdahl, Brian; Jain, Pooja

    2007-01-01

    Human T cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 transcriptional transactivator protein Tax plays an integral role in virus replication and disease progression. Traditionally, Tax is described as a nuclear protein where it performs its primary role as a transcriptional transactivator. However, recent studies have clearly shown that Tax can also be localized to t...

  14. HTLV-1 tax specific CD8+ T cells express low levels of Tim-3 in HTLV-1 infection: implications for progression to neurological complications.

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    Lishomwa C Ndhlovu

    2011-04-01

    Full Text Available The T cell immunoglobulin mucin 3 (Tim-3 receptor is highly expressed on HIV-1-specific T cells, rendering them partially "exhausted" and unable to contribute to the effective immune mediated control of viral replication. To elucidate novel mechanisms contributing to the HTLV-1 neurological complex and its classic neurological presentation called HAM/TSP (HTLV-1 associated myelopathy/tropical spastic paraparesis, we investigated the expression of the Tim-3 receptor on CD8(+ T cells from a cohort of HTLV-1 seropositive asymptomatic and symptomatic patients. Patients diagnosed with HAM/TSP down-regulated Tim-3 expression on both CD8(+ and CD4(+ T cells compared to asymptomatic patients and HTLV-1 seronegative controls. HTLV-1 Tax-specific, HLA-A*02 restricted CD8(+ T cells among HAM/TSP individuals expressed markedly lower levels of Tim-3. We observed Tax expressing cells in both Tim-3(+ and Tim-3(- fractions. Taken together, these data indicate that there is a systematic downregulation of Tim-3 levels on T cells in HTLV-1 infection, sustaining a profoundly highly active population of potentially pathogenic T cells that may allow for the development of HTLV-1 complications.

  15. Rinite crônica em portadores do HTLV-1: estudo histopatológico Chronic rhinitis in HTLV-1 carriers: a histopathologic study

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    Fernando P. Gaspar Sobrinho

    2012-04-01

    Full Text Available A histopatologia nasal de portadores do HTLV-1 com rinite crônica é desconhecida. OBJETIVO: Descrever aspectos histopatológicos de portadores do HTLV-1 com rinite crônica. CASUÍSTICA E MÉTODOS: Amostras de mucosa nasal de 10 portadores do HTLV-1 com rinite crônica, sendo oito com rinite alérgica e dois com rinite não alérgica, foram estudadas por microscopia de luz. Amostras de 10 pacientes com rinite alérgica não infectados pelo HTLV-1 serviram como controle. RESULTADOS: Fibrose subepitelial foi maior nos pacientes com rinite alérgica infectados pelo HTLV-1 (p=0,01, enquanto o espessamento da membrana basal foi maior nos controles (p=0,03. Houve tendência a menor eosinofilia e edema entre os infectados pelo HTLV-1, sem significância estatística (p=0,2. Para o infiltrado linfocítico, não houve diferença entre os pacientes com rinite alérgica infectados e não infectados (p=1,0. Fibrose subepitelial com infiltrado linfocítico de intensidade leve a moderada foram os achados encontrados nos dois portadores do HTLV-1 com rinite não alérgica. CONCLUSÕES: O estudo sugere que a infecção pelo HTLV-1 pode modificar a histopatologia da rinite alérgica, sobretudo por maior fibrose, e pode estar relacionada a uma rinite crônica não alérgica com infiltrado linfocítico.The nasal histopathology of HTLV-1 carriers with chronic rhinitis is unknown. OBJECTIVE: To describe the histopathological features of HTLV-1 carriers with chronic rhinitis. MATERIALS AND METHODS: Biopsies of nasal mucosa of ten HTLV-1 carriers with chronic rhinitis (eight patients with allergic rhinitis and two patients with non-allergic rhinitis were studied using a light microscope. Samples from ten patients with allergic rhinitis not infected with HTLV-1 were used as controls. RESULTS: Subepithelial fibrosis was more pronounced in patients with allergic rhinitis infected with HTLV-1 (p=0.01, while the basement membrane thickness was greater in controls (p=0

  16. Human T-Lymphotropic Virus Type 1 (HTLV-1 and Regulatory T Cells in HTLV-1-Associated Neuroinflammatory Disease

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    Yoshihisa Yamano

    2011-08-01

    Full Text Available Human T-lymphotropic virus type 1 (HTLV-1 is a retrovirus that is the causative agent of adult T cell leukemia/lymphoma (ATL and associated with multiorgan inflammatory disorders, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP and uveitis. HTLV-1-infected T cells have been hypothesized to contribute to the development of these disorders, although the precise mechanisms are not well understood. HTLV-1 primarily infects CD4+ T helper (Th cells that play a central role in adaptive immune responses. Based on their functions, patterns of cytokine secretion, and expression of specific transcription factors and chemokine receptors, Th cells that are differentiated from naïve CD4+ T cells are classified into four major lineages: Th1, Th2, Th17, and T regulatory (Treg cells. The CD4+CD25+CCR4+ T cell population, which consists primarily of suppressive T cell subsets, such as the Treg and Th2 subsets in healthy individuals, is the predominant viral reservoir of HTLV-1 in both ATL and HAM/TSP patients. Interestingly, CD4+CD25+CCR4+ T cells become Th1-like cells in HAM/TSP patients, as evidenced by their overproduction of IFN-γ, suggesting that HTLV-1 may intracellularly induce T cell plasticity from Treg to IFN-γ+ T cells. This review examines the recent research into the association between HTLV-1 and Treg cells that has greatly enhanced understanding of the pathogenic mechanisms underlying immune dysregulation in HTLV-1-associated neuroinflammatory disease.

  17. Immunological profile of HTLV-1-infected patients associated with infectious or autoimmune dermatological disorders.

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    Jordana Grazziela Alves Coelho-dos-Reis

    Full Text Available In the present study, the frequency, the activation and the cytokine and chemokine profile of HTLV-1 carriers with or without dermatological lesions were thoroughly described and compared. The results indicated that HTLV-1-infected patients with dermatological lesions have distinct frequency and activation status when compared to asymptomatic carriers. Alterations in the CD4(+HLA-DR(+, CD8(+ T cell, macrophage-like and NKT subsets as well as in the serum chemokines CCL5, CXCL8, CXCL9 and CXCL10 were observed in the HTLV-1-infected group with skin lesions. Additionally, HTLV-1 carriers with dermatological skin lesions showed more frequently high proviral load as compared to asymptomatic carriers. The elevated proviral load in HTLV-1 patients with infectious skin lesions correlated significantly with TNF-α/IL-10 ratio, while the same significant correlation was found for the IL-12/IL-10 ratio and the high proviral load in HTLV-1-infected patients with autoimmune skin lesions. All in all, these results suggest a distinct and unique immunological profile in the peripheral blood of HTLV-1-infected patients with skin disorders, and the different nature of skin lesion observed in these patients may be an outcome of a distinct unbalance of the systemic inflammatory response upon HTLV-1 infection.

  18. Roles of HTLV-1 basic Zip Factor (HBZ in Viral Chronicity and Leukemic Transformation. Potential New Therapeutic Approaches to Prevent and Treat HTLV-1-Related Diseases

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    Jean-Michel Mesnard

    2015-12-01

    Full Text Available More than thirty years have passed since human T-cell leukemia virus type 1 (HTLV-1 was described as the first retrovirus to be the causative agent of a human cancer, adult T-cell leukemia (ATL, but the precise mechanism behind HTLV-1 pathogenesis still remains elusive. For more than two decades, the transforming ability of HTLV-1 has been exclusively associated to the viral transactivator Tax. Thirteen year ago, we first reported that the minus strand of HTLV-1 encoded for a basic Zip factor factor (HBZ, and since then several teams have underscored the importance of this antisense viral protein for the maintenance of a chronic infection and the proliferation of infected cells. More recently, we as well as others have demonstrated that HBZ has the potential to transform cells both in vitro and in vivo. In this review, we focus on the latest progress in our understanding of HBZ functions in chronicity and cellular transformation. We will discuss the involvement of this paradigm shift of HTLV-1 research on new therapeutic approaches to treat HTLV-1-related human diseases.

  19. Inhibition of Geranylgeranyl Transferase-I Decreases Cell Viability of HTLV-1-Transformed Cells

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    Cynthia A. Pise-Masison

    2011-10-01

    Full Text Available Human T-cell leukemia virus type-1 (HTLV-1 is the etiological agent of adult T-cell leukemia (ATL, an aggressive and highly chemoresistant malignancy. Rho family GTPases regulate multiple signaling pathways in tumorigenesis: cytoskeletal organization, transcription, cell cycle progression, and cell proliferation. Geranylgeranylation of Rho family GTPases is essential for cell membrane localization and activation of these proteins. It is currently unknown whether HTLV-1-transformed cells are preferentially sensitive to geranylgeranylation inhibitors, such as GGTI-298. In this report, we demonstrate that GGTI-298 decreased cell viability and induced G2/M phase accumulation of HTLV-1-transformed cells, independent of p53 reactivation. HTLV-1-LTR transcriptional activity was inhibited and Tax protein levels decreased following treatment with GGTI-298. Furthermore, GGTI-298 decreased activation of NF-κB, a downstream target of Rho family GTPases. These studies suggest that protein geranylgeranylation contributes to dysregulation of cell survival pathways in HTLV-1-transformed cells.

  20. Epidemiological analysis of HTLV-1 and HTLV-2 infection among different population in Central China.

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    Yunyun Ma

    Full Text Available BACKGROUND: HTLV-1 and HTLV-2 are retroviruses linked etiologically to various human diseases, and both of them can be transmitted by vertical route, sexual intercourse, blood transfusion and intravenous drug use. Recently, some HTLV-infected cases have been reported and this virus is mainly present in the Southeast coastal areas in China, but has not been studied for the people in Central China. OBJECTIVES: To know the epidemiologic patterns among different population samples in Central China and further identify risk factor for HTLV-1 and HTLV-2 infection. METHODS: From January 2008 to December 2011, 5480 blood samples were screened for HTLV-1/2 antibodies by using enzyme immunoassay, followed by Western Blot. RESULTS: The prevalence of HTLV-1 and HTLV-2 was found with infection rates 0.13% and 0.05% among all population samples for HTLV-1 and HTLV-2, respectively. The highest percentages of infection, 0.39% and 0.20%, were found in the high risk group, while only 0.06% and 0.03% in the blood donor group. There was only one case of HTLV-1 infection (0.11% among patients with malignant hematological diseases. Of seven HTLV-1 positive cases, six were co-infected with HBV, two with HCV and one with HIV. Among three HTLV-2 positive individuals all were co-infected with HBV, one with HCV. CONCLUSIONS: HTLV-1 and HTLV-2 have been detected in the Central China at low prevalence, with the higher infection rate among high risk group. It was also found that co-infection of HTLV-1/2 with HIV and HBV occurred, presumably due to their similar transmission routes. HTLV-1/2 antibody screen among certain population would be important to prevent the spread of the viruses.

  1. Prevalence and phylogenetic analysis of HTLV-1 in a segregated population in Iran.

    Science.gov (United States)

    Rafatpanah, Houshang; Torkamani, Mahmood; Valizadeh, Narges; Vakili, Rosita; Meshkani, Baratali; Khademi, Hassan; Gerayli, Sina; Mozhgani, Sayed Hamid Reza; Rezaee, Seyed Abdolrahim

    2016-07-01

    Human T-lymphotropic virus type 1 (HTLV-1) infection is an important health issue that affects a variety of endemic areas. The Khorasan province, mainly its capital Mashhad in northeastern Iran, was reported to be as one of these endemic regions. Torbat-e Heydarieh, a large city Southwest border to Mashhad with a segregated population was investigated for the prevalence and associated risk factors of HTLV-1 infection in 400 randomly selected individuals. Blood samples were tested for the presence of HTLV-1 antibodies via the ELISA method and then were confirmed by an Immunoblot test. For the presence of HTLV-1 in lymphocytes of infected subjects, PCR was performed on LTR and TAX regions. DNA sequencing of LTR fragment was also carried out to determine the phylogenetic of HTLV-1, using the Maximum likelihood method. HTLV-1 sero-reactivity (sero-prevalence) among the study population was 2% (8/400), of which 1.25% had HTLV-1 provirus in lymphocytes (actual prevalence). HTLV-1 infection was significantly associated with the age, marital status, and history of blood transfusion (P cosmopolitan subtype A. HTLV-1 prevalence in Torbat-e Heydarieh (1.25%) is low comparing to those of both Mashhad (2-3%) and Neishabour (3.5-5%) in the province of Khorasan. Thus, traveling mobility and population mixing such as marriage, bureaucratic affairs, occupation, and economic activities could be the usual routs of HTLV-1 new wave of spreading in this segregated city. © 2015 Wiley Periodicals, Inc.

  2. I-mfa domain proteins specifically interact with HTLV-1 Tax and repress its transactivating functions

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    Kusano, Shuichi, E-mail: skusano@m2.kufm.kagoshima-u.ac.jp [Division of Persistent and Oncogenic Viruses, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Yoshimitsu, Makoto; Hachiman, Miho [Division of Hematology and Immunology, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Ikeda, Masanori [Division of Persistent and Oncogenic Viruses, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan)

    2015-12-15

    The I-mfa domain proteins HIC (also known as MDFIC) and I-mfa (also known as MDFI) are candidate tumor suppressor genes that are involved in cellular and viral transcriptional regulation. Here, we show that HIC and I-mfa directly interact with human T-cell leukemia virus type-1 (HTLV-1) Tax protein in vitro. In addition, HIC and I-mfa repress Tax-dependent transactivation of an HTLV-1 long terminal repeat (LTR) reporter construct in COS-1, Jurkat and high-Tax-producing HTLV-1-infected T cells. HIC also interacts with Tax through its I-mfa domain in vivo and represses Tax-dependent transactivation of HTLV-1 LTR and NF-κB reporter constructs in an interaction-dependent manner. Furthermore, we show that HIC decreases the nuclear distribution and stimulates the proteasomal degradation of Tax. These data reveal that HIC specifically interacts with HTLV-1 Tax and negatively regulates Tax transactivational activity by altering its subcellular distribution and stability. - Highlights: • I-mfa domain proteins, HIC and I-mfa, specifically interact with HTLV-1 Tax. • HIC and I-mfa repress the Tax-dependent transactivation of HTLV-1 LTR. • HIC represses the Tax-dependent transactivation of NF-κΒ. • HIC decreases the nuclear distribution of Tax. • HIC stimulates the proteasomal degradation of Tax.

  3. Association of Sicca Syndrome with Proviral Load and Proinflammatory Cytokines in HTLV-1 Infection

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    Clara Mônica Lima

    2016-01-01

    Full Text Available The Sjögren syndrome has been diagnosed in patients with HTLV-1 associated myelopathy and dry mouth and dry eyes are documented in HTLV-1 carriers. However the diagnosis of Sjögren syndrome in these subjects has been contested. In this cross-sectional study, we evaluated the role of immunological factors and proviral load, in sicca syndrome associated with HTLV-1 in patients without myelopathy. Subjects were recruited in the HTLV-1 Clinic, from 2009 to 2011. The proviral load and cytokine levels (IFN-γ, TNF-α, IL-5, and IL-10 were obtained from a database containing the values presented by the subjects at admission in the clinic. Of the 272 participants, 59 (21.7% had sicca syndrome and in all of them anti-Sjögren syndrome related antigen A (SSA and antigen B (SSB were negatives. The production of TNF-α and IFN-γ was higher in the group with sicca syndrome (P<0.05 than in HTLV-1 infected subjects without sicca syndrome. Our data indicates that patients with sicca syndrome associated with HTLV-1 do not have Sjögren syndrome. However the increased production of TNF-α and IFN-γ in this group of patients may contribute to the pathogenesis of sicca syndrome associated with HTLV-1.

  4. I-mfa domain proteins specifically interact with HTLV-1 Tax and repress its transactivating functions

    International Nuclear Information System (INIS)

    Kusano, Shuichi; Yoshimitsu, Makoto; Hachiman, Miho; Ikeda, Masanori

    2015-01-01

    The I-mfa domain proteins HIC (also known as MDFIC) and I-mfa (also known as MDFI) are candidate tumor suppressor genes that are involved in cellular and viral transcriptional regulation. Here, we show that HIC and I-mfa directly interact with human T-cell leukemia virus type-1 (HTLV-1) Tax protein in vitro. In addition, HIC and I-mfa repress Tax-dependent transactivation of an HTLV-1 long terminal repeat (LTR) reporter construct in COS-1, Jurkat and high-Tax-producing HTLV-1-infected T cells. HIC also interacts with Tax through its I-mfa domain in vivo and represses Tax-dependent transactivation of HTLV-1 LTR and NF-κB reporter constructs in an interaction-dependent manner. Furthermore, we show that HIC decreases the nuclear distribution and stimulates the proteasomal degradation of Tax. These data reveal that HIC specifically interacts with HTLV-1 Tax and negatively regulates Tax transactivational activity by altering its subcellular distribution and stability. - Highlights: • I-mfa domain proteins, HIC and I-mfa, specifically interact with HTLV-1 Tax. • HIC and I-mfa repress the Tax-dependent transactivation of HTLV-1 LTR. • HIC represses the Tax-dependent transactivation of NF-κΒ. • HIC decreases the nuclear distribution of Tax. • HIC stimulates the proteasomal degradation of Tax.

  5. HTLV-1-infected thymic epithelial cells convey the virus to CD4+ T lymphocytes.

    Science.gov (United States)

    Carvalho Barros, Luciana Rodrigues; Linhares-Lacerda, Leandra; Moreira-Ramos, Klaysa; Ribeiro-Alves, Marcelo; Machado Motta, Maria Cristina; Bou-Habib, Dumith Chequer; Savino, Wilson

    2017-12-01

    The human T-lymphotropic virus type-1 (HTLV-1) is the causative agent of adult T cell leukemia/lymphoma (ATL) and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). CD4 + T cells are the main target of HTLV-1, but other cell types are known to be infected, including immature lymphocytes. Developing T cells undergo differentiation in the thymus, through migration and interaction with the thymic microenvironment, in particular with thymic epithelial cells (TEC) the major component of this three dimensional meshwork of non-lymphoid cells. Herein, we show that TEC express the receptors for HTLV-1 and can be infected by this virus through cell-cell contact and by cell-free virus suspensions. The expression of anti-apoptosis, chemokine and adhesion molecules genes are altered in HTLV-1-infected TEC, although gene expression of antigen presentation molecules remained unchanged. Furthermore, HTLV-1-infected TEC transmitted the virus to a CD4 + T cell line and to CD4 + T cells from healthy donors, during in vitro cellular co-cultures. Altogether, our data point to the possibility that the human thymic epithelial cells play a role in the establishment and progression of HTLV-1 infection, functioning as a reservoir and transmitting the virus to maturing CD4 + T lymphocytes, which in turn will cause disease in the periphery. Copyright © 2017. Published by Elsevier GmbH.

  6. How to Control HTLV-1-Associated Diseases: Preventing de Novo Cellular Infection Using Antiviral Therapy

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    Amandine Pasquier

    2018-03-01

    Full Text Available Five to ten million individuals are infected by Human T-cell Leukemia Virus type 1 (HTLV-1. HTLV-1 is transmitted through prolonged breast-feeding, by sexual contacts and by transmission of infected T lymphocytes through blood transfusion. One to ten percent of infected carriers will develop a severe HTLV-1-associated disease: Adult-T-cell leukemia/lymphoma (ATLL, or a neurological disorder named Tropical Spastic Paraparesis/HTLV-1 Associated Myelopathy (TSP/HAM. In vivo, HTLV-1 is mostly detected in CD4+ T-cells, and to a lesser extent in CD8+ T cells and dendritic cells. There is a strong correlation between HTLV-1 proviral load (PVL and clinical status of infected individuals. Thus, reducing PVL could be part of a strategy to prevent or treat HTLV-1-associated diseases among carriers. Treatment of ATLL patients using conventional chemotherapy has very limited benefit. Some chronic and acute ATLL patients are, however, efficiently treated with a combination of interferon α and zidovudine (IFN-α/AZT, to which arsenic trioxide is added in some cases. On the other hand, no efficient treatment for TSP/HAM patients has been described yet. It is therefore crucial to develop therapies that could either prevent the occurrence of HTLV-1-associated diseases or at least block the evolution of the disease in the early stages. In vivo, reverse transcriptase (RT activity is low in infected cells, which is correlated with a clonal mode of viral replication. This renders infected cells resistant to nucleoside RT inhibitors such as AZT. However, histone deacetylase inhibitors (HDACi associated to AZT efficiently induces viral expression and prevent de novo cellular infection. In asymptomatic STLV-1 infected non-human primates, HDACi/AZT combination allows a strong decrease in the PVL. Unfortunately, rebound in the PVL occurs when the treatment is stopped, highlighting the need for better antiviral compounds. Here, we review previously used strategies

  7. Biophysical analysis of HTLV-1 particles reveals novel insights into particle morphology and Gag stochiometry

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    Fogarty Keir H

    2010-09-01

    Full Text Available Abstract Background Human T-lymphotropic virus type 1 (HTLV-1 is an important human retrovirus that is a cause of adult T-cell leukemia/lymphoma. While an important human pathogen, the details regarding virus replication cycle, including the nature of HTLV-1 particles, remain largely unknown due to the difficulties in propagating the virus in tissue culture. In this study, we created a codon-optimized HTLV-1 Gag fused to an EYFP reporter as a model system to quantitatively analyze HTLV-1 particles released from producer cells. Results The codon-optimized Gag led to a dramatic and highly robust level of Gag expression as well as virus-like particle (VLP production. The robust level of particle production overcomes previous technical difficulties with authentic particles and allowed for detailed analysis of particle architecture using two novel methodologies. We quantitatively measured the diameter and morphology of HTLV-1 VLPs in their native, hydrated state using cryo-transmission electron microscopy (cryo-TEM. Furthermore, we were able to determine HTLV-1 Gag stoichiometry as well as particle size with the novel biophysical technique of fluorescence fluctuation spectroscopy (FFS. The average HTLV-1 particle diameter determined by cryo-TEM and FFS was 71 ± 20 nm and 75 ± 4 nm, respectively. These values are significantly smaller than previous estimates made of HTLV-1 particles by negative staining TEM. Furthermore, cryo-TEM reveals that the majority of HTLV-1 VLPs lacks an ordered structure of the Gag lattice, suggesting that the HTLV-1 Gag shell is very likely to be organized differently compared to that observed with HIV-1 Gag in immature particles. This conclusion is supported by our observation that the average copy number of HTLV-1 Gag per particle is estimated to be 510 based on FFS, which is significantly lower than that found for HIV-1 immature virions. Conclusions In summary, our studies represent the first quantitative biophysical

  8. Tropical spastic paraparesis and HTLV-1 associated myelopathy: clinical, epidemiological, virological and therapeutic aspects.

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    Gessain, A; Mahieux, R

    2012-03-01

    In 1980, Human T cell leukemia/lymphoma virus type 1 (HTLV-1) was the first oncogenic human retrovirus to be discovered. HTLV-1 belongs to the Retroviridae family, the Orthoretrovirinae subfamily and to the deltaretrovirus genus. HTLV-1 preferentially infects CD4(+) lymphoid cells in vivo. Three molecules have been identified for binding and/or entry of HTLV-1: heparan sulfate proteoglycans, neuropilin-1, and glucose transporter 1. An efficient transfer of the virus from an infected cell to a target cell can occur through the formation of a viral synapse and/or by virofilm structure. As for all retroviruses, HTLV-1 genome possesses three major ORFs (gag, pol and env) encoding the structural and enzymatic proteins. HTLV-1 encodes also some regulatory and auxillary proteins including the tax protein with transforming activities and the HBZ protein which plays a role in the proliferation and maintenance of the leukemic cells. HTLV-1 is present throughout the world with clusters of high endemicity including mainly Southern Japan, the Caribbean region, areas in South America and in intertropical Africa. The worldwide HTLV-1 infected population is estimated to be around 10-20 million. HTLV-1 has three modes of transmission: (1): mother to child, mainly linked to prolonged breast-feeding; (2): sexual, mainly occurring from male to female and (3): contaminated blood products. HTLV-1 possesses a remarkable genetic stability. HTLV-1 is the etiological agent of mainly two severe diseases: a malignant T CD4(+) cell lymphoproliferation, of very poor prognosis, named Adult T cell Leukemia/Lymphoma (ATLL), and a chronic neuro-myelopathy named Tropical spastic paraparesis/HTLV-1 Associated Myelopathy (TSP/HAM). The lifetime risk among HTLV-1 carriers is estimated to be around 0.25 to 3%. TSP/HAM mainly occurs in adults, with a mean age at onset of 40-50 years and it is more common in women than in men. Blood transfusion is a major risk factor for TSP/HAM development. Clinically

  9. Infection with human T-lymphotropic virus types-1 and -2 (HTLV-1 and -2): Implications for blood transfusion safety.

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    Murphy, E L

    2016-02-01

    Many countries currently perform antibody screening for HTLV-1 infection in blood donors, and this intervention is likely cost-effective in preventing HTLV-1 related diseases in high prevalence countries. However, a number of high-income countries with low prevalence of HTLV-1 infection also perform universal HTLV-1 screening and debate has arisen regarding the cost-effectiveness of these strategies. Filter-based leukoreduction is likely to substantially reduce HTLV-1 transmission by removing infected lymphocytes, but actual laboratory data on its efficacy is currently lacking. Similarly, cost-effectiveness research on HTLV-1 prevention strategies is limited by poor data on prevalence, transmission efficacy and the cost of treating HTLV1 diseases. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  10. Psychiatric Disorders in HTLV-1-Infected Individuals with Bladder Symptoms.

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    Glória O Orge

    Full Text Available Previous studies have reported high rates of depression and anxiety in HTLV-1 infected individuals with the neurological disease and in the asymptomatic phase. No study has investigated the rates in individuals that already show bladder symptoms without severe neurological changes; that is, during the oligosymptomatic phase. The present study investigated patients in this intermediate form on the spectrum of the infection.Participants answered a sociodemographic questionnaire, the Mini International Neuropsychiatric Interview Brazilian Version 5.0.0 (MINI PLUS and the Hospital Anxiety and Depression Scale (HADS. Data analysis was performed in STATA statistical software (version 12.0. Depressive disorder was the most frequent comorbidity. Current depressive disorder was higher in the group of overactive bladder subjects (11.9%, and lifelong depression was more frequent in the HAM/TSP group (35%. The three groups had similar frequencies of anxiety disorders. Increased frequency and severity of anxiety and depression symptoms were observed in the overactive bladder group.The results suggest that individuals with overactive bladders need a more thorough assessment from the mental health perspective. These patients remain an understudied group regarding psychiatric comorbidities.

  11. [Duodenal Linphoma asociated to Strongyloides stercoralis infection. Two types of HTLV-1 infection].

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    Guevara Miranda, Julissa; Guzmán Rojas, Patricia; Espinoza-Ríos, Jorge; Mejía Cordero, Fernando

    2017-01-01

    Infection by the Human T- Lymphotropic virus I (HTLV-1) causes Adult T cell Leukemia-lymphoma (ATLL), being the duodenal involvement rare. Commonly, patients co-infected with HTLV-1 and Strongyloides stercoralis are seen due to the lack of TH2 response found on these patients. We describe a 48-year- old woman, from the jungle of Peru, with a family history of HTLV-1 infection, who presented with a History of chronic diarrhea and weight loss. HTLV-1 infection with ATLL and strongyloidiasis were diagnosed. Ivermectin treatment and chemotherapy were initiated, being stabilized, and discharged. We report this case because of the unusual coexistence in the duodenum of ATLL and strongyloidiasis.

  12. Clinical and immunological features of patients with atopy and concomitant HTLV-1 infection

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    F.P. Gaspar-Sobrinho

    2010-12-01

    Full Text Available Human T-cell lymphotropic virus type 1 (HTLV-1 induces an exacerbated type 1 immune response characterized by high spontaneous IFN-γ and TNF-α production. Allergic rhinitis and asthma are associated with the type 2 immune response, with elevated secretion of IL-4 and IL-5. The aim of this study was to characterize the immune response in atopic HTLV-1 carriers. The cytokine profile of atopic HTLV-1 carriers (N = 10; all females was compared with that of non-atopic HTLV-1 carriers (N = 14; 9 females and 5 males. Mean patient age of atopic and non-atopic groups was 45 ± 8 and 38 ± 11 years, respectively. All atopic HTLV-1 carriers had rhinitis with or without asthma and a skin prick test positive for Dermatophagoides pteronyssinus antigen 1 (Derp-1. There was no difference in cytokine levels between the two groups in unstimulated peripheral blood mononuclear cell cultures. In cultures stimulated with Derp-1, IFN-γ levels tended to be higher (P = 0.06 and IL-5 levels were higher (P = 0.02 in atopic HTLV-1 patients than in non-atopic subjects. In contrast, IL-10 was lower (P = 0.004 in atopic than in non-atopic HTLV-1-infected subjects. This study shows that HTLV-1 infection with an exaggerated type 1 immune response does not prevent atopy. In this case, the exacerbated type 1 and type 2 immune responses were due to a lack of IL-10 production, a cytokine that plays an important role in down-modulating type 1 and type 2 immune responses and in preventing the development of chronic inflammatory diseases.

  13. Immune activation induces immortalization of HTLV-1 LTR-Tax transgenic CD4+ T cells

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    Swaims, Alison Y.; Khani, Francesca; Zhang, Yingyu; Roberts, Arthur I.; Devadas, Satish; Shi, Yufang; Rabson, Arnold B.

    2010-01-01

    Infection with the human T-cell leukemia virus-1 (HTLV-1) results in a variety of diseases including adult T-cell leukemia/lymphoma (ATL). Although the pathogenesis of these disorders is poorly understood, it involves complex interactions with the host immune system. Activation of infected T cells may play an important role in disease pathogenesis through induction of the oncogenic HTLV-1 Tax transactivator protein. To test this hypothesis, we employed transgenic mice in which Tax is regulate...

  14. HTLV-1 bZIP factor induces T-cell lymphoma and systemic inflammation in vivo.

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    Yorifumi Satou

    2011-02-01

    Full Text Available Human T-cell leukemia virus type 1 (HTLV-1 is the causal agent of a neoplastic disease of CD4+ T cells, adult T-cell leukemia (ATL, and inflammatory diseases including HTLV-1 associated myelopathy/tropical spastic paraparesis, dermatitis, and inflammatory lung diseases. ATL cells, which constitutively express CD25, resemble CD25+CD4+ regulatory T cells (T(reg. Approximately 60% of ATL cases indeed harbor leukemic cells that express FoxP3, a key transcription factor for T(reg cells. HTLV-1 encodes an antisense transcript, HTLV-1 bZIP factor (HBZ, which is expressed in all ATL cases. In this study, we show that transgenic expression of HBZ in CD4+ T cells induced T-cell lymphomas and systemic inflammation in mice, resembling diseases observed in HTLV-1 infected individuals. In HBZ-transgenic mice, CD4+Foxp3+ T(reg cells and effector/memory CD4+ T cells increased in vivo. As a mechanism of increased T(reg cells, HBZ expression directly induced Foxp3 gene transcription in T cells. The increased CD4+Foxp3+ T(reg cells in HBZ transgenic mice were functionally impaired while their proliferation was enhanced. HBZ could physically interact with Foxp3 and NFAT, thereby impairing the suppressive function of T(reg cells. Thus, the expression of HBZ in CD4+ T cells is a key mechanism of HTLV-1-induced neoplastic and inflammatory diseases.

  15. Frequent HTLV-1 infection in the offspring of Peruvian women with HTLV-1-associated myelopathy/tropical spastic paraparesis or strongyloidiasis Infección frecuente por HTLV-1 en los hijos de mujeres peruanas con mielopatía/paraparesia espástica tropical asociada con el HTLV-1 o con estrongiloidiasis

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    Eduardo Gotuzzo

    2007-10-01

    Full Text Available OBJECTIVES: To describe the frequency of HTLV-1 infection among offspring of mothers who had presented with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP, strongyloidiasis, or asymptomatic HTLV-1 infection, and to identify factors associated with HTLV-1 infection. METHODS: In a descriptive study, records were reviewed of HTLV-1-positive women and their offspring who had been tested for HTLV infection at a public hospital in Lima, Peru, from 1989 to 2003. Sons and daughters of women who had presented with strongyloidiasis, HAM/TSP, or asymptomatic infection were eligible for this study. RESULTS: Three hundred seventy subjects were included: 279 were the offspring of 104 mothers presenting with HAM/TSP, 58 were the offspring of 22 mothers with strongyloidiasis, and 33 were the offspring of 26 asymptomatic mothers. Mean age of the offspring at the time of testing was 26 years (standard deviation 12. Nineteen percent of the offspring tested positive for HTLV-1: 6% (2/33 of those with asymptomatic mothers, 19% (52/279 among the offspring of mothers with HAM/TSP, and 31% (18/58 among the offspring of mothers presenting with strongyloidiasis On multiple logistic regression analysis, three factors were significantly associated with HTLV-1: (a duration of breast-feeding (odds ratio [OR] = 15.1; [4.2-54.1] for 12 to 24 months versus less than 6 months breast-feeding; (b clinical condition of the mother (OR = 8.3 [1.0-65.3] for HAM/TSP and OR = 11.5 [1.4-98.4] for strongyloidiasis in comparison with offspring of asymptomatic mothers; and (c transfusion history (OR = 5.5 [2.0-15.2]. CONCLUSIONS: In addition to known risk factors for HTLV-1 transmission (duration of breast-feeding and history of blood transfusion, maternal HAM/TSP and strongyloidiasis were associated with seropositivity among offspring of HTLV-1-infected mothers.OBJETIVOS: Describir la frecuencia de la infección por HTLV-1 en los hijos e hijas de madres diagnosticadas

  16. Seroprevalencia de HTLV-1/2 en donantes de sangre de la Provincia de Misiones Seroprevalence of HTLV-1/2 in blood donors from Misiones Province

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    Richard Malan

    2010-02-01

    Full Text Available El Virus Linfotrópico T Humano tipo 1 (HTLV-1, primer oncorretrovirus humano descubierto, es el causante etiológico de la leucemia de células T del adulto (ATL y de la mielopatía asociada al HTLV-1 o paraparesia espástica tropical (HAM/TSP. Es endémico en distintas partes del mundo, inclusive en el noroeste argentino, donde ambas enfermedades fueron detectadas. El HTLV-2, no tiene un rol etiológico definido, si bien ha sido asociado con síndromes neurológicos similares a la HAM/TSP. Ambos virus son endémicos en comunidades originarias del continente americano, tribus de Africa y poblaciones en riesgo. Ambos retrovirus se transmiten por vía sexual, parenteral y de madre a hijo. El objetivo de este trabajo fue determinar la seroprevalencia de HTLV-1/2 en una población de donantes de sangre de la provincia de Misiones. Se analizaron 6912 donaciones de sangre recibidas en el Banco de Sangre Central de la Provincia de Misiones durante 2008. La detección de anticuerpos se realizó por ELISA y aglutinación de partículas, y las muestras reactivas fueron confirmadas por Western Blot. Del total de muestras, 5 resultaron seropositivas con una prevalencia final de 0.00072. De ellas, una era HTLV, tres HTLV-1 y una HTLV-2 positiva. Los donantes positivos provenían de Posadas, Eldorado y Oberá, sin antecedentes de riesgo. Este estudio demuestra la presencia de HTLV-1/2 en donantes de sangre de Misiones, con cifras similares a las notificadas en donantes de sangre de zonas no endémicas.Human T-cell Lymphotropic viruses type 1 (HTLV-1, the first human oncoretrovirus to be discovered, is the etiologic agent of Adult T-cell Leukemia (ATL and HTLV-1 Associated Mielopathy or Tropical Spastic Paraparesis (HAM/TSP. It is endemic worldwide, including the North of Argentina where both associated diseases have also been detected. No etiologic role has been described for HTLV-2, although it has been associated with HAM/TSP-like neurologic syndromes

  17. Role of IL-21 in HTLV-1 infections with emphasis on HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP).

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    Rajaei, Taraneh; Farajifard, Hamid; Rafatpanah, Houshang; Bustani, Reza; Valizadeh, Narges; Rajaei, Bahareh; Rezaee, Seyed Abdolrahim

    2017-06-01

    Interleukin-21 (IL-21) enhances the survival and cytotoxic properties of cytotoxic T cells (CTLs) and exhibits essential roles in controlling chronic viral infections. HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic progressive inflammatory disease of the nervous system. The main determinant of disease progression is efficiency of the CTL response to Human T lymphotropic virus types I (HTLV-1). In this study, the expression of host IL-21 and HTLV-I Tax and proviral load (PVL) was evaluated to understand the role and mechanism of IL-21 in HTLV-1 infections and the subsequent development of HAM/TSP. A cross-sectional study was carried out on 20 HAM/TSP patients, 20 asymptomatic HTLV-1 carriers (ACs) and 20 healthy controls (HCs) to evaluate the expression of IL-21 and Tax and PVL in non-activated and phorbol myristate acetate (PMA)-ionomycin-activated peripheral blood mononuclear cells (PBMCs). The mean mRNA expression of IL-21 in the non-activated and activated PBMCs was higher (by 5-13 times) in the HAM/TSP patients than in ACs and HCs (p Tax and PVL was observed in the HAM/TSP subjects than ACs (p Tax gene expression was positively correlated with PVL (R = 0.595, p = 0.000) and IL-21 gene expression (R = 0.395, p = 0.021) in the HTLV-1-infected subjects. In conclusion, the increase in IL-21 mRNA expression may reflect the attempt of infected T cells to induce an appropriate antiviral response, and the decrease in IL-21 protein expression may reflect the inhibition of IL-21 mRNA translation by viral factors in favour of virus evasion and dissemination.

  18. Cytoplasmic Localization of HTLV-1 HBZ Protein: A Biomarker of HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP).

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    Baratella, Marco; Forlani, Greta; Raval, Goutham U; Tedeschi, Alessandra; Gout, Olivier; Gessain, Antoine; Tosi, Giovanna; Accolla, Roberto S

    2017-01-01

    HTLV-1 is the causative agent of a severe form of adult T cell leukemia/Lymphoma (ATL), and of a chronic progressive neuromyelopathy designated HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). Two important HTLV-1-encoded proteins, Tax-1 and HBZ, play crucial roles in the generation and maintenance of the oncogenic process. Less information is instead available on the molecular and cellular mechanisms leading to HAM/TSP. More importantly, no single specific biomarker has been described that unambiguously define the status of HAM/TSP. Here we report for the first time the finding that HBZ, described until now as an exclusive nuclear protein both in chronically infected and in ATL cells, is instead exclusively localized in the cytoplasm of peripheral blood mononuclear cells (PBMC) from patients suffering of HAM/TSP. Interestingly, at the single cell level, HBZ and Tax-1 proteins are never found co-expressed in the same cell, suggesting the existence of mechanisms of expression uncoupling of these two important HTLV-1 viral products in HAM/TSP patients. Cells expressing cytoplasmic HBZ were almost exclusively found in the CD4+ T cell compartment that was not, at least in a representative HAM/TSP patient, expressing the CD25 marker. Less than 1 percent CD8+ T cells were fond positive for HBZ, while B cells and NK cells were found negative for HBZ in HAM/TSP patients. Our results identify the cytoplasmic localization of HBZ in HAM/TSP patient as a possible biomarker of this rather neglected tropical disease, and raise important hypotheses on the role of HBZ in the pathogenesis of the neuromyelopathy associated to HTLV-1 infection.

  19. Cytoplasmic Localization of HTLV-1 HBZ Protein: A Biomarker of HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP.

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    Marco Baratella

    2017-01-01

    Full Text Available HTLV-1 is the causative agent of a severe form of adult T cell leukemia/Lymphoma (ATL, and of a chronic progressive neuromyelopathy designated HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP. Two important HTLV-1-encoded proteins, Tax-1 and HBZ, play crucial roles in the generation and maintenance of the oncogenic process. Less information is instead available on the molecular and cellular mechanisms leading to HAM/TSP. More importantly, no single specific biomarker has been described that unambiguously define the status of HAM/TSP. Here we report for the first time the finding that HBZ, described until now as an exclusive nuclear protein both in chronically infected and in ATL cells, is instead exclusively localized in the cytoplasm of peripheral blood mononuclear cells (PBMC from patients suffering of HAM/TSP. Interestingly, at the single cell level, HBZ and Tax-1 proteins are never found co-expressed in the same cell, suggesting the existence of mechanisms of expression uncoupling of these two important HTLV-1 viral products in HAM/TSP patients. Cells expressing cytoplasmic HBZ were almost exclusively found in the CD4+ T cell compartment that was not, at least in a representative HAM/TSP patient, expressing the CD25 marker. Less than 1 percent CD8+ T cells were fond positive for HBZ, while B cells and NK cells were found negative for HBZ in HAM/TSP patients. Our results identify the cytoplasmic localization of HBZ in HAM/TSP patient as a possible biomarker of this rather neglected tropical disease, and raise important hypotheses on the role of HBZ in the pathogenesis of the neuromyelopathy associated to HTLV-1 infection.

  20. HTLV-1 specific CD8+ T cell function augmented by blockade of 2B4/CD48 interaction in HTLV-1 infection.

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    Chibueze Chioma Ezinne

    Full Text Available CD8+ T cell response is important in the response to viral infections; this response though is regulated by inhibitory receptors. Expression of inhibitory receptors has been positively correlated with CD8+ T cell exhaustion; the consequent effect of simultaneous blockade of these inhibitory receptors on CD8+ T cell response in viral infections have been studied, however, the role of individual blockade of receptor-ligand pair is unclear. 2B4/CD48 interaction is involved in CD8+T cell regulation, its signal transducer SAP (signaling lymphocyte activation molecule (SLAM-associated protein is required for stimulatory function of 2B4/CD244 on lymphocytes hence, we analyzed 2B4/CD244 (natural killer cell receptor and SAP (signaling lymphocyte activation molecule(SLAM-associated protein on total CD8+ and HTLV-1 specific CD8+T cells in HTLV-1 infection and the effect of blockade of interaction with ligand CD48 on HTLV-1 specific CD8+ T cell function. We observed a high expression of 2B4/CD244 on CD8+ T cells relative to uninfected and further upregulation on HTLV-1 specific CD8+ T cells. 2B4+ CD8+ T cells exhibited more of an effector and terminally differentiated memory phenotype. Blockade of 2B4/CD48 interaction resulted in improvement in function via perforin expression and degranulation as measured by CD107a surface mobilization on HTLV-1 specific CD8+ T cells. In the light of these findings, we thus propose an inhibitory role for 2B4/CD48 interaction on CD8+T cell function.

  1. Establishment of a Pcr Technique for Determination of Htlv-1 Infection in Paraffin-Embedded Tissues

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    M Rastin

    2007-04-01

    Full Text Available Introduction: HTLV-1 , the first known human retrovirus belongs to oncovirus subfamily of retroviruses. The major characteristic of HTLV-1 is its highly restricted geographic prevalence. Northern part of Khorasan is an endemic region of HTLV-1 infection. Epidemiological studies can help in designing preventive programs for HTLV-1 infection. The aim of this study was the establishment of a PCR technique for determination of HTLV-1 infection in paraffin-embedded tissues. Methods: In this experimental laboratory study for establishment of a technique, PCR was initially optimized using Beta-actin primers on various formalin fixed paraffin-embedded tissues from liver, spleen, skin and lymph nodes. The optimized concentration of Mgcl2 was 2mm, primer was 8 pmol. Optimized concentration of DNA was different according to the kind of tissue. HTLV-1 infection was determined by applying tax, pol, env and LTR primers on 50 paraffin-embedded lymph node tissues . The reporoducibility of this technique was shown for skin and lymph node tissues infected with HTLV-1. Resuls: In 50 lymph node tissues, one case with pathologic diagnosis of NHL was positive with all 5 sets of primers (tax, Pol, env and LTR primers and the other case was positive with only two sets of tax primers but was negative with pol, env and LTR primers. The prevalence of infection was 2% among lymph node specimens. (1 of 50 specimens and if the second case is considered, the prevalence would be 4%. Conclusion: Comparison of the results of this study with another study on blood specimens (seroprevalence2.3% was not statistically significant thus confirming the results of one another. (P=0.883

  2. HTLV-1 Rex: the courier of viral messages, making use of the host vehicle

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    Kazumi eNakano

    2012-09-01

    Full Text Available The human T-cell leukemia virus type 1 (HTLV-1 is a retrovirus causing an aggressive T-cell malignancy, adult T-cell leukemia (ATL. Although HTLV-1 has a compact RNA genome, it has evolved elaborate mechanisms to maximize its coding potential. The structural proteins Gag, Pro, and Pol are encoded in the unspliced form of viral mRNA, whereas the Env protein is encoded in singly spliced viral mRNA. Regulatory and accessory proteins, such as Tax, Rex, p30II, p12, and p13, are translated only from fully spliced mRNA. For effective viral replication, translation from all forms of HTLV-1 transcripts has to be achieved in concert, although unspliced mRNA are extremely unstable in mammalian cells. It has been well recognized that HTLV-1 Rex enhances the stability of unspliced and singly spliced HTLV-1 mRNA by promoting nuclear export and thereby, removing them from the splicing site. Rex specifically binds to the highly structured Rex responsive element (RxRE located at the 3′ end of all HTLV-1 mRNA. Rex then binds to the cellular nuclear exporter, CRM1, via its nuclear export signal domain and the Rex-viral transcript complex is selectively exported from the nucleus to the cytoplasm for effective translation of the viral proteins. Yet, the mechanisms by which Rex inhibits the cellular splicing machinery and utilizes the cellular pathways beneficial to viral survival in the host cell have not been fully explored. Furthermore, physiological impacts of Rex against homeostasis of the host cell via interactions with numerous cellular proteins have been largely left uninvestigated. In this review, we focus on the biological importance of HTLV-1 Rex in the HTLV-1 life cycle by following the historical path in the literature concerning this viral post-transcriptional regulator from its discovery to this day. In addition, for future studies, we discuss recently discovered aspects of HTLV-1 Rex as a post-transcriptional regulator and its use in host cellular

  3. Frequency of mental disturbances in HTLV-1 patients in the state of Bahia, Brazil.

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    Carvalho, André Gordilho Joaquim de; Galvão-Phileto, Ana Verena; Lima, Nana Santos; Jesus, Rogério Santos de; Galvão-Castro, Bernardo; Lima, Manuela Garcia

    2009-02-01

    Viral infections and chronic diseases have been associated with psychiatric disorders. Among these, increased depression has been reported in HTLV-1 patients. However, no studies on the prevalence of other mental disturbances have been carried out in these patients. Salvador is the city with the highest rate of infection with HTLV-1 in Brazil and it is estimated that approximately 40,000 inhabitants are infected. In our cross sectional study, we examined the frequency of mental disturbances in 50 HTLV-1 seropositive patients followed at the Centro Integrativo e Multidisciplinar de HTLV e Hepatites Virais (CHTLV) of the Escola Bahiana de Medicina e Saude Pública (EBMSP) in Salvador from January to November 2007. We used a questionnaire to collect clinical-epidemiologic data and the Mini International Neuropsychiatric Interview Brazilian Version 5.0.0 (M.I.N.I.) to evaluate the psychiatric disorders. The Statistical Package for Social Sciences (SPSS) was used for the analyses. Twenty-one (42%) HTLV-1 patients had a psychiatric co-morbidity; 17(34%) had mood disorders, 11 (22%) were anxious and one (2%) was an alcoholic. We found a high frequency of mental disturbances among HTLV-1 infected individuals, suggesting a possible association of this infection with psychiatric diseases.

  4. Neurological aspects of HTLV-1 infection in Bahia: results from an 8-year cohort

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    Davi Tanajura

    2015-01-01

    Full Text Available HTLV-1 is the causal agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP, a disease observed in up to 5% of individuals infected with HTLV-1. However, infected individuals without the disease can present neurological complaints relating to sensory, motor or urinary manifestations. The aim of this study was to investigate the incidence of neurological manifestations among patients with HTLV-1. Method HTLV-1 patients in Salvador, Bahia, Brazil, were enrolled into a cohort study. Results Among 414 subjects, 76 had definite and 87 had possible or probable HAM/TSP at the baseline, whereas 251 subjects had no neurological signs or symptoms. Definite HAM/TSP developed in 5 patients (1.74%. The asymptomatic subjects were selected for analysis. The incidence rate expressed per 1,000 persons-year was calculated. It was 206 for hand numbness, 129 for nocturia and 126 for urinary urgency. In the neurological examination, leg hyperreflexia presented an average incidence rate of 76; leg paraparesis, 52; and Babinski sign, 36. Kaplan-Meyer curves categorized according to gender and proviral load showed that females and patients with proviral load of more than 100,000 copies per 106 peripheral blood mononuclear cells (PBMCs presented higher risk. Conclusion Development of neurological symptoms or signs occurred in up to 30% of asymptomatic subjects during 8 years of follow-up. Female gender and high proviral load were risk factors for neurological disease.

  5. Prevalencia de anticuerpos contra HTLV-1 en una población negra de Colombia

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    María C. Navas

    1995-03-01

    Full Text Available El virus linfotrópico humano 1 (HTLV-1 ha sido asociado con la leucemia de células T del adulto (ATL y la paraparesia espástica tropical (PET o mielopatía asociada con HTLV-1 (HAM. Aunque la prevalencia de anticuerpos contra el HTLV-1 ha sido descrita en diversos países, especialmente en Japón, poco se conoce acerca de este marcador de contacto viral en nuestra población. En este artículo describimos la ausencia de niveles de anticuerpos anti-HTLV-1 en el suero, medidos por la prueba de ELISA, en una población negra de la costa atlántica de Colombia. Nuestros hallazgos sugieren que: a este grupo descendiente de África no se ha expuesto al virus; b puede ser que algunos de los individuos incluidos en el estudio estén en período de incubación y, que debido a su juventud, no fue posible demostrar una respuesta humoral contra el virus; y, c como ha sido descrito en otros estudios, la prevalencia de anticuerpos anti-HTLV- 1 varía entre las diferentes regiones de Colombia.

  6. Prevalence ratio of HTLV-1 in nursing mothers from the state of Paraiba, Northeastern Brazil.

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    Pimenta, Flávia C F; Kashima Haddad, Simone; de Medeiros Filho, João G; Costa, Maria José C; Diniz, Margareth F M; Fernandes, Melina P; de Araújo, Lenisio B; Pombo-de-Oliveira, Maria S

    2008-08-01

    The human T-cell lymphotropic virus type 1 (HTLV-1) was the first human retrovirus known as a direct causal agent of a malignant disease. The vertical route of HTLV transmission is the most frequent pathway of the virus contamination. This study was performed to determine the prevalence ratio of HTLV-1 infection among nursing women. From January 2004 to January 2005, blood samples from 1033 nursing mothers from Paraíba, Brazil were evaluated for HTLV antibodies by ELISA and HTLV-1 viral particles confirmed by polymerase chain reaction (PCR). HTLV antibodies were detected in 7 women. The overall seroprevalence ratio was 0.68% and HTLV-1 viral sequences were confirmed by PCR in 2 women. These preliminary data suggest that HTLV screening should be introduced as a mandatory test before breastfeeding and breast milk donation in Paraíba, Brazil. Additionally, counseling programs would help reduce the prevalence ratio of HTLV-1 infected individuals in this Brazilian region.

  7. Leukotrienes are upregulated and associated with human T-lymphotropic virus type 1 (HTLV-1-associated neuroinflammatory disease.

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    Bruno Caetano Trindade

    Full Text Available Leukotrienes (LTs are lipid mediators involved in several inflammatory disorders. We investigated the LT pathway in human T-lymphotropic virus type 1 (HTLV-1 infection by evaluating LT levels in HTLV-1-infected patients classified according to the clinical status as asymptomatic carriers (HACs and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP patients. Bioactive LTB(4 and CysLTs were both increased in the plasma and in the supernatant of peripheral blood mononuclear cell cultures of HTLV-1-infected when compared to non-infected. Interestingly, CysLT concentrations were increased in HAM/TSP patients. Also, the concentration of plasma LTB(4 and LTC(4 positively correlated with the HTLV-1 proviral load in HTLV-1-infected individuals. The gene expression levels of LT receptors were differentially modulated in CD4(+ and CD8(+ T cells of HTLV-1-infected patients. Analysis of the overall plasma signature of immune mediators demonstrated that LT and chemokine amounts were elevated during HTLV-1 infection. Importantly, in addition to CysLTs, IP-10 was also identified as a biomarker for HAM/TSP activity. These data suggest that LTs are likely to be associated with HTLV-1 infection and HAM/TSP development, suggesting their putative use for clinical monitoring.

  8. Seroprevalence of HTLV1,2 Virus Among Injection Drug Addicts in Isfahan, 2007-2008

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    Sh Farzaneh

    2009-10-01

    Full Text Available Introduction: Human T-cell lymphotropic virus (HTLV, is a member of the retroviridae family. Infection with this virus leads to adult T-cell leukemia (ATL and tropical spastic paraparesis (TSP. HTLV is endemic in Japan, parts of central Africa, Caribbean basin and Iran (Mashhad. Transmission routes of HTLV are believed to be from mother to child, especially during breastfeeding, sexual contact, and through blood transfusion or needle sharing. Considering the risk of HTLV infection among injection drug addicts, the authors evaluated the seroprevalence of HTLV1,2 infection among injection drug addicts in Isfahan Methods: This cross sectional study included a total of 150 injection drug users who were recruited at the drug abuse treatment clinic and the infectious diseases department of Alzahra university Hospital. Participants were interviewed using a structured questionnaire. Epidemiologic data were recorded and their blood samples were tested for HBs Ag and antibodies against HTLV1,2, human immunodeficiency virus (HIV and hepatitis C (HCV by Elisa method . Results were analyzed by SPSS software version 13. Results: Seroprevalence of HTLV1,2, HBV(HBs Ag, HCV and HIV was 2.7%, 1.3% 23.3% and 2.7%, respectively. Some of the subjects were co infected with two viruses. One patient was infected with both HCV Ab and HBs Ag , while another was positive for HIV Ab plus HBs Ag . Three were co infected with HCV and HIV. Among those with HTLV1,2, only one was HCV Ab positive. Only in one person with HTLV1,2 Ab had a positive history of blood transfusion. Conclusion: This study shows that this virus is present in injection drug users community of Isfahan and can be a potential source for transmission. But proposal of screening of HTLV1,2 among injection drug users in Isfahan requires further investigations.

  9. Doenças reumáticas auto-imunes em indivíduos infectados pelo HTLV-1 Autoimmune rheumatic diseases in HTLV-1 infected individuals

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    Mônica Martinelli Nunes de Carvalho

    2006-10-01

    Full Text Available O HTLV-1 foi o primeiro retrovírus humano a ser associado às doenças malignas leucemia e linfoma de células T do adulto (LLTA. Ele está relacionado também a uma doença inflamatória crônica do sistema nervoso central (SNC conhecida como paraparesia espástica tropical/mielopatia associada ao HTLV-1 (PET/MAH. O HTLV-1 tem sido implicado na patogênese de várias doenças auto-imunes, tais como: diabetes, esclerose múltipla, dermatite infectiva, uveíte e artropatia. Ao longo dos anos, a infecção retroviral tem assumido um importante papel na patogênese das doenças reumáticas auto-imunes. Partículas semelhantes aos retrovírus têm sido identificadas em tecidos de pacientes com artrite reumatóide (AR, síndrome de Sjögren, lúpus eritematoso sistêmico (LES e polimiosite. A síndrome de Sjögren e a AR têm sido as doenças reumáticas mais encontradas nos pacientes infectados pelo HTLV-1, sendo a freqüência mais elevada nos pacientes com mielopatia. A alta prevalência de síndrome de Sjögren e de AR entre os indivíduos com mielopatia sugere que a carga viral e a resposta inflamatória exacerbada, que concorrem para o desenvolvimento da mielopatia, devem também influenciar no desenvolvimento das doenças reumáticas auto-imunes.The HTLV-1 was the first human retrovirus associated with adult T-cell leukemia/lymphoma (LLTA. The virus also causes a chronic inflammatory disease of the central nervous system named HTLV-1-associated myelopathy or tropical spastic paraparesis (HAM/TSP. HTLV-1 has been implicated in the pathogenesis of many autoimmune diseases, such as diabetes, multiple sclerosis, infective dermatitis, uveitis and arthropathy. It has long been suggested that retroviral infection may play a role in the pathogenesis of autoimmune rheumatic diseases. Particles resembling retroviruses have been reported in tissue from patients with rheumatoid arthritis (RA, Sjögren’s syndrome, systemic lupus erythematosus (SLE and

  10. Evidence of a higher prevalence of HPV infection in HTLV-1-infected women: a cross-sectional study

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    Sônia Sampaio Lôpo

    2012-06-01

    Full Text Available INTRODUCTION:HTLV-1 infection increases susceptibility to other infections. Few studies have addressed the co-infection between HPV and HTLV-1 and the immune response involved in this interaction. The aim of this study was to determine the prevalence of cervical HPV infection in HTLV-1-infected women and to establish the risk factors involved in this co-infection. METHODS: A cross-sectional study was carried out in Salvador, Brazil, between September 2005 and December 2008, involving 50 HTLV-1-infected women from the HTLV Reference Center and 40 uninfected patients from gynecological clinic, both at the Bahiana School of Medicine. HPV infection was assessed using hybrid capture. HTLV-1 proviral load was quantified using real-time polymerase chain reaction (PCR. RESULTS: The mean age of HTLV-1-infected women (38 ± 10 years was similar to that of the control group (36 ± 13 years. The prevalence of HPV infection was 44% in the HTLV-1-infected group and 22.5% in uninfected women (p = 0.03. HTLV-1-infected women had lower mean age at onset of sexual life (17 ± 3 years versus 19 ± 3 years; p = 0.03 and greater number of lifetime partners compared with the control group (4 ± 3 versus 2 ± 1; p < 0.01. In the group of HTLV-1-infected patients, there was neither difference in HTLV-1 proviral load between HPV-infected women and the uninfected. CONCLUSIONS: The prevalence of HPV infection was higher in HTLV-1-infected women. Further studies should be performed to evaluate the progression of this co-infection.

  11. From Immunodeficiency to Humanization: The Contribution of Mouse Models to Explore HTLV-1 Leukemogenesis

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    Eléonore Pérès

    2015-12-01

    Full Text Available The first discovered human retrovirus, Human T-Lymphotropic Virus type 1 (HTLV-1, is responsible for an aggressive form of T cell leukemia/lymphoma. Mouse models recapitulating the leukemogenesis process have been helpful for understanding the mechanisms underlying the pathogenesis of this retroviral-induced disease. This review will focus on the recent advances in the generation of immunodeficient and human hemato-lymphoid system mice with a particular emphasis on the development of mouse models for HTLV-1-mediated pathogenesis, their present limitations and the challenges yet to be addressed.

  12. Presentation of human T cell leukemia virus type 1 (HTLV-1) Tax protein by dendritic cells: the underlying mechanism of HTLV-1-associated neuroinflammatory disease.

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    Manuel, Sharrón L; Schell, Todd D; Acheampong, Edward; Rahman, Saifur; Khan, Zafar K; Jain, Pooja

    2009-11-01

    HTLV-1 is the etiologic agent of a debilitating neurologic disorder, HAM/TSP. This disease features a robust immune response including the oligoclonal expansion of CD8+ CTLs specific for the viral oncoprotein Tax. The key pathogenic process resulting in the proliferation of CTLs and the presentation of Tax peptide remains uncharacterized. We have investigated the role of APCs, particularly DCs, in priming of the anti-Tax CTL response under in vitro and in vivo conditions. We investigated two routes (direct vs. indirect) of Tax presentation using live virus, infected primary CD4+/CD25+ T cells, and the CD4+ T cell line (C8166, a HTLV-1-mutated line that only expresses Tax). Our results indicated that DCs are capable of priming a pronounced Tax-specific CTL response in cell cultures consisting of naïve PBLs as well as in HLA-A*0201 transgenic mice (line HHD II). DCs were able to direct the presentation of Tax successfully through infected T cells, live virus, and cell-free Tax. These observations were comparable with those made with a known stimulant of DC maturation, a combination of CD40L and IFN-gamma. Our studies clearly establish a role for this important immune cell component in HTLV-1 immuno/neuropathogenesis and suggest that modulation of DC functions could be an important tool for therapeutic interventions.

  13. The nuclear import of the human T lymphotropic virus type I (HTLV-1) tax protein is carrier- and energy-independent.

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    Tsuji, Takahiro; Sheehy, Noreen; Gautier, Virginie W; Hayakawa, Hitoshi; Sawa, Hirofumi; Hall, William W

    2007-05-04

    HTLV-1 is the etiologic agent of the adult T cell leukemialymphoma (ATLL). The viral regulatory protein Tax plays a central role in leukemogenesis as a transcriptional transactivator of both viral and cellular gene expression, and this requires Tax activity in both the cytoplasm and the nucleus. In the present study, we have investigated the mechanisms involved in the nuclear localization of Tax. Employing a GFP fusion expression system and a range of Tax mutants, we could confirm that the N-terminal 60 amino acids, and specifically residues within the zinc finger motif in this region, are important for nuclear localization. Using an in vitro nuclear import assay, it could be demonstrated that the transportation of Tax to the nucleus required neither energy nor carrier proteins. Specific and direct binding between Tax and p62, a nucleoporin with which the importin beta family of proteins have been known to interact was also observed. The nuclear import activity of wild type Tax and its mutants and their binding affinity for p62 were also clearly correlated, suggesting that the entry of Tax into the nucleus involves a direct interaction with nucleoporins within the nuclear pore complex (NPC). The nuclear export of Tax was also shown to be carrier independent. It could be also demonstrated that Tax it self may have a carrier function and that the NF-kappaB subunit p65 could be imported into the nucleus by Tax. These studies suggest that Tax could alter the nucleocytoplasmic distribution of cellular proteins, and this could contribute to the deregulation of cellular processes observed in HTLV-1 infection.

  14. Stimulation of interleukin-13 expression by human T-cell leukemia virus type 1 oncoprotein Tax via a dually active promoter element responsive to NF-kappaB and NFAT.

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    Silbermann, Katrin; Schneider, Grit; Grassmann, Ralph

    2008-11-01

    The human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein transforms human lymphocytes and is critical for the pathogenesis of HTLV-1-induced adult T-cell leukaemia. In HTLV-transformed cells, Tax upregulates interleukin (IL)-13, a cytokine with proliferative and anti-apoptotic functions that is linked to leukaemogenesis. Tax-stimulated IL-13 is thought to result in autocrine stimulation of HTLV-infected cells and thus may be relevant to their growth. The causal transactivation of the IL-13 promoter by Tax is predominantly dependent on a nuclear factor of activated T cells (NFAT)-binding P element. Here, it was shown that the isolated IL-13 Tax-responsive element (IL13TaxRE) was sufficient to mediate IL-13 transactivation by Tax and NFAT1. However, cyclosporin A, a specific NFAT inhibitor, revealed that Tax transactivation of IL13TaxRE or wild-type IL-13 promoter was independent of NFAT and that NFAT did not contribute to IL-13 upregulation in HTLV-transformed cells. By contrast, Tax stimulation was repressible by an efficient nuclear factor (NF)-kappaB inhibitor (IkBaDN), indicating the requirement for NF-kappaB. The capacity of NF-kappaB to stimulate IL13TaxRE was demonstrated by a strong response to NF-kappaB in reporter assays and by direct binding of NF-kappaB to IL13TaxRE. Thus, IL13TaxRE in the IL-13 promoter represents a dually active promoter element responsive to NF-kappaB and NFAT. Together, these results indicate that Tax causes IL-13 upregulation in HTLV-1-infected cells via NF-kappaB.

  15. Standardisation of Western blotting to detect HTLV-1 antibodies synthesised in the central nervous system of HAM/TSP patients

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    Luiz Claudio Pereira Ribeiro

    2013-09-01

    Full Text Available Intrathecal synthesis of human T-lymphotropic virus type 1 (HTLV-1 antibodies (Abs represents conclusive evidence of a specific immune response in the central nervous system of HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP patients. Western blotting (WB for HTLV Abs in serum is a confirmatory test for HTLV-1 infection. The aim of this study was to standardise the Western blot to demonstrate the intrathecal pattern of Abs against HTLV-1 proteins in HAM/TSP patients. Paired cerebrospinal fluid (CSF and serum samples were selected from 20 patients with definite HAM/TSP, 19 HTLV-1 seronegative patients and two HTLV-1 patients without definite HAM/TSP. The presence of reactive bands of greater intensity in the CSF compared to serum (or bands in only the CSF indicated the intrathecal synthesis of anti-HTLV-1 Abs. All definite HAM/TSP patients presented with an intrathecal synthesis of anti-HTLV-1 Abs; these Abs were not detected in the control patients. The most frequent intrathecal targets of anti-HTLV-1 Abs were GD21, rgp46-I and p24 and, to a lesser extent, p19, p26, p28, p32, p36, p53 gp21 and gp46. The intrathecal immune response against env (GD21 and rgp46-I and gag (p24 proteins represents the most important humoral pattern in HAM/TSP. This response may be used as a diagnostic marker, considering the frequent association of intrathecal anti-HTLV-1 Ab synthesis with HAM/TSP and the pathogenesis of this neurological disease.

  16. Fine tuning of the temporal expression of HTLV-1 and HTLV-2

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    Ilaria eCavallari

    2013-09-01

    Full Text Available Human T-cell leukemia virus types 1 and 2 (HTLV-1 and HTLV-2 are deltaretroviruses that share a common overall genetic organization, splicing pattern, and ability to infect and immortalize T-cells in vitro. However, HTLV-1 and HTLV-2 exhibit a clearly distinct pathogenic potential in infected patients. To find clues to the possible viral determinants of the biology of these viruses, recent studies investigated the timing of expression and the intracellular compartmentalization of viral transcripts in ex-vivo samples from infected patients.Results of these studies revealed a common overall pattern of expression of HTLV-1 and -2 with a two-phase kinetics of expression and a nuclear accumulation of minus-strand transcripts. Studies in cells transfected with HTLV-1 molecular clones demonstrated the strict Rex-dependency of this "two-phase" kinetics. These studies also highlighted interesting differences in the relative abundance of transcripts encoding the Tax and Rex regulatory proteins, and that of the accessory proteins controlling Rex expression and function, thus suggesting a potential basis for the different pathobiology of the two viruses.

  17. Identification and characterization of HTLV-1 HBZ post-translational modifications.

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    Nathan Dissinger

    Full Text Available Human T-cell leukemia virus type-1 (HTLV-1 is estimated to infect 15-25 million people worldwide, with several areas including southern Japan and the Caribbean basin being endemic. The virus is the etiological agent of debilitating and fatal diseases, for which there is currently no long-term cure. In the majority of cases of leukemia caused by HTLV-1, only a single viral gene, hbz, and its cognate protein, HBZ, are expressed and their importance is increasingly being recognized in the development of HTLV-1-associated disease. We hypothesized that HBZ, like other HTLV-1 proteins, has properties and functions regulated by post-translational modifications (PTMs that affect specific signaling pathways important for disease development. To date, PTM of HBZ has not been described. We used an affinity-tagged protein and mass spectrometry method to identify seven modifications of HBZ for the first time. We examined how these PTMs affected the ability of HBZ to modulate several pathways, as measured using luciferase reporter assays. Herein, we report that none of the identified PTMs affected HBZ stability or its regulation of tested pathways.

  18. Role of resident CNS cell populations in HTLV-1-associated neuroinflammatory disease.

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    Lepoutre, Veronique; Jain, Pooja; Quann, Kevin; Wigdahl, Brian; Khan, Zafar K

    2009-01-01

    Human T cell leukemia virus type 1 (HTLV-1), the first human retrovirus discovered, is the etiologic agent for a number of disorders; the two most common pathologies include adult T cell leukemia (ATL) and a progressive demyelinating neuroinflammatory disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The neurologic dysfunction associated with HAM/TSP is a result of viral intrusion into the central nervous system (CNS) and the generation of a hyperstimulated host response within the peripheral and central nervous system that includes expanded populations of CD4+ and CD8+ T cells and proinflammatory cytokines/chemokines in the cerebrospinal fluid (CSF). This robust, yet detrimental immune response likely contributes to the death of myelin producing oligodendrocytes and degeneration of neuronal axons. The mechanisms of neurological degeneration in HAM/TSP have yet to be fully delineated in vivo and may involve the immunogenic properties of the HTLV-1 transactivator protein Tax. This comprehensive review characterizes the available knowledge to date concerning the effects of HTLV-1 on CNS resident cell populations with emphasis on both viral and host factors contributing to the genesis of HAM/TSP.

  19. Adult T-cell leukemia/lymphoma associated with HTLV-1 infection in a Brazilian adolescent

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    VALLE Antonio Carlos Francesconi do

    2001-01-01

    Full Text Available We present the case of a 15-year-old patient infected with HTLV-1 who developed a cutaneous T-cell lymphoma, confirmed by histopathological and immunohistochemical examination, as well as clinically and hematologically confirmed leukemia. The patient died 3 months after initial presentation of the disease. The rarity of the disease in this age group justifies the present report.

  20. Telomere Length, Proviral Load and Neurologic Impairment in HTLV-1 and HTLV-2-Infected Subjects

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    Benjamin Usadi

    2016-08-01

    Full Text Available Short or damaged telomeres have been implicated in degenerative conditions. We hypothesized that analysis of telomere length (TL in human T-cell lymphotropic virus (HTLV infection and HTLV-associated neuropathy might provide clues to the etiology of HTLV-associated disease and viral dynamics. A subset of 45 human T-cell lymphotropic virus type 1 (HTLV-1, 45 human T-cell lymphotropic virus type 2 (HTLV-2, and 45 seronegative subjects was selected from the larger HTLV Outcomes Study (HOST cohort, matched on age, sex and race/ethnicity. Telomere-to-single-copy gene (T/S ratio (a measure of TL and HTLV-1 and HTLV-2 proviral loads were measured in peripheral blood mononuclear cells (PBMCs using quantitative PCR (qPCR. Vibration sensation measured by tuning fork during neurologic examinations performed as part of the HOST study allowed for an assessment of peripheral neuropathy. TL was compared between groups using t-tests, linear and logistic regression. Mean T/S ratio was 1.02 ± 0.16 in HTLV-1, 1.03 ± 0.17 in HTLV-2 and 0.99 ± 0.18 in HTLV seronegative subjects (p = 0.322. TL was not associated with HTLV-1 or -2 proviral load. Shorter TL was significantly associated with impaired vibration sense in the HTLV-2 positive group only. Overall, we found no evidence that telomere length was affected by chronic HTLV-1 and HTLV-2 infection. That TL was only associated with peripheral neuropathy in the HTLV-2-positive group is intriguing, but should be interpreted cautiously. Studies with larger sample size and telomere length measurement in lymphocyte subsets may clarify the relationship between TL and HTLV-infection.

  1. Genetic characterization of human T-cell lymphotropic virus type 1 in Mozambique: transcontinental lineages drive the HTLV-1 endemic.

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    Ana Carolina P Vicente

    2011-04-01

    Full Text Available Human T-Cell Lymphotropic Virus Type 1 (HTLV-1 is the etiological agent of adult T-cell leukemia (ATL and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP. It has been estimated that 10-20 million people are infected worldwide, but no successful treatment is available. Recently, the epidemiology of this virus was addressed in blood donors from Maputo, showing rates from 0.9 to 1.2%. However, the origin and impact of HTLV endemic in this population is unknown.To assess the HTLV-1 molecular epidemiology in Mozambique and to investigate their relationship with HTLV-1 lineages circulating worldwide.Blood donors and HIV patients were screened for HTLV antibodies by using enzyme immunoassay, followed by Western Blot. PCR and sequencing of HTLV-1 LTR region were applied and genetic HTLV-1 subtypes were assigned by the neighbor-joining method. The mean genetic distance of Mozambican HTLV-1 lineages among the genetic clusters were determined. Human mitochondrial (mt DNA analysis was performed and individuals classified in mtDNA haplogroups.LTR HTLV-1 analysis demonstrated that all isolates belong to the Transcontinental subgroup of the Cosmopolitan subtype. Mozambican HTLV-1 sequences had a high inter-strain genetic distance, reflecting in three major clusters. One cluster is associated with the South Africa sequences, one is related with Middle East and India strains and the third is a specific Mozambican cluster. Interestingly, 83.3% of HIV/HTLV-1 co-infection was observed in the Mozambican cluster. The human mtDNA haplotypes revealed that all belong to the African macrohaplogroup L with frequencies representatives of the country.The Mozambican HTLV-1 genetic diversity detected in this study reveals that although the strains belong to the most prevalent and worldwide distributed Transcontinental subgroup of the Cosmopolitan subtype, there is a high HTLV diversity that could be correlated with at least 3 different HTLV-1 introductions

  2. BCL11B is frequently downregulated in HTLV-1-infected T-cells through Tax-mediated proteasomal degradation.

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    Permatasari, Happy Kurnia; Nakahata, Shingo; Ichikawa, Tomonaga; Morishita, Kazuhiro

    2017-08-26

    Human T-cell leukemia virus type 1 (HTLV-1) is a causative agent of adult T-cell leukemia-lymphoma (ATLL). The HTLV-1-encoded protein Tax plays important roles in the proliferation of HTLV-1-infected T-cells by affecting cellular proteins. In this study, we showed that Tax transcriptionally and post-transcriptionally downregulates the expression of the tumor suppressor gene B-cell leukemia/lymphoma 11B (BCL11B), which encodes a lymphoid-related transcription factor. BCL11B expression was downregulated in HTLV-1-infected T-cell lines at the mRNA and protein levels, and forced expression of BCL11B suppressed the proliferation of these cells. The proteasomal inhibitor MG132 increased BCL11B expression in HTLV-1-infected cell lines, and colocalization of Tax with BCL11B was detected in the cytoplasm of HTLV-1-infected T-cells following MG132 treatment. shRNA knock-down of Tax expression also increased the expression of BCL11B in HTLV-1-infected cells. Moreover, we found that Tax physically binds to BCL11B protein and induces the polyubiquitination of BCL11B and proteasome-dependent degradation of BCL11B. Thus, inactivation of BCL11B by Tax protein may play an important role in the Tax-mediated leukemogenesis. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Human parvovirus 4 prevalence among HTLV-1/2 infected individuals in Brazil.

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    Slavov, Svetoslav Nanev; Otaguiri, Katia Kaori; Smid, Jerusa; de Oliveira, Augusto Cesar Penalva; Casseb, Jorge; Martinez, Edson Zangiacomi; Covas, Dimas Tadeu; Eis-Hübinger, Anna Maria; Kashima, Simone

    2017-04-01

    Human parvovirus 4 (PARV4), a Tetraparvovirus, has been largely found in HIV, HBV, or HCV infected individuals. However, there is no data for the PARV4 occurrence in Human T-lymphotropic virus (HTLV-1/2) infected individuals, despite similar transmission routes. Here, PARV4 viremia was evaluated in 130 HTLV infected patients under care of a Brazilian HTLV outpatient clinic. PARV4 viremia was detected in 6.2% of the HTLV-1 infected patients. Most PARV4 positives showed no evidence for parenterally transmitted infections. It is suggested that in Brazil, transmission routes of PARV4 are more complex than in Europe and North America and resemble those in Africa. J. Med. Virol. 89:748-752, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  4. Origin of HTLV-1 in hunters of nonhuman primates in Central Africa.

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    Kazanji, Mirdad; Mouinga-Ondémé, Augustin; Lekana-Douki-Etenna, Sonia; Caron, Mélanie; Makuwa, Maria; Mahieux, Renaud; Gessain, Antoine

    2015-02-01

    Of 78 Gabonese individuals who had received bites from nonhuman primates (NHPs) while hunting, 7 were infected with human T lymphotropic virus (HTLV-1). Five had been bitten by gorillas and were infected with subtype B strains; however, a 12-year-old girl who was severely bitten by a Cercopithecus nictitans was infected with a subtype D strain that was closely related to the simian T lymphotropic virus (STLV-1) that infects this monkey species. Her mother was infected with a subtype B strain. These data confirm that hunters in Africa can be infected by HTLV-1 that is closely related to the strains circulating among local NHP game. Our findings strongly suggest that a severe bite represent a risk factor for STLV-1 acquisition. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  5. Molecular insights on analogs of HIV PR inhibitors toward HTLV-1 PR through QM/MM interactions and molecular dynamics studies: comparative structure analysis of wild and mutant HTLV-1 PR.

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    Selvaraj, Chandrabose; Singh, Poonam; Singh, Sanjeev Kumar

    2014-12-01

    Retroviruses HTLV-1 and HIV-1 are the primary causative agents of fatal adult T-cell leukemia and acquired immune deficiency syndrome (AIDS) disease. Both retroviruses are similar in characteristics mechanism, and it encodes for protease that mainly involved in the viral replication process. On the basis of the therapeutic success of HIV-1 PR inhibitors, the protease of HTLV-1 is mainly considered as a potential target for chemotherapy. At the same time, structural similarities in both enzymes that originate HIV PR inhibitors can also be an HTLV-1 PR inhibitor. But the expectations failed because of rejection of HIV PR inhibitors from the HTLV-1 PR binding pocket. In this present study, the reason for the HIV PR inhibitor rejection from the HTLV-1 binding site was identified through sequence analysis and molecular dynamics simulation method. Functional analysis of M37A mutation in HTLV PR clearly shows that the MET37 specificity and screening of potential inhibitors targeting MET37 is performed by using approved 90% similar HIV PR inhibitor compounds. From this approach, we report few compounds with a tendency to accept/donate electron specifically to an important site residue MET37 in HTLV-1 PR binding pocket. Copyright © 2014 John Wiley & Sons, Ltd.

  6. HTLV-1 cosmopolitan and HTLV-2 subtype b among pregnant women of non-endemic areas of Argentina.

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    Berini, Carolina A; Delfino, Cecilia; Torres, Oscar; García, Gabriela; Espejo, Rogelio; Pianciola, Luis; Juarez, Mirna; Arribere, Graciela; Nadal, Mónica; Eirin, Maria E; Biglione, Mirna M

    2013-06-01

    The objective of this study was to estimate the prevalence of human T cell lymphotropic virus (HTLV)-1/2, HIV-1, hepatitis B virus (HBV), Trypanosoma cruzi, Treponema pallidum and Toxoplasma gondii infections and to identify the subtypes/subgroups of HTLV-1/2 among pregnant women (PW) from non-endemic provinces of Argentina. Methods A total of 2403 samples were screened for HTLV-1/2 and confirmed by western blot and PCR. The long terminal repeat (LTR) of HTLV-1 and HTLV-2 were amplified. Phylogenetic analysis was performed by Neighbour Joining by using molecular evolutionary genetics analysis (MEGA) 4.0. Among a total of 2403 PW studied, 6 (0.25%) tested positive for HTLV-1/2 (3 HTLV-1 (0.12%) and 3 HTLV-2 (0.12%)). The total prevalence when distributed by province was 0.3% (3/804) for Buenos Aires (BA), 0.4% (1/241) for BA surroundings, 0.1% (1/707) for Neuquen and 1.0% (1/95) for Ushuaia. In San Juan, no PW were HTLV-1/2 positive. The prevalence was similar when compared with rates among blood donors of the same areas and years. The phylogenetic analysis classified one sequence as HTLV-1 aA and one as HTLV-2b. The prevalence of HIV-1, HBV, T cruzi, T pallidum and T gondii was 0.6%, 0.2%, 1.4%, 1.2% and 20.9%, respectively. One case of HTLV-1/HIV-1 and one of HTLV-2/HIV-1 co-infection were detected. HTLV-1/2, which have been associated with different diseases, are circulating among PW of Argentina, even in non-endemic areas. Therefore, testing should be recommended in women who have risk factors for these infections given that the majority of HTLV-1/2 mother to child transmission can be prevented by the avoidance of breast feeding.

  7. Evaluation of the role of TAX, HBZ, and HTLV-1 proviral load on the survival of ATLL patients.

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    Akbarin, Mohammad Mehdi; Shirdel, Abbas; Bari, Alireza; Mohaddes, Seyedeh Tahereh; Rafatpanah, Houshang; Karimani, Ehsan Ghayour; Etminani, Kobra; Golabpour, Amin; Torshizi, Reza

    2017-06-01

    Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy with very poor prognosis and short survival, caused by the human T-lymphotropic virus type-1 (HTLV-1). The HTLV-1 biomarkers trans-activator x (TAX) and HTLV-1 basic leucine zipper factor (HBZ) are main oncogenes and life-threatening elements. This study aimed to assess the role of the TAX and HBZ genes and HTLV-1 proviral load (PVL) in the survival of patients with ATLL. Forty-three HTLV-1-infected individuals, including 18 asymptomatic carriers (AC) and 25 ATLL patients (ATLL), were evaluated between 2011 and 2015. The mRNA expression of TAX and HBZ and the HTLV-1 PVL were measured by quantitative PCR. Significant differences in the mean expression levels of TAX and HBZ were observed between the two study groups (ATLL and AC, P =0.014 and P =0.000, respectively). In addition, the ATLL group showed a significantly higher PVL than AC ( P =0.000). There was a significant negative relationship between PVL and survival among all study groups ( P =0.047). The HTLV-1 PVL and expression of TAX and HBZ were higher in the ATLL group than in the AC group. Moreover, a higher PVL was associated with shorter survival time among all ATLL subjects. Therefore, measurement of PVL, TAX , and HBZ may be beneficial for monitoring and predicting HTLV-1-infection outcomes, and PVL may be useful for prognosis assessment of ATLL patients. This research demonstrates the possible correlation between these virological markers and survival in ATLL patients.

  8. Motor behavioral abnormalities and histopathological findings of Wistar rats inoculated with HTLV-1-infected MT2 cells

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    C.C. Câmara

    2010-07-01

    Full Text Available The objective of the present study was to describe motor behavioral changes in association with histopathological and hematological findings in Wistar rats inoculated intravenously with human T-cell lymphotropic virus type 1 (HTLV-1-infected MT2 cells. Twenty-five 4-month-old male rats were inoculated with HTLV-1-infected MT2 cells and 13 control rats were inoculated with normal human lymphocytes. The behavior of the rats was observed before and 5, 10, 15, and 20 months after inoculation during a 30-min/rat testing time for 5 consecutive days. During each of 4 periods, a subset of rats was randomly chosen to be sacrificed in order to harvest the spinal cord for histopathological analysis and to obtain blood for serological and molecular studies. Behavioral analyses of the HTLV-1-inoculated rats showed a significant decrease of climbing, walking and freezing, and an increase of scratching, sniffing, biting, licking, and resting/sleeping. Two of the 25 HTLV-1-inoculated rats (8% developed spastic paraparesis as a major behavioral change. The histopathological changes were few and mild, but in some cases there was diffuse lymphocyte infiltration. The minor and major behavioral changes occurred after 10-20 months of evolution. The long-term observation of Wistar rats inoculated with HTLV-1-infected MT2 cells showed major (spastic paraparesis and minor motor abnormalities in association with the degree of HTLV-1-induced myelopathy.

  9. Regulation of HTLV-1 Gag budding by Vps4A, Vps4B, and AIP1/Alix

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    Yokosawa Hideyoshi

    2007-07-01

    Full Text Available Abstract Background HTLV-1 Gag protein is a matrix protein that contains the PTAP and PPPY sequences as L-domain motifs and which can be released from mammalian cells in the form of virus-like particles (VLPs. The cellular factors Tsg101 and Nedd4.1 interact with PTAP and PPPY, respectively, within the HTLV-1 Gag polyprotein. Tsg101 forms a complex with Vps28 and Vps37 (ESCRT-I complex and plays an important role in the class E Vps pathway, which mediates protein sorting and invagination of vesicles into multivesicular bodies. Nedd4.1 is an E3 ubiquitin ligase that binds to the PPPY motif through its WW motif, but its function is still unknown. In the present study, to investigate the mechanism of HTLV-1 budding in detail, we analyzed HTLV-1 budding using dominant negative (DN forms of the class E proteins. Results Here, we report that DN forms of Vps4A, Vps4B, and AIP1 inhibit HTLV-1 budding. Conclusion These findings suggest that HTLV-1 budding utilizes the MVB pathway and that these class E proteins may be targets for prevention of mother-to-infant vertical transmission of the virus.

  10. HTLV-1 bZIP factor induces inflammation through labile Foxp3 expression.

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    Nanae Yamamoto-Taguchi

    2013-09-01

    Full Text Available Human T-cell leukemia virus type 1 (HTLV-1 causes both a neoplastic disease and inflammatory diseases, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP. The HTLV-1 basic leucine zipper factor (HBZ gene is encoded in the minus strand of the proviral DNA and is constitutively expressed in infected cells and ATL cells. HBZ increases the number of regulatory T (Treg cells by inducing the Foxp3 gene transcription. Recent studies have revealed that some CD4⁺Foxp3⁺ T cells are not terminally differentiated but have a plasticity to convert to other T-cell subsets. Induced Treg (iTreg cells tend to lose Foxp3 expression, and may acquire an effector phenotype accompanied by the production of inflammatory cytokines, such as interferon-γ (IFN-γ. In this study, we analyzed a pathogenic mechanism of chronic inflammation related with HTLV-1 infection via focusing on HBZ and Foxp3. Infiltration of lymphocytes was observed in the skin, lung and intestine of HBZ-Tg mice. As mechanisms, adhesion and migration of HBZ-expressing CD4⁺ T cells were enhanced in these mice. Foxp3⁻CD4⁺ T cells produced higher amounts of IFN-γ compared to those from non-Tg mice. Expression of Helios was reduced in Treg cells from HBZ-Tg mice and HAM/TSP patients, indicating that iTreg cells are predominant. Consistent with this finding, the conserved non-coding sequence 2 region of the Foxp3 gene was hypermethylated in Treg cells of HBZ-Tg mice, which is a characteristic of iTreg cells. Furthermore, Treg cells in the spleen of HBZ-transgenic mice tended to lose Foxp3 expression and produced an excessive amount of IFN-γ, while Foxp3 expression was stable in natural Treg cells of the thymus. HBZ enhances the generation of iTreg cells, which likely convert to Foxp3⁻T cells producing IFN-γ. The HBZ-mediated proinflammatory phenotype of CD4⁺ T cells is implicated in the pathogenesis of HTLV-1-associated inflammation.

  11. Dendritic cell maturation, but not type I interferon exposure, restricts infection by HTLV-1, and viral transmission to T-cells.

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    Gergès Rizkallah

    2017-04-01

    Full Text Available Human T lymphotropic Virus type 1 (HTLV-1 is the etiological agent of Adult T cell Leukemia/Lymphoma (ATLL and HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP. Both CD4+ T-cells and dendritic cells (DCs infected with HTLV-1 are found in peripheral blood from HTLV-1 carriers. We previously demonstrated that monocyte-derived IL-4 DCs are more susceptible to HTLV-1 infection than autologous primary T-cells, suggesting that DC infection precedes T-cell infection. However, during blood transmission, breast-feeding or sexual transmission, HTLV-1 may encounter different DC subsets present in the blood, the intestinal or genital mucosa respectively. These different contacts may impact HTLV-1 ability to infect DCs and its subsequent transfer to T-cells. Using in vitro monocyte-derived IL-4 DCs, TGF-β DCs and IFN-α DCs that mimic DCs contacting HTLV-1 in vivo, we show here that despite their increased ability to capture HTLV-1 virions, IFN-α DCs restrict HTLV-1 productive infection. Surprisingly, we then demonstrate that it is not due to the antiviral activity of type-I interferon produced by IFN-α DCs, but that it is likely to be linked to a distinct trafficking route of HTLV-1 in IL-4 DCs vs. IFN-α DCs. Finally, we demonstrate that, in contrast to IL-4 DCs, IFN-α DCs are impaired in their capacity to transfer HTLV-1 to CD4 T-cells, both after viral capture and trans-infection and after their productive infection. In conclusion, the nature of the DCs encountered by HTLV-1 upon primo-infection and the viral trafficking route through the vesicular pathway of these cells determine the efficiency of viral transmission to T-cells, which may condition the fate of infection.

  12. Infección por HTLV-1 y HIV en pacientes con herpes zoster en Perú

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    Sandra Delgado

    2011-07-01

    Full Text Available Objetivos: Determinar la frecuencia de infección por el virus linfotrópico humano tipo 1 (HTLV-1 y VIH en pacientes con herpes zoster. Material y métodos: Estudio prospectivo observacional realizado entre agosto de 2005 y agosto de 2006. Se incluyeron pacientes adultos con diagnóstico de herpes zoster atendidos en los diferentes servicios del Hospital Nacional Cayetano Heredia. Un cuestionario de características clínicas y factores de riesgo asociados con infección por HTLV-1 y VIH fue completado previo a la toma de muestra. Se excluyeron los pacientes con resultados positivos previos para HTLV-1 y HIV. Resultados: Se incluyeron 44 pacientes, la edad promedio fue 48,1 ± 19,5; 24/44 (55% fueron mujeres. Infección solo por VIH se encontró en 4/44 (9% pacientes, todos menores de 35 años, mientras que infección solo por HTLV-1 se encontró en 2/44 (5% pacientes, todas mujeres mayores de 50 años. Un caso de infección dual fue encontrado en una mujer de 56 años. La tasa de infección por HTLV-1 fue 25% (3/12 en mujeres mayores de 50 años con compromiso de múltiples dermatomas. Conclusiones: En nuestro escenario, la infección por HTLV-1 es ligeramente mas frecuente en mujeres mayores de 50 años con herpes zoster. Por ello, el despistaje de HTLV-1 debe ser recomendado en este grupo etario, mientras que el despistaje de VIH es aún particularmente importante en pacientes jóvenes.(Rev Med Hered 2011;22:98-102.

  13. HTLV-1 Infection and Adult T-Cell Leukemia/Lymphoma—A Tale of Two Proteins: Tax and HBZ

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    Giam, Chou-Zen; Semmes, Oliver John

    2016-01-01

    HTLV-1 (Human T-cell lymphotropic virus type 1) is a complex human delta retrovirus that currently infects 10–20 million people worldwide. While HTLV-1 infection is generally asymptomatic, 3%–5% of infected individuals develop a highly malignant and intractable T-cell neoplasm known as adult T-cell leukemia/lymphoma (ATL) decades after infection. How HTLV-1 infection progresses to ATL is not well understood. Two viral regulatory proteins, Tax and HTLV-1 basic zipper protein (HBZ), encoded by the sense and antisense viral transcripts, respectively, are thought to play indispensable roles in the oncogenic process of ATL. This review focuses on the roles of Tax and HBZ in viral replication, persistence, and oncogenesis. Special emphasis is directed towards recent literature on the mechanisms of action of these two proteins and the roles of Tax and HBZ in influencing the outcomes of HTLV-1 infection including senescence induction, viral latency and persistence, genome instability, cell proliferation, and ATL development. Attempts are made to integrate results from cell-based studies of HTLV-1 infection and studies of HTLV-1 proviral integration site preference, clonality, and clonal expansion based on high throughput DNA sequencing. Recent data showing that Tax hijacks key mediators of DNA double-strand break repair signaling—the ubiquitin E3 ligase, ring finger protein 8 (RNF8) and the ubiquitin E2 conjugating enzyme (UBC13)—to activate the canonical nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) and other signaling pathways will be discussed. A perspective on how the Tax-RNF8 signaling axis might impact genomic instability and how Tax may collaborate with HBZ to drive oncogenesis is provided. PMID:27322308

  14. Quantitative comparison of HTLV-1 and HIV-1 cell-to-cell infection with new replication dependent vectors.

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    Dmitriy Mazurov

    2010-02-01

    Full Text Available We have developed an efficient method to quantify cell-to-cell infection with single-cycle, replication dependent reporter vectors. This system was used to examine the mechanisms of infection with HTLV-1 and HIV-1 vectors in lymphocyte cell lines. Effector cells transfected with reporter vector, packaging vector, and Env expression plasmid produced virus-like particles that transduced reporter gene activity into cocultured target cells with zero background. Reporter gene expression was detected exclusively in target cells and required an Env-expression plasmid and a viral packaging vector, which provided essential structural and enzymatic proteins for virus replication. Cell-cell fusion did not contribute to infection, as reporter protein was rarely detected in syncytia. Coculture of transfected Jurkat T cells and target Raji/CD4 B cells enhanced HIV-1 infection two fold and HTLV-1 infection ten thousand fold in comparison with cell-free infection of Raji/CD4 cells. Agents that interfere with actin and tubulin polymerization strongly inhibited HTLV-1 and modestly decreased HIV-1 cell-to-cell infection, an indication that cytoskeletal remodeling was more important for HTLV-1 transmission. Time course studies showed that HTLV-1 transmission occurred very rapidly after cell mixing, whereas slower kinetics of HIV-1 coculture infection implies a different mechanism of infectious transmission. HTLV-1 Tax was demonstrated to play an important role in altering cell-cell interactions that enhance virus infection and replication. Interestingly, superantigen-induced synapses between Jurkat cells and Raji/CD4 cells did not enhance infection for either HTLV-1 or HIV-1. In general, the dependence on cell-to-cell infection was determined by the virus, the effector and target cell types, and by the nature of the cell-cell interaction.

  15. HTLV-1 Infection and Adult T-Cell Leukemia/Lymphoma—A Tale of Two Proteins: Tax and HBZ

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    Chou-Zen Giam

    2016-06-01

    Full Text Available HTLV-1 (Human T-cell lymphotropic virus type 1 is a complex human delta retrovirus that currently infects 10–20 million people worldwide. While HTLV-1 infection is generally asymptomatic, 3%–5% of infected individuals develop a highly malignant and intractable T-cell neoplasm known as adult T-cell leukemia/lymphoma (ATL decades after infection. How HTLV-1 infection progresses to ATL is not well understood. Two viral regulatory proteins, Tax and HTLV-1 basic zipper protein (HBZ, encoded by the sense and antisense viral transcripts, respectively, are thought to play indispensable roles in the oncogenic process of ATL. This review focuses on the roles of Tax and HBZ in viral replication, persistence, and oncogenesis. Special emphasis is directed towards recent literature on the mechanisms of action of these two proteins and the roles of Tax and HBZ in influencing the outcomes of HTLV-1 infection including senescence induction, viral latency and persistence, genome instability, cell proliferation, and ATL development. Attempts are made to integrate results from cell-based studies of HTLV-1 infection and studies of HTLV-1 proviral integration site preference, clonality, and clonal expansion based on high throughput DNA sequencing. Recent data showing that Tax hijacks key mediators of DNA double-strand break repair signaling—the ubiquitin E3 ligase, ring finger protein 8 (RNF8 and the ubiquitin E2 conjugating enzyme (UBC13—to activate the canonical nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB and other signaling pathways will be discussed. A perspective on how the Tax-RNF8 signaling axis might impact genomic instability and how Tax may collaborate with HBZ to drive oncogenesis is provided.

  16. HTLV-1 Infection and Neuropathogenesis in the Context of Rag1-/-γc-/- (RAG1-Hu) and BLT Mice.

    Science.gov (United States)

    Ginwala, Rashida; Caruso, Breanna; Khan, Zafar K; Pattekar, Ajinkya; Chew, Glen M; Corley, Michael J; Loonawat, Ronak; Jacobson, Steven; Sreedhar, Sreesha; Ndhlovu, Lishomwa C; Jain, Pooja

    2017-09-01

    To date, the lack of a suitable small animal model has hindered our understanding of Human T-cell lymphotropic virus (HTLV)-1 chronic infection and associated neuropathogenesis defined as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The host immune response plays a critical role in the outcome of HTLV-1 infection, which could be better tested in the context of humanized (hu) mice. Thus, we employ here the Balb/c-Rag1 -/- γc -/- or Rag1 as well as Bone marrow-Liver-Thymic (BLT) mouse models for engraftment of human CD34 + hematopoietic stem cells. Flow cytometry and histological analyses confirmed reconstitution of Rag1 and BLT mice with human immune cells. Following HTLV-1 infection, proviral load (PVL) was detected in the blood of Rag-1 and BLT hu-mice as early as 2 weeks post-infection (wpi) with sustained elevation in the subsequent weeks followed by Tax expression. Additionally, infection was compared between adult and neonatal Rag1 mice with both PVL and Tax expression considerably higher in the adult Rag1 mice as compared to the neonates. Establishment of peripheral infection led to lymphocytic infiltration with concomitant Tax expression and resulting myelin disruption within the central nervous system of infected mice. In addition, up-regulation in the expression of several immune checkpoint mediators such as programmed cell death-1 (PD-1), T-cell Ig and ITIM domain (TIGIT), and T cell Ig and mucin domain-3 protein (Tim-3) were observed on CD8 + T cells in various organs including the CNS of infected hu-mice. Collectively, these studies represent the first attempt to establish HTLV-1 neuropathogenesis in the context of Rag-1 and BLT hu-mice as potential novel tools for understanding HTLV-1 neuropathogenesis and testing of novel therapies such as immune checkpoint blockade in the amelioration of chronic HTLV-1 infection.

  17. Functional comparison of antisense proteins of HTLV-1 and HTLV-2 in viral pathogenesis

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    Benoit eBarbeau

    2013-08-01

    Full Text Available The production of antisense transcripts from the 3’ long terminal repeat (LTR in human T-lymphotropic retroviruses has now been clearly demonstrated. After the identification of the antisense strand-encoded HTLV-1 bZIP (HBZ factor, we reported that HBZ could interact with CREB transcription factors and consequently turn off the important activating potential of the viral Tax protein on HTLV-1 5’ LTR promoter activity. We have recently accumulated new results demonstrating that antisense transcripts also exist in HTLV-2, -3 and -4. Furthermore, our data have confirmed the existence of encoded proteins from these antisense transcripts (termed antisense proteins of HTLVs or APHs. APHs are also involved in the down-regulation of Tax-dependent viral transcription. In this review, we will focus on the different molecular mechanisms used by HBZ and APH-2 to control viral expression. While HBZ interacts with CREB through its basic zipper domain, APH-2 binds to this cellular factor through a five amino acid motif localized in its carboxyl terminus. Moreover, unlike APH-2, HBZ possesses an N-terminal activation domain that also contributes to the inhibition of the viral transcription by interacting with the KIX domain of p300/CBP. On the other hand, HBZ was found to induce T-cell proliferation while APH-2 was unable to promote such proliferation. Interestingly, HTLV-2 has not been causally linked to human T-cell leukemia, while HTLV-1 is responsible for the development of the Adult T-cell Leukemia/Lymphoma (ATLL. We will further discuss the possible role played by antisense proteins in the establishment of pathologies induced by viral infection.

  18. Molecular epidemiology of HIV, HBV, HCV, and HTLV-1/2 in drug abuser inmates in central Javan prisons, Indonesia.

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    Prasetyo, Afiono Agung; Dirgahayu, Paramasari; Sari, Yulia; Hudiyono, Hudiyono; Kageyama, Seiji

    2013-06-15

    This study was conducted to determine the current molecular prevalence of human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), and human T lymphotropic virus-1/2 (HTLV-1/2) circulating among drug abuser inmates incarcerated in prisons located in Central Java, Indonesia. Socio-epidemiological data and blood specimens were collected from 375 drug abuser inmates in four prisons. The blood samples were analyzed with serological and molecular testing for HIV, HBV, HCV, HDV, and HTLV-1/2. The seroprevalence of HIV, HBsAg, HCV, HDV, and HTLV-1/2 in drug abuser inmates was 4.8% (18/375), 3.2% (12/375), 34.1% (128/375), 0% (0/375), and 3.7% (14/375), respectively. No co-infections of HIV and HBV were found. Co-infections of HIV/HCV, HIV/HTLV-1/2, HBV/HCV, HBV/HTLV-1/2, and HCV/HTLV-1/2 were prevalent at rates of 4% (15/375), 1.3% (5/375), 1.1% (4/375), 0.3% (1/375), and 2.1% (8/375), respectively. The HIV/HCV co-infection rate was significantly higher in injection drug users (IDUs) compared to non-IDUs. Triple co-infection of HIV/HCV/HTLV-1/2 was found only in three IDUs (0.8%). HIV CRF01_AE was found to be circulating in the inmates. HBV genotype B3 predominated, followed by C1. Subtypes adw and adr were found. HCV genotype 1a predominated among HCV-infected inmates, followed by 1c, 3k, 3a, 4a, and 1b. All HTLV-1 isolates shared 100% homology with HTLV-1 isolated in Japan, while all of the HTLV-2 isolates were subtype 2a. Drug abuser inmates in prisons may offer a unique community to bridge prevention and control of human blood-borne virus infection to the general community.

  19. TCF1 and LEF1 act as T-cell intrinsic HTLV-1 antagonists by targeting Tax.

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    Ma, Guangyong; Yasunaga, Jun-ichirou; Akari, Hirofumi; Matsuoka, Masao

    2015-02-17

    Human T-cell leukemia virus type 1 (HTLV-1) is a delta-type retrovirus that induces malignant and inflammatory diseases during its long persistence in vivo. HTLV-1 can infect various kinds of cells; however, HTLV-1 provirus is predominantly found in peripheral CD4 T cells in vivo. Here we find that TCF1 and LEF1, two Wnt transcription factors that are specifically expressed in T cells, inhibit viral replication through antagonizing Tax functions. TCF1 and LEF1 can each interact with Tax and inhibit Tax-dependent viral expression and activation of NF-κB and AP-1. As a result, HTLV-1 replication is suppressed in the presence of either TCF1 or LEF1. On the other hand, T-cell activation suppresses the expression of both TCF1 and LEF1, and this suppression enables Tax to function as an activator. We analyzed the thymus of a simian T-cell leukemia virus type 1 (STLV-1) infected Japanese macaque, and found a negative correlation between proviral load and TCF1/LEF1 expression in various T-cell subsets, supporting the idea that TCF1 and LEF1 negatively regulate HTLV-1 replication and the proliferation of infected cells. Thus, this study identified TCF1 and LEF1 as Tax antagonistic factors in vivo, a fact which may critically influence the peripheral T-cell tropism of this virus.

  20. T CD4+ cells count among patients co-infected with human immunodeficiency virus type 1 (HIV-1 and human T-cell leukemia virus type 1 (HTLV-1: high prevalence of tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM Contagens de células T CD4+ na co-infecção HIV-1 e HTLV-1: alta prevalência da paraparesia espástica tropical/mielopatia associada ao HTLV-1

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    Jorge Casseb

    2007-08-01

    Full Text Available INTRODUCTION: HIV positive patients co-infected with HTLV-1 may have an increase in their T CD4+ cell counts, thus rendering this parameter useless as an AIDS-defining event. OBJECTIVE: To study the effects induced by the co-infection of HIV-1 and HTLV-1 upon CD4+ cells. MATERIAL AND METHODS: Since 1997, our group has been following a cohort of HTLV-1-infected patients, in order to study the interaction of HTLV-1 with HIV and/or with hepatitis C virus (HCV, as well as HTLV-1-only infected asymptomatic carriers and those with tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM. One hundred and fifty HTLV-1-infected subjects have been referred to our clinic at the Institute of Infectious Diseases "Emílio Ribas", São Paulo. Twenty-seven of them were also infected with HIV-1 and HTLV-1-infection using two ELISAs and confirmed and typed by Western Blot (WB or polymerase chain reaction (PCR. All subjects were evaluated by two neurologists, blinded to the patient's HTLV status, and the TSP/HAM diagnostic was based on the World Health Organization (WHO classification. AIDS-defining events were in accordance with the Centers for Disease Control (CDC classification of 1988. The first T CD4+ cells count available before starting anti-retroviral therapy are shown compared to the HIV-1-infected subjects at the moment of AIDS defining event. RESULTS: A total of 27 HIV-1/HTLV-1 co-infected subjects were identified in this cohort; 15 already had AIDS and 12 remained free of AIDS. The median of T CD4+ cell counts was 189 (98-688 cells/mm³ and 89 (53-196 cells/mm³ for co-infected subjects who had an AIDS-defining event, and HIV-only infected individuals, respectively (p = 0.036. Eight of 27 co-infected subjects (30% were diagnosed as having a TSP/HAM simile diagnosis, and three of them had opportunistic infections but high T CD4+ cell counts at the time of their AIDS- defining event. DISCUSSION: Our results indicate that higher T CD4+ cells

  1. NF-κB signaling mechanisms in HTLV-1-induced adult T-cell leukemia/lymphoma.

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    Harhaj, Edward William; Giam, Chou-Zen

    2018-05-03

    The human T-cell leukemia virus type 1 (HTLV-1) is a complex deltaretrovirus linked to adult T-cell leukemia/lymphoma (ATLL), a fatal CD4+ malignancy in 3-5% of infected individuals. The HTLV-1 Tax regulatory protein plays indispensable roles in regulating viral gene expression and activating cellular signaling pathways that drive the proliferation and clonal expansion of T cells bearing HTLV-1 proviral integrations. Tax is a potent activator of NF-κB, a key signaling pathway that is essential for the survival and proliferation of HTLV-1 infected T cells. However, constitutive NF-κB activation by Tax also triggers a senescence response, suggesting the possibility that only T cells capable of overcoming NF-κB-induced senescence can selectively undergo clonal expansion after HTLV-1 infection. Tax expression is often silenced in the majority of ATLL due to genetic alterations in the tax gene or DNA hypermethylation of the 5'-LTR. Despite the loss of Tax, NF-κB activation remains persistently activated in ATLL due to somatic mutations in genes in the T/B-cell receptor (T/BCR) and NF-κB signaling pathways. In this review, we focus on the key events driving Tax-dependent and independent mechanisms of NF-κB activation during the multi-step process leading to ATLL. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  2. PRMT5 Is Upregulated in HTLV-1-Mediated T-Cell Transformation and Selective Inhibition Alters Viral Gene Expression and Infected Cell Survival

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    Amanda R. Panfil

    2015-12-01

    Full Text Available Human T-cell leukemia virus type-1 (HTLV-1 is a tumorigenic retrovirus responsible for development of adult T-cell leukemia/lymphoma (ATLL. This disease manifests after a long clinical latency period of up to 2–3 decades. Two viral gene products, Tax and HBZ, have transforming properties and play a role in the pathogenic process. Genetic and epigenetic cellular changes also occur in HTLV-1-infected cells, which contribute to transformation and disease development. However, the role of cellular factors in transformation is not completely understood. Herein, we examined the role of protein arginine methyltransferase 5 (PRMT5 on HTLV-1-mediated cellular transformation and viral gene expression. We found PRMT5 expression was upregulated during HTLV-1-mediated T-cell transformation, as well as in established lymphocytic leukemia/lymphoma cell lines and ATLL patient PBMCs. shRNA-mediated reduction in PRMT5 protein levels or its inhibition by a small molecule inhibitor (PRMT5i in HTLV-1-infected lymphocytes resulted in increased viral gene expression and decreased cellular proliferation. PRMT5i also had selective toxicity in HTLV-1-transformed T-cells. Finally, we demonstrated that PRMT5 and the HTLV-1 p30 protein had an additive inhibitory effect on HTLV-1 gene expression. Our study provides evidence for PRMT5 as a host cell factor important in HTLV-1-mediated T-cell transformation, and a potential target for ATLL treatment.

  3. Direct inhibition of RNAse T2 expression by the HTLV-1 viral protein Tax.

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    Polakowski, Nicholas; Han, Hongjin; Lemasson, Isabelle

    2011-08-01

    Adult T-cell leukemia (ATL) is one of the primary diseases caused by Human T-cell Leukemia Virus type 1 (HTLV-1) infection. The virally-encoded Tax protein is believed to initiate early events in the development of this disease, as it is able to promote immortalization of T-cells and transformation of other cell types. These processes may be aided by the ability of the viral protein to directly deregulate expression of specific cellular genes through interactions with numerous transcriptional regulators. To identify gene promoters where Tax is localized, we isolated Tax-DNA complexes from an HTLV-1-infected T-cell line through a chromatin immunoprecipitation (ChIP) assay and used the DNA to probe a CpG island microarray. A site within the RNASET2 gene was found to be occupied by Tax. Real-time PCR analysis confirmed this result, and transient expression of Tax in uninfected cells led to the recruitment of the viral protein to the promoter. This event correlated with a decrease in the level of RNase T2 mRNA and protein, suggesting that Tax represses expression of this gene. Loss of RNase T2 expression occurs in certain hematological malignancies and other forms of cancer, and RNase T2 was recently reported to function as a tumor suppressor. Consequently, a reduction in the level of RNase T2 by Tax may play a role in ATL development.

  4. Direct Inhibition of RNAse T2 Expression by the HTLV-1 Viral Protein Tax

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    Isabelle Lemasson

    2011-08-01

    Full Text Available Adult T-cell leukemia (ATL is one of the primary diseases caused by Human T-cell Leukemia Virus type 1 (HTLV-1 infection. The virally-encoded Tax protein is believed to initiate early events in the development of this disease, as it is able to promote immortalization of T-cells and transformation of other cell types. These processes may be aided by the ability of the viral protein to directly deregulate expression of specific cellular genes through interactions with numerous transcriptional regulators. To identify gene promoters where Tax is localized, we isolated Tax-DNA complexes from an HTLV-1-infected T-cell line through a chromatin immunoprecipitation (ChIP assay and used the DNA to probe a CpG island microarray. A site within the RNASET2 gene was found to be occupied by Tax. Real-time PCR analysis confirmed this result, and transient expression of Tax in uninfected cells led to the recruitment of the viral protein to the promoter. This event correlated with a decrease in the level of RNase T2 mRNA and protein, suggesting that Tax represses expression of this gene. Loss of RNase T2 expression occurs in certain hematological malignancies and other forms of cancer, and RNase T2 was recently reported to function as a tumor suppressor. Consequently, a reduction in the level of RNase T2 by Tax may play a role in ATL development.

  5. Neurological manifestations in individuals with HTLV-1-associated myelopathy/tropical spastic paraparesis in the Amazon.

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    Dias, G A S; Yoshikawa, G T; Koyama, R V L; Fujihara, S; Martins, L C S; Medeiros, R; Quaresma, J A S; Fuzii, H T

    2016-02-01

    A cross-sectional observational study was conducted. The aim was to analyze the clinical-functional profile of patients diagnosed with HTLV-1 (human T-lymphotropic virus type 1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in the Amazon region. Reference center for HTLV in the city of Belém, state of Pará, Brazil. Muscle strength, muscle tone, balance and the need for gait assistance among patients with HAM/TSP were evaluated. Among the 82 patients infected with HTLV-1, 27 (10 men and 17 women) were diagnosed with HAM/TSP. No statistically significant difference in muscle tone or strength was found between the lower limbs. Muscle weakness and spasticity were predominant in the proximal lower limbs. Patients with HAM/TSP are at a high risk of falls (P=0.03), and predominantly use either a cane or a crutch on one side as a gait-assistance device (P=0.02). Patients with HAM/TSP exhibit a similar clinical pattern of muscle weakness and spasticity, with a high risk of falls, requiring gait-assistance devices.

  6. INTERFERON BETA-1A TREATMENT IN HTLV-1-ASSOCIATED MYELOPATHY/TROPICAL SPASTIC PARAPARESIS: A CASE REPORT

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    Graça Maria de Castro Viana

    2014-09-01

    Full Text Available Here a young patient (< 21 years of age with a history of infective dermatitis is described. The patient was diagnosed with myelopathy associated with HTLV-1/tropical spastic paraparesis and treated with interferon beta-1a. The disease was clinically established as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP, and laboratory tests confirmed the presence of antibodies to HTLV-1 in the cerebrospinal fluid (CSF. Mumps, cytomegalovirus, Epstein-Barr virus, schistosomiasis, herpes virus 1 and 2, rubella, measles, varicella-zoster toxoplasmosis, hepatitis, HIV, and syphilis were excluded by serology. The patient was diagnosed with neurogenic bladder and presented with nocturia, urinary urgency, paresthesia of the lower left limb, a marked reduction of muscle strength in the lower limbs, and a slight reduction in upper limb strength. During the fourth week of treatment with interferon beta-1a, urinary urgency and paresthesia disappeared and clinical motor skills improved.

  7. Tax gene expression and cell cycling but not cell death are selected during HTLV-1 infection in vivo

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    Pinatel Christiane

    2010-03-01

    Full Text Available Abstract Background Adult T cell leukemia results from the malignant transformation of a CD4+ lymphoid clone carrying an integrated HTLV-1 provirus that has undergone several oncogenic events over a 30-60 year period of persistent clonal expansion. Both CD4+ and CD8+ lymphocytes are infected in vivo; their expansion relies on CD4+ cell cycling and on the prevention of CD8+ cell death. Cloned infected CD4+ but not CD8+ T cells from patients without malignancy also add up nuclear and mitotic defects typical of genetic instability related to theexpression of the virus-encoded oncogene tax. HTLV-1 expression is cancer-prone in vitro, but in vivo numerous selection forces act to maintain T cell homeostasis and are possibly involved in clonal selection. Results Here we demonstrate that the HTLV-1 associated CD4+ preleukemic phenotype and the specific patterns of CD4+ and CD8+ clonal expansion are in vivo selected processes. By comparing the effects of recent (1 month experimental infections performed in vitro and those observed in cloned T cells from patients infected for >6-26 years, we found that in chronically HTLV-1 infected individuals, HTLV-1 positive clones are selected for tax expression. In vivo, infected CD4+ cells are positively selected for cell cycling whereas infected CD8+ cells and uninfected CD4+ cells are negatively selected for the same processes. In contrast, the known HTLV-1-dependent prevention of CD8+ T cell death pertains to both in vivo and in vitro infected cells. Conclusions Therefore, virus-cell interactions alone are not sufficient to initiate early leukemogenesis in vivo.

  8. Prevalence of HTLV-1/2 in pregnant women living in the metropolitan area of Rio de Janeiro.

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    Denise Leite Maia Monteiro

    2014-09-01

    Full Text Available HTLV-1/2 infection can cause severe and disabling diseases in children and adults. The aim of the study was to estimate the prevalence of HTLV-1/2 infection in pregnant women living in the metropolitan area of Rio de Janeiro.1,204 pregnant women were tested upon hospital admission for delivery in two public hospitals in the cities of Rio de Janeiro and Mesquita, between November, 2012 and April, 2013. The samples were screened by chemiluminescent microparticle immunoassay (CMIA and reactive ones were confirmed by Western blot (WB. Epi-info software was used for building the database and performing the statistical analysis. Eight patients had confirmed HTLV-1/2 infection (7 HTLV-1, one HTLV-2, equivalent to a prevalence rate of 0.66%. Two further reactive screening tests had negative Western blot results and therefore were considered negative in the statistical analysis. All HTLV-1/2-positive patients were born in Rio de Janeiro, most were non-Caucasian (87.5%, in a stable relationship (62.5%, had at least ten years of formal education (62.5% and a monthly family income of up to US$600.00 (87.5%. There was only one case of coinfection with syphilis and none with HIV. The mean age of the infected women was 28.4 (SD = 6.3 years and of the seronegative ones was 24.8 (SD = 6.5 (p = 0.10. The median number of pregnancies were 3.0 and 1.0 (p = 0.06 and the median number of sexual partners were 3.5 and 3.0 (p = 0.33 in the seropositive and negative groups, respectively. There were no statistically significant differences between the groups.A significant prevalence of HTLV-1/2 was found in our population. The socio-epidemiological profile of carrier mothers was similar to the controls. Such findings expose the need for a public health policy of routine HTLV-1/2 screening in antenatal care, since counselling and preventive measures are the only strategies currently available to interrupt the chain of transmission and the future development of HTLV-1

  9. The frequency of CD127low expressing CD4+CD25high T regulatory cells is inversely correlated with human T lymphotrophic virus type-1 (HTLV-1 proviral load in HTLV-1-infection and HTLV-1-associated myelopathy/tropical spastic paraparesis

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    Chieia Marco

    2008-07-01

    Full Text Available Abstract Background CD4+CD25high regulatory T (TReg cells modulate antigen-specific T cell responses, and can suppress anti-viral immunity. In HTLV-1 infection, a selective decrease in the function of TReg cell mediated HTLV-1-tax inhibition of FOXP3 expression has been described. The purpose of this study was to assess the frequency and phenotype of TReg cells in HTLV-1 asymptomatic carriers and in HTLV-1-associated neurological disease (HAM/TSP patients, and to correlate with measures of T cell activation. Results We were able to confirm that HTLV-I drives activation, spontaneous IFNγ production, and proliferation of CD4+ T cells. We also observed a significantly lower proportion of CTLA-4+ TReg cells (CD4+CD25high T cells in subjects with HAM/TSP patients compared to healthy controls. Ki-67 expression was negatively correlated to the frequency of CTLA-4+ TReg cells in HAM/TSP only, although Ki-67 expression was inversely correlated with the percentage of CD127low TReg cells in healthy control subjects. Finally, the proportion of CD127low TReg cells correlated inversely with HTLV-1 proviral load. Conclusion Taken together, the results suggest that TReg cells may be subverted in HAM/TSP patients, which could explain the marked cellular activation, spontaneous cytokine production, and proliferation of CD4+ T cells, in particular those expressing the CD25highCD127low phenotype. TReg cells represent a potential target for therapeutic intervention for patients with HTLV-1-related neurological diseases.

  10. Cloning and transmembrane glycoprotein expression of the retrovirus HTLV-1 in mammals' cells

    OpenAIRE

    Penteado, Flora Cristina Lobo; Medeiros, Luciene; Orellana, Maristela Delgado; Palma, Patricia; Fontes, Aparecida Maria; Takayanagui, Osvaldo Massaiti; Covas, Dimas Tadeu

    2006-01-01

    O retrovírus linfotrópico de células T humanas tipo 1 é o agente etiológico da leucemia das células T do adulto e da paraparesia espástica tropical/mielopatia associada ao HTLV-1. O genoma proviral é composto por 9.032 pares de bases, contendo genes estruturais e regulatórios. A glicoproteína transmembrana gp 21 é codificada pelo gene estrutural env. O desenvolvimento de metodologias para a expressão heteróloga de proteínas, assim como a obtenção de uma linhagem celular que expresse a gp 21 r...

  11. Urodynamic features of the voiding dysfunction in HTLV-1 infected individuals

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    Neviton M. Castro

    2007-04-01

    Full Text Available OBJECTIVE:To describe urodynamic abnormalities in HTLV-1 infected individuals presenting urinary symptoms and verify if these findings and quality of life (QOL evaluation correlate with overall neurological impairment. MATERIALS AND METHODS: From January/2001 to May/2004, 324 HTLV-1 seropositive subjects were evaluated to determine the occurrence of urinary symptoms. Urodynamic testing was performed in those who complained of frequency, urgency, or incontinence. They went through a complete clinical, neurological, and urological examination to investigate symptoms and signs of myelopathy. Neurological disability was assessed by Expanded Disability Status Scale (EDSS. RESULTS: From the 324 patients evaluated, 78 underwent the urodynamic testing. Fifty-seven individuals were females (73.1% and age ranged from 23 to 76 years (mean = 48.7 years; SD ± 11.6. Urodynamic testing was abnormal in 63 patients (80.8%. The major abnormality was detrusor overactivity (DO, observed in 33 individuals (33/63; 52.4%, followed by detrusor-external sphincter dyssynergia (DESD, diagnosed in 15 subjects (15/63; 25.4%. HAM/TSP patients had significantly more DESD than the HTLV-I carriers (p = 0.005; OR = 5.5; CI: 1.6 to 19.4. QOL was severely compromised in HAM/TSP patients. CONCLUSIONS: Prominent urodynamic abnormalities were identified in individuals genuinely considered as HTLV-I carriers, suggesting an early compromise of the urinary tract; whereas HAM/TSP patients presented urodynamic findings, which posed a potential risk to the upper urinary tract (dyssynergia. Urodynamic evaluation should be performed in all HTLV-I-infected individuals with voiding complaints.

  12. Effect of TPA and HTLV-1 Tax on BRCA1 and ERE controlled genes expression.

    Science.gov (United States)

    Jabareen, Azhar; Abu-Jaafar, Aya; Abou-Kandil, Ammar; Huleihel, Mahmoud

    2017-07-18

    Interference with the expression and/or functions of the multifunctional tumor suppressor BRCA1 leads to a high risk of breast and ovarian cancers. BRCA1 expression is usually activated by the estrogen (E2) liganded ERα receptor. Activated ERα is considered as a potent transcription factor which activates various genes expression by 2 pathways. A classical pathway, ERα binds directly to E2-responsive elements (EREs) in the promoters of the responsive genes and a non-classical pathway where ERα indirectly binds with the appropriate gene promoter. In our previous study, HTLV-1Tax was found to strongly inhibit ERα induced BRCA1 expression while stimulating ERα induced ERE dependent genes. TPA is a strong PKC activator which found to induce the expression of HTLV-1. Here we examined the effect of TPA on the expression of BRCA1 and genes controlled by ERE region in MCF-7 cells and on Tax activity on these genes. Our results showed strong stimulatory effect of TPA on both BRCA1 and ERE expression without treatment with E2. Tax did not show any significant effect on these TPA activities. It seems that TPA activation of BRCA1 and ERE expression is dependent on PKC activity but not through the NFκB pathway. However, 53BP1 may be involved in this TPA activity because its overexpression significantly reduced the TPA stimulatory effect on BRCA1 and ERE expression. Additionally, our Chip assay results probably exclude possible involvement of ERα pathway in this TPA activity because TPA did not interfere with the binding of ERα to both BRCA1 promoter and ERE region.

  13. Divergent strains of human T-lymphotropic virus type 1 (HTLV-1) within the Cosmopolitan subtype in Argentina.

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    Eirin, Maria E; Dilernia, Dario A; Berini, Carolina A; Jones, Leandro R; Pando, Maria A; Biglione, Mirna M

    2008-10-01

    HTLV-1 Cosmopolitan subtype Transcontinental subgroup A has been described among aboriginal communities from the northwest endemic area of Argentina. Moreover, Transcontinental subgroup A and the Japanese subgroup B were reported among blood donors from the nonendemic central region of the country. We carried out the first HTLV-1 phylogenetic study in individuals residing in Buenos Aires capital city. Phylogenetic analysis performed on the LTR region showed that all 44 new strains clustered within the Cosmopolitan subtype, with 42 (95.4%) belonging to Transcontinental subgroup A. Of them, 20 (45.5%) strains grouped in the large Latin American cluster and 4 (9.1%) in the small Latin American cluster. The majority of them belonged to individuals of nonblack origin, grouped with Amerindian strains. Three (6.8%) were closely related to South African references and two monophyletic clusters including only HIV/HTLV-1 coinfected individuals were observed. Interestingly, two (4.5%) new sequences (divergent strains) branched off from all five known Cosmopolitan subgroups in a well-supported clade. In summary, these findings show that HTLV-1 Cosmopolitan subtype Transcontinental subgroup A is infecting residents of Buenos Aires, a nonendemic area of Argentina, and confirm the introduction of divergent strains in the country.

  14. Quantitative PCR for HTLV-1 provirus in adult T-cell leukemia/lymphoma using paraffin tumor sections.

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    Kato, Junki; Masaki, Ayako; Fujii, Keiichiro; Takino, Hisashi; Murase, Takayuki; Yonekura, Kentaro; Utsunomiya, Atae; Ishida, Takashi; Iida, Shinsuke; Inagaki, Hiroshi

    2016-11-01

    Detection of HTLV-1 provirus using paraffin tumor sections may assist the diagnosis of adult T-cell leukemia/lymphoma (ATLL). For the detection, non-quantitative PCR assay has been reported, but its usefulness and limitations remain unclear. To our knowledge, quantitative PCR assay using paraffin tumor sections has not been reported. Using paraffin sections from ATLLs and non-ATLL T-cell lymphomas, we first performed non-quantitative PCR for HTLV-1 provirus. Next, we determined tumor ratios and carried out quantitative PCR to obtain provirus copy numbers. The results were analyzed with a simple regression model and a novel criterion, cut-off using 95 % rejection limits. Our quantitative PCR assay showed an excellent association between tumor ratios and the copy numbers (r = 0.89, P paraffin tumor sections may be useful for the screening of ATLL cases, especially in HTLV-1 non-endemic areas where easy access to serological testing for HTLV-1 infection is limited. © 2016 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.

  15. Hijacking of the O-GlcNAcZYME complex by the HTLV-1 Tax oncoprotein facilitates viral transcription.

    Science.gov (United States)

    Groussaud, Damien; Khair, Mostafa; Tollenaere, Armelle I; Waast, Laetitia; Kuo, Mei-Shiue; Mangeney, Marianne; Martella, Christophe; Fardini, Yann; Coste, Solène; Souidi, Mouloud; Benit, Laurence; Pique, Claudine; Issad, Tarik

    2017-07-01

    The viral Tax oncoprotein plays a key role in both Human T-cell lymphotropic virus type 1 (HTLV-1)-replication and HTLV-1-associated pathologies, notably adult T-cell leukemia. Tax governs the transcription from the viral 5'LTR, enhancing thereby its own expression, via the recruitment of dimers of phosphorylated CREB to cAMP-response elements located within the U3 region (vCRE). In addition to phosphorylation, CREB is also the target of O-GlcNAcylation, another reversible post-translational modification involved in a wide range of diseases, including cancers. O-GlcNAcylation consists in the addition of O-linked-N-acetylglucosamine (O-GlcNAc) on Serine or Threonine residues, a process controlled by two enzymes: O-GlcNAc transferase (OGT), which transfers O-GlcNAc on proteins, and O-GlcNAcase (OGA), which removes it. In this study, we investigated the status of O-GlcNAcylation enzymes in HTLV-1-transformed T cells. We found that OGA mRNA and protein expression levels are increased in HTLV-1-transformed T cells as compared to control T cell lines while OGT expression is unchanged. However, higher OGA production coincides with a reduction in OGA specific activity, showing that HTLV-1-transformed T cells produce high level of a less active form of OGA. Introducing Tax into HEK-293T cells or Tax-negative HTLV-1-transformed TL-om1 T cells is sufficient to inhibit OGA activity and increase total O-GlcNAcylation, without any change in OGT activity. Furthermore, Tax interacts with the OGT/OGA complex and inhibits the activity of OGT-bound OGA. Pharmacological inhibition of OGA increases CREB O-GlcNAcylation as well as HTLV-1-LTR transactivation by Tax and CREB recruitment to the LTR. Moreover, overexpression of wild-type CREB but not a CREB protein mutated on a previously described O-GlcNAcylation site enhances Tax-mediated LTR transactivation. Finally, both OGT and OGA are recruited to the LTR. These findings reveal the interplay between Tax and the O-GlcNAcylation pathway

  16. Short communication an interferon-γ ELISPOT assay with two cytotoxic T cell epitopes derived from HTLV-1 tax region 161-233 discriminates HTLV-1-associated myelopathy/tropical spastic paraparesis patients from asymptomatic HTLV-1 carriers in a Peruvian population.

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    Best, Ivan; López, Giovanni; Talledo, Michael; MacNamara, Aidan; Verdonck, Kristien; González, Elsa; Tipismana, Martín; Asquith, Becca; Gotuzzo, Eduardo; Vanham, Guido; Clark, Daniel

    2011-11-01

    HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic and progressive disorder caused by the human T-lymphotropic virus type 1 (HTLV-1). In HTLV-1 infection, a strong cytotoxic T cell (CTL) response is mounted against the immunodominant protein Tax. Previous studies carried out by our group reported that increased IFN-γ enzyme-linked immunospot (ELISPOT) responses against the region spanning amino acids 161 to 233 of the Tax protein were associated with HAM/TSP and increased HTLV-1 proviral load (PVL). An exploratory study was conducted on 16 subjects with HAM/TSP, 13 asymptomatic carriers (AC), and 10 HTLV-1-seronegative controls (SC) to map the HAM/TSP-associated CTL epitopes within Tax region 161-233. The PVL of the infected subjects was determined and the specific CTL response was evaluated with a 6-h incubation IFN-γ ELISPOT assay using peripheral blood mononuclear cells (PBMCs) stimulated with 16 individual overlapping peptides covering the Tax region 161-233. Other proinflammatory and Th1/Th2 cytokines were also quantified in the supernatants by a flow cytometry multiplex assay. In addition, a set of human leukocyte antigen (HLA) class I alleles that bind with high affinity to the CTL epitopes of interest was determined using computational tools. Univariate analyses identified an association between ELISPOT responses to two new CTL epitopes, Tax 173-185 and Tax 181-193, and the presence of HAM/TSP as well as an increased PVL. The HLA-A*6801 allele, which is predicted to bind to the Tax 181-193 peptide, was overpresented in the HAM/TSP patients tested.

  17. Stable human T-cell lymphotropic virus type 1 (HTLV-1) subtype a/subgroup a endemicity in Amerindians from Northwest Argentina: a health problem to be resolved.

    Science.gov (United States)

    Eirin, Maria E; Berini, Carolina A; Jones, Leandro R; Dilernia, Dario A; Puca, Alberto A; Biglione, Mirna M

    2010-12-01

    Jujuy province, in Northwest Argentina, is known to be endemic for HTLV-1 infection. Moreover, foci of HTLV-1 associated pathologies have also been described in this region. To gain an insight into the current situation of HTLV-1/2 in this endemic area, a seroprevalence and phylogenetic study was performed among a Kolla community from Abra Pampa city and surroundings. Out of 112 individuals, 11 (9.8%) were confirmed as HTLV-1 positive and no HTLV-2 infection was detected. The phylogenetic analysis of the LTR region showed that all the HTLV-1 sequences belonged to the Cosmopolitan subtype a/transcontinental subgroup A, and were closely related to reference sequences from Peru, Argentina, and the South of Brazil (P = 0.82). Considering the cultural and historical features of this community and in spite of the mandatory detection of anti-HTLV-1/2 antibodies in blood banks since 2005, it would be important to implement new public health measures focused on decreasing HTLV-1 transmission in this endemic area.

  18. The transcription elongation factor ELL2 is specifically upregulated in HTLV-1-infected T-cells and is dependent on the viral oncoprotein Tax

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    Mann, Melanie C., E-mail: melanie.mann@viro.med.uni-erlangen.de; Strobel, Sarah, E-mail: sarah.strobel@viro.med.uni-erlangen.de; Fleckenstein, Bernhard, E-mail: bernhard.fleckenstein@viro.med.uni-erlangen.de; Kress, Andrea K., E-mail: andrea.kress@viro.med.uni-erlangen.de

    2014-09-15

    The oncoprotein Tax of human T-cell leukemia virus type 1 (HTLV-1) is a potent transactivator of viral and cellular transcription. Here, we identified ELL2 as the sole transcription elongation factor to be specifically upregulated in HTLV-1-/Tax-transformed T-cells. Tax contributes to regulation of ELL2, since transient transfection of Tax increases ELL2 mRNA, Tax transactivates the ELL2 promoter, and repression of Tax results in decrease of ELL2 in transformed T-lymphocytes. However, we also measured upregulation of ELL2 in HTLV-1-transformed cells exhibiting undetectable amounts of Tax, suggesting that ELL2 can still be maintained independent of continuous Tax expression. We further show that Tax and ELL2 synergistically activate the HTLV-1 promoter, indicating that ELL2 cooperates with Tax in viral transactivation. This is supported by our findings that Tax and ELL2 accumulate in nuclear fractions and that they co-precipitate upon co-expression in transiently-transfected cells. Thus, upregulation of ELL2 could contribute to HTLV-1 gene regulation. - Highlights: • ELL2, a transcription elongation factor, is upregulated in HTLV-1-positive T-cells. • Tax transactivates the ELL2 promoter. • Tax and ELL2 synergistically activate the HTLV-1 promoter. • Tax and ELL2 interact in vivo.

  19. The transcription elongation factor ELL2 is specifically upregulated in HTLV-1-infected T-cells and is dependent on the viral oncoprotein Tax

    International Nuclear Information System (INIS)

    Mann, Melanie C.; Strobel, Sarah; Fleckenstein, Bernhard; Kress, Andrea K.

    2014-01-01

    The oncoprotein Tax of human T-cell leukemia virus type 1 (HTLV-1) is a potent transactivator of viral and cellular transcription. Here, we identified ELL2 as the sole transcription elongation factor to be specifically upregulated in HTLV-1-/Tax-transformed T-cells. Tax contributes to regulation of ELL2, since transient transfection of Tax increases ELL2 mRNA, Tax transactivates the ELL2 promoter, and repression of Tax results in decrease of ELL2 in transformed T-lymphocytes. However, we also measured upregulation of ELL2 in HTLV-1-transformed cells exhibiting undetectable amounts of Tax, suggesting that ELL2 can still be maintained independent of continuous Tax expression. We further show that Tax and ELL2 synergistically activate the HTLV-1 promoter, indicating that ELL2 cooperates with Tax in viral transactivation. This is supported by our findings that Tax and ELL2 accumulate in nuclear fractions and that they co-precipitate upon co-expression in transiently-transfected cells. Thus, upregulation of ELL2 could contribute to HTLV-1 gene regulation. - Highlights: • ELL2, a transcription elongation factor, is upregulated in HTLV-1-positive T-cells. • Tax transactivates the ELL2 promoter. • Tax and ELL2 synergistically activate the HTLV-1 promoter. • Tax and ELL2 interact in vivo

  20. Impact of depression on quality of life in people living with human T cell lymphotropic virus type 1 (HTLV-1) in Salvador, Brazil.

    Science.gov (United States)

    Galvão-Castro, Ana Verena; Boa-Sorte, Ney; Kruschewsky, Ramon Almeida; Grassi, Maria Fernanda Rios; Galvão-Castro, Bernardo

    2012-11-01

    A previous study found the prevalence of depression in HTLV-1-infected patients to be approximately 30%, but few studies have attempted to correlate depression with quality of life (QOL) in these patients. The present study investigates the association between depression and QOL in people living with HTLV-1. A clinical-epidemiological questionnaire, the Mini International Neuropsychiatric Interview and the WHOQOL-Bref were applied to 88 HTLV-1-infected patients (32 with TSP/HAM) at the HTLV Center of the Bahiana School of Medicine and Public Health, Salvador, Brazil. The prevalence of depression among people living with HTLV-1 was 34.1%. Depression was significantly associated with a poor QOL in the physical, psychological, social relationship and environment domains, when controlling for other variables, such as gender, age, time of knowledge of serological diagnosis and presence of tropical spastic paraparesis/HTLV-1associated myelopathy (TSP/HAM). Moreover, patients with TSP/HAM experienced a reduction in their QOL in the physical, psychological and environment domains. Our results showed that depression negatively affects the quality of life of people living with HTLV-1, regardless of the presence of TSP/HAM. Since it is possible to improve a patient's QOL by treating depression, psychological evaluations are strongly recommended as a measure to integrate the treatment protocols of HTLV-1 intervention programs.

  1. Involvement of TORC2, a CREB co-activator, in the in vivo-specific transcriptional control of HTLV-1

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    Furuta Rika A

    2009-08-01

    Full Text Available Abstract Background Human T-cell leukemia virus type 1 (HTLV-1 causes adult T -cell leukemia (ATL but the expression of HTLV-1 is strongly suppressed in the peripheral blood of infected people. However, such suppression, which may explain the long latency in the development of ATL, is readily reversible, and viral expression resumes quickly with ex vivo culture of infected T -cells. To investigate the mechanism of in vivo -specific transcriptional suppression, we established a mouse model in which mice were intraperitoneally administered syngeneic EL4 T -lymphoma cells transduced with a recombinant retrovirus expressing a GFP-Tax fusion protein, Gax, under the control of the HTLV-1 enhancer (EL4-Gax. Results Gax gene transcription was silenced in vivo but quickly up-regulated in ex vivo culture. Analysis of integrated Gax reporter gene demonstrated that neither CpG methylation of the promoter DNA nor histone modification was associated with the reversible suppression. ChIP-analysis of LTR under suppression revealed reduced promoter binding of TFIIB and Pol-II, but no change in the binding of CREB or CBP/p300 to the viral enhancer sequence. However, the expression of TORC2, a co-activator of CREB, decreased substantially in the EL4-Gax cells in vivo, and this returned to normal levels in ex vivo culture. The reduced expression of TORC2 was associated with translocation from the nucleus to the cytoplasm. A knock-down experiment with siRNA confirmed that TORC2 was the major functional protein of the three TORC-family proteins (TORC1, 2, 3 in EL4-Gax cells. Conclusion These results suggest that the TORC2 may play an important role in the in vivo -specific transcriptional control of HTLV-1. This study provides a new model for the reversible mechanism that suppresses HTLV-1 expression in vivo without the DNA methylation or hypoacetylated histones that is observed in the primary cells of most HTLV-1 -infected carriers and a substantial number of ATL

  2. HTLV-1 modulates the frequency and phenotype of FoxP3+CD4+ T cells in virus-infected individuals

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    Satou Yorifumi

    2012-05-01

    Full Text Available Abstract Background HTLV-1 utilizes CD4 T cells as the main host cell and maintains the proviral load via clonal proliferation of infected CD4+ T cells. Infection of CD4+ T cells by HTLV-1 is therefore thought to play a pivotal role in HTLV-1-related pathogenicity, including leukemia/lymphoma of CD4+ T cells and chronic inflammatory diseases. Recently, it has been reported that a proportion of HTLV-1 infected CD4+ T cells express FoxP3, a master molecule of regulatory T cells. However, crucial questions remain unanswered on the relationship between HTLV-1 infection and FoxP3 expression. Results To investigate the effect of HTLV-1 infection on CD4+ T-cell subsets, we used flow cytometry to analyze the T-cell phenotype and HTLV-1 infection in peripheral mononuclear cells (PBMCs of four groups of subjects, including 23 HTLV-1-infected asymptomatic carriers (AC, 10 patients with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP, 10 patients with adult T-cell leukemia (ATL, and 10 healthy donors. The frequency of FoxP3+ cells in CD4+ T cells in AC with high proviral load and patients with HAM/TSP or ATL was higher than that in uninfected individuals. The proviral load was positively correlated with the percentage of CD4+ T cells that were FoxP3+. The CD4+FoxP3+ T cells, themselves, were frequently infected with HTLV-1. We conclude that FoxP3+ T- cells are disproportionately infected with HTLV-1 during chronic infection. We next focused on PBMCs of HAM/TSP patients. The expression levels of the Treg associated molecules CTLA-4 and GITR were decreased in CD4+FoxP3+ T cells. Further we characterized FoxP3+CD4+ T-cell subsets by staining CD45RA and FoxP3, which revealed an increase in CD45RA−FoxP3low non-suppressive T-cells. These findings can reconcile the inflammatory phenotype of HAM/TSP with the observed increase in frequency of FoxP3+ cells. Finally, we analyzed ATL cells and observed not only a high frequency of FoxP3 expression

  3. Kefir induces cell-cycle arrest and apoptosis in HTLV-1-negative malignant T-lymphocytes

    Science.gov (United States)

    Maalouf, Katia; Baydoun, Elias; Rizk, Sandra

    2011-01-01

    Background: Adult lymphoblastic leukemia (ALL) is a malignancy that occurs in white blood cells. The overall cure rate in children is 85%, whereas it is only 40% in adults. Kefir is an important probiotic that contains many bioactive ingredients, which give it unique health benefits. It has been shown to control several cellular types of cancer. Purpose: The present study investigates the effect of a cell-free fraction of kefir on CEM and Jurkat cells, which are human T-lymphotropic virus type I (HTLV-1)-negative malignant T-lymphocytes. Methods: Cells were incubated with different kefir concentrations. The cytotoxicity of the compound was evaluated by determining the percentage viability of cells. The effect of all the noncytotoxic concentrations of kefir on the proliferation of CEM and Jurkat cells was then assessed. The levels of transforming growth factor-alpha (TGF-α), transforming growth factor- beta1 (TGF-β1), matrix metalloproteinase-2 (MMP-2), and MMP-9 mRNA upon kefir treatment were then analyzed using reverse transcriptase polymerase chain reaction (RT-PCR). Finally, the growth inhibitory effects of kefir on cell-cycle progression/apoptosis were assessed by Cell Death Detection (ELISA) and flow cytometry. Results: The maximum cytotoxicity recorded after 48-hours treatment with 80 μg/μL kefir was only 42% and 39% in CEM and Jurkat cells, respectively. The percent reduction in proliferation was very significant, and was dose-, and time-dependent. In both cell lines, kefir exhibited its antiproliferative effect by downregulating TGF-α and upregulating TGF-β1 mRNA expression. Upon kefir treatment, a marked increase in cell-cycle distribution was noted in the preG1 phase of CEM and Jurkat cells, indicating the proapoptotic effect of kefir, which was further confirmed by Cell Death Detection ELISA. However, kefir did not affect the mRNA expression of metalloproteinases needed for the invasion of leukemic cell lines. Conclusion: In conclusion, kefir is

  4. Kefir induces cell-cycle arrest and apoptosis in HTLV-1-negative malignant T-lymphocytes

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    Katia Maalouf

    2011-02-01

    Full Text Available Katia Maalouf1, Elias Baydoun2, Sandra Rizk11Department of Natural Sciences, Lebanese American University, Beirut, Lebanon; 2Department of Biology, American University of Beirut, Beirut, LebanonBackground: Adult lymphoblastic leukemia (ALL is a malignancy that occurs in white blood cells. The overall cure rate in children is 85%, whereas it is only 40% in adults. Kefir is an important probiotic that contains many bioactive ingredients, which give it unique health benefits. It has been shown to control several cellular types of cancer.Purpose: The present study investigates the effect of a cell-free fraction of kefir on CEM and Jurkat cells, which are human T-lymphotropic virus type I (HTLV-1-negative malignant T-lymphocytes.Methods: Cells were incubated with different kefir concentrations. The cytotoxicity of the compound was evaluated by determining the percentage viability of cells. The effect of all the noncytotoxic concentrations of kefir on the proliferation of CEM and Jurkat cells was then assessed. The levels of transforming growth factor-alpha (TGF-α, transforming growth factor- beta1 (TGF-β1, matrix metalloproteinase-2 (MMP-2, and MMP-9 mRNA upon kefir treatment were then analyzed using reverse transcriptase polymerase chain reaction (RT-PCR. Finally, the growth inhibitory effects of kefir on cell-cycle progression/apoptosis were assessed by Cell Death Detection (ELISA and flow cytometry.Results: The maximum cytotoxicity recorded after 48-hours treatment with 80 µg/µL kefir was only 42% and 39% in CEM and Jurkat cells, respectively. The percent reduction in proliferation was very significant, and was dose-, and time-dependent. In both cell lines, kefir exhibited its antiproliferative effect by downregulating TGF-α and upregulating TGF- β1 mRNA expression. Upon kefir treatment, a marked increase in cell-cycle distribution was noted in the preG1 phase of CEM and Jurkat cells, indicating the proapoptotic effect of kefir, which was

  5. Kefir induces cell-cycle arrest and apoptosis in HTLV-1-negative malignant T-lymphocytes

    International Nuclear Information System (INIS)

    Maalouf, Katia; Baydoun, Elias; Rizk, Sandra

    2011-01-01

    Adult lymphoblastic leukemia (ALL) is a malignancy that occurs in white blood cells. The overall cure rate in children is 85%, whereas it is only 40% in adults. Kefir is an important probiotic that contains many bioactive ingredients, which give it unique health benefits. It has been shown to control several cellular types of cancer. The present study investigates the effect of a cell-free fraction of kefir on CEM and Jurkat cells, which are human T-lymphotropic virus type I (HTLV-1)-negative malignant T-lymphocytes. Cells were incubated with different kefir concentrations. The cytotoxicity of the compound was evaluated by determining the percentage viability of cells. The effect of all the noncytotoxic concentrations of kefir on the proliferation of CEM and Jurkat cells was then assessed. The levels of transforming growth factor-alpha (TGF-α), transforming growth factor- beta1 (TGF-β1), matrix metalloproteinase-2 (MMP-2), and MMP-9 mRNA upon kefir treatment were then analyzed using reverse transcriptase polymerase chain reaction (RT-PCR). Finally, the growth inhibitory effects of kefir on cell-cycle progression/apoptosis were assessed by Cell Death Detection (ELISA) and flow cytometry. The maximum cytotoxicity recorded after 48-hours treatment with 80 μg/μL kefir was only 42% and 39% in CEM and Jurkat cells, respectively. The percent reduction in proliferation was very significant, and was dose-, and time-dependent. In both cell lines, kefir exhibited its antiproliferative effect by downregulating TGF-α and upregulating TGF-β1 mRNA expression. Upon kefir treatment, a marked increase in cell-cycle distribution was noted in the preG 1 phase of CEM and Jurkat cells, indicating the proapoptotic effect of kefir, which was further confirmed by Cell Death Detection ELISA. However, kefir did not affect the mRNA expression of metalloproteinases needed for the invasion of leukemic cell lines. In conclusion, kefir is effective in inhibiting proliferation and inducing

  6. Lesões dermatológicas em pacientes infectados pelo vírus linfotrópico humano de células T do tipo 1 (HTLV-1 Dermatologic lesions in patients infected with the human T-cell lymphotropic vírus type 1 (HTLV-1

    Directory of Open Access Journals (Sweden)

    Vandack Nobre

    2005-02-01

    Full Text Available O vírus linfotrópico humano de células T do tipo 1 (HTLV-1 é o primeiro retrovírus isolado do ser humano. Descreveu-se, em pouco tempo, o seu papel etiológico em algumas doenças, com destaque para a leucemia/linfoma de células T do adulto (ATLL, a mielopatia associada ao HTLV-1/paraparesia espástica tropical (HAM/TSP e a uveíte associada ao HTLV-1 (HAU. Na década de 90, o HTLV-1 foi associado a eczema grave da infância, conhecido como dermatite infecciosa (DI. Desde então, diversos outros tipos de lesões cutâneas têm sido observados em pacientes infectados pelo HTLV-1, em especial, nos doentes de HAM/TSP ou de ATLL. Porém, mesmo portadores assintomáticos do vírus apresentam doenças dermatológicas. Excetuando-se a dermatite infecciosa, não há lesão da pele específica da infecção pelo HTLV-1. Aqui, os autores apresentam as principais lesões dermatológicas descritas em pacientes infectados pelo HTLV-1, destacando o valor epidemiológico e clínico desses achados.Human T-cell Lymphotropic vírus type I (HTLV-1 was the first human retrovírus described. Some time after its discovery a group of diseases were related to this vírus, such as, adult T-cell leukemia lymphoma (ATLL, HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP and HTLV-1 associated uveitis (HAU. In the nineties, HTLV-1 was associated to a severe eczema of children, called infective dermatitis (ID. Since then, several other skin manifestations have been observed in HTLV-1-infected individuals, particularly in patients with ATLL or HAM/TSP. However, according to some reports, dermatologic lesions are also common in asymptomatic HTLV-1 carriers. Besides ID, all other skin lesions reported are nonspecific. The aim of this review is to outline the dermatologic manifestations reported in HTLV-1 infected patients, emphasizing the clinical and epidemiological value of these findings.

  7. HTLV-1 Tax plugs and freezes UPF1 helicase leading to nonsense-mediated mRNA decay inhibition.

    Science.gov (United States)

    Fiorini, Francesca; Robin, Jean-Philippe; Kanaan, Joanne; Borowiak, Malgorzata; Croquette, Vincent; Le Hir, Hervé; Jalinot, Pierre; Mocquet, Vincent

    2018-01-30

    Up-Frameshift Suppressor 1 Homolog (UPF1) is a key factor for nonsense-mediated mRNA decay (NMD), a cellular process that can actively degrade mRNAs. Here, we study NMD inhibition during infection by human T-cell lymphotropic virus type I (HTLV-1) and characterise the influence of the retroviral Tax factor on UPF1 activity. Tax interacts with the central helicase core domain of UPF1 and might plug the RNA channel of UPF1, reducing its affinity for nucleic acids. Furthermore, using a single-molecule approach, we show that the sequential interaction of Tax with a RNA-bound UPF1 freezes UPF1: this latter is less sensitive to the presence of ATP and shows translocation defects, highlighting the importance of this feature for NMD. These mechanistic insights reveal how HTLV-1 hijacks the central component of NMD to ensure expression of its own genome.

  8. Intracellular Localization and Cellular Factors Interaction of HTLV-1 and HTLV-2 Tax Proteins: Similarities and Functional Differences

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    Maria Grazia Romanelli

    2011-05-01

    Full Text Available Human T-lymphotropic viruses type 1 (HTLV-1 and type 2 (HTLV-2 present very similar genomic structures but HTLV-1 is more pathogenic than HTLV-2. Is this difference due to their transactivating Tax proteins, Tax-1 and Tax-2, which are responsible for viral and cellular gene activation? Do Tax-1 and Tax-2 differ in their cellular localization and in their interaction pattern with cellular factors? In this review, we summarize Tax-1 and Tax-2 structural and phenotypic properties, their interaction with factors involved in signal transduction and their localization-related behavior within the cell. Special attention will be given to the distinctions between Tax-1 and Tax-2 that likely play an important role in their transactivation activity.

  9. Prevalence and genetic characterisation of HTLV-1 and 2 dual infections in patients with pulmonary tuberculosis in Central-West Brazil

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    Aline Garcia Kozlowski

    2014-02-01

    Full Text Available Human T-cell lymphotropic virus (HTLV may impact the clinical course of tuberculosis (TB. Both infections are highly endemic in Brazil. The aim of this study was to assess the prevalence of HTLV-1/2 in TB patients in Central-West Brazil and to perform a genetic characterisation of the respective isolates. Of the 402 patients, six (1.49% were positive for anti-HTLV and five (1.24%; 95% confidence interval: 0.46-3.05 were infected with HTLV-1/2. Genetic characterisation demonstrated that the four HTLV-1 isolates belonged to the Transcontinental subgroup A of the Cosmopolitan subtype a and that the HTLV-2 isolate belonged to subtype a (HTLV-2a/c. The prevalence of HTLV infection observed in this study is higher than that observed in local blood donors and the HTLV-1 and 2 subtypes identified are consistent with those circulating in Brazil.

  10. Regulatory T cell expansion in HTLV-1 and strongyloidiasis co-infection is associated with reduced IL-5 responses to Strongyloides stercoralis antigen.

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    Martin Montes

    2009-06-01

    Full Text Available Human strongyloidiasis varies from a chronic but limited infection in normal hosts to hyperinfection in patients treated with corticosteroids or with HTLV-1 co-infection. Regulatory T cells dampen immune responses to infections. How human strongyloidiasis is controlled and how HTLV-1 infection affects this control are not clear. We hypothesize that HTLV-1 leads to dissemination of Strongyloides stercoralis infection by augmenting regulatory T cell numbers, which in turn down regulate the immune response to the parasite.To measure peripheral blood T regulatory cells and Strongyloides stercoralis larval antigen-specific cytokine responses in strongyloidiasis patients with or without HTLV-1 co-infection.Peripheral blood mononuclear cells (PBMCs were isolated from newly diagnosed strongyloidiasis patients with or without HTLV-1 co-infection. Regulatory T cells were characterized by flow cytometry using intracellular staining for CD4, CD25 and FoxP3. PBMCs were also cultured with and without Strongyloides larval antigens. Supernatants were analyzed for IL-5 production.Patients with HTLV-1 and Strongyloides co-infection had higher parasite burdens. Eosinophil counts were decreased in the HTLV-1 and Strongyloides co-infected subjects compared to strongyloidiasis-only patients (70.0 vs. 502.5 cells/mm(3, p = 0.09, Mann-Whitney test. The proportion of regulatory T cells was increased in HTLV-1 positive subjects co-infected with strongyloidiasis compared to patients with only strongyloidiasis or asymptomatic HTLV-1 carriers (median = 17.9% vs. 4.3% vs. 5.9 p<0.05, One-way ANOVA. Strongyloides antigen-specific IL-5 responses were reduced in strongyloidiasis/HTLV-1 co-infected patients (5.0 vs. 187.5 pg/ml, p = 0.03, Mann-Whitney test. Reduced IL-5 responses and eosinophil counts were inversely correlated to the number of CD4+CD25+FoxP3+ cells.Regulatory T cell counts are increased in patients with HTLV-1 and Strongyloides stercoralis co-infection and

  11. Human T-cell lymphotropic virus type 1 subtype C molecular variants among indigenous australians: new insights into the molecular epidemiology of HTLV-1 in Australo-Melanesia.

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    Olivier Cassar

    Full Text Available BACKGROUND: HTLV-1 infection is endemic among people of Melanesian descent in Papua New Guinea, the Solomon Islands and Vanuatu. Molecular studies reveal that these Melanesian strains belong to the highly divergent HTLV-1c subtype. In Australia, HTLV-1 is also endemic among the Indigenous people of central Australia; however, the molecular epidemiology of HTLV-1 infection in this population remains poorly documented. FINDINGS: Studying a series of 23 HTLV-1 strains from Indigenous residents of central Australia, we analyzed coding (gag, pol, env, tax and non-coding (LTR genomic proviral regions. Four complete HTLV-1 proviral sequences were also characterized. Phylogenetic analyses implemented with both Neighbor-Joining and Maximum Likelihood methods revealed that all proviral strains belong to the HTLV-1c subtype with a high genetic diversity, which varied with the geographic origin of the infected individuals. Two distinct Australians clades were found, the first including strains derived from most patients whose origins are in the North, and the second comprising a majority of those from the South of central Australia. Time divergence estimation suggests that the speciation of these two Australian clades probably occurred 9,120 years ago (38,000-4,500. CONCLUSIONS: The HTLV-1c subtype is endemic to central Australia where the Indigenous population is infected with diverse subtype c variants. At least two Australian clades exist, which cluster according to the geographic origin of the human hosts. These molecular variants are probably of very ancient origin. Further studies could provide new insights into the evolution and modes of dissemination of these retrovirus variants and the associated ancient migration events through which early human settlement of Australia and Melanesia was achieved.

  12. Low nuclear body formation and tax SUMOylation do not prevent NF-kappaB promoter activation

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    Bonnet Amandine

    2012-09-01

    Full Text Available Abstract Background The Tax protein encoded by Human T-lymphotropic virus type 1 (HTLV-1 is a powerful activator of the NF-κB pathway, a property critical for HTLV-1-induced immortalization of CD4+ T lymphocytes. Tax permanently stimulates this pathway at a cytoplasmic level by activating the IκB kinase (IKK complex and at a nuclear level by enhancing the binding of the NF-κB factor RelA to its cognate promoters and by forming nuclear bodies, believed to represent transcriptionally active structures. In previous studies, we reported that Tax ubiquitination and SUMOylation play a critical role in Tax localization and NF-κB activation. Indeed, analysis of lysine Tax mutants fused or not to ubiquitin or SUMO led us to propose a two-step model in which Tax ubiquitination first intervenes to activate IKK while Tax SUMOylation is subsequently required for promoter activation within Tax nuclear bodies. However, recent studies showing that ubiquitin or SUMO can modulate Tax activities in either the nucleus or the cytoplasm and that SUMOylated Tax can serve as substrate for ubiquitination suggested that Tax ubiquitination and SUMOylation may mediate redundant rather than successive functions. Results In this study, we analyzed the properties of a new Tax mutant that is properly ubiquitinated, but defective for both nuclear body formation and SUMOylation. We report that reducing Tax SUMOylation and nuclear body formation do not alter the ability of Tax to activate IKK, induce RelA nuclear translocation, and trigger gene expression from a NF-κB promoter. Importantly, potent NF-κB promoter activation by Tax despite low SUMOylation and nuclear body formation is also observed in T cells, including CD4+ primary T lymphocytes. Moreover, we show that Tax nuclear bodies are hardly observed in HTLV-1-infected T cells. Finally, we provide direct evidence that the degree of NF-κB activation by Tax correlates with the level of Tax ubiquitination, but not

  13. Low nuclear body formation and tax SUMOylation do not prevent NF-kappaB promoter activation.

    Science.gov (United States)

    Bonnet, Amandine; Randrianarison-Huetz, Voahangy; Nzounza, Patrycja; Nedelec, Martine; Chazal, Maxime; Waast, Laetitia; Pene, Sabrina; Bazarbachi, Ali; Mahieux, Renaud; Bénit, Laurence; Pique, Claudine

    2012-09-25

    The Tax protein encoded by Human T-lymphotropic virus type 1 (HTLV-1) is a powerful activator of the NF-κB pathway, a property critical for HTLV-1-induced immortalization of CD4⁺ T lymphocytes. Tax permanently stimulates this pathway at a cytoplasmic level by activating the IκB kinase (IKK) complex and at a nuclear level by enhancing the binding of the NF-κB factor RelA to its cognate promoters and by forming nuclear bodies, believed to represent transcriptionally active structures. In previous studies, we reported that Tax ubiquitination and SUMOylation play a critical role in Tax localization and NF-κB activation. Indeed, analysis of lysine Tax mutants fused or not to ubiquitin or SUMO led us to propose a two-step model in which Tax ubiquitination first intervenes to activate IKK while Tax SUMOylation is subsequently required for promoter activation within Tax nuclear bodies. However, recent studies showing that ubiquitin or SUMO can modulate Tax activities in either the nucleus or the cytoplasm and that SUMOylated Tax can serve as substrate for ubiquitination suggested that Tax ubiquitination and SUMOylation may mediate redundant rather than successive functions. In this study, we analyzed the properties of a new Tax mutant that is properly ubiquitinated, but defective for both nuclear body formation and SUMOylation. We report that reducing Tax SUMOylation and nuclear body formation do not alter the ability of Tax to activate IKK, induce RelA nuclear translocation, and trigger gene expression from a NF-κB promoter. Importantly, potent NF-κB promoter activation by Tax despite low SUMOylation and nuclear body formation is also observed in T cells, including CD4⁺ primary T lymphocytes. Moreover, we show that Tax nuclear bodies are hardly observed in HTLV-1-infected T cells. Finally, we provide direct evidence that the degree of NF-κB activation by Tax correlates with the level of Tax ubiquitination, but not SUMOylation. These data reveal that the

  14. HTLV-1/2 transfusional e hemovigilância: a contribuição dos estudos de look-back Transfusion-transmitted HTLV-1/2 and hemovigilance: the contribution of look-back studies

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    Maria Sueli S. N. Lopes

    2008-01-01

    Full Text Available Os vírus linfotrópicos de células T humana tipo 1 (HTLV-1 e tipo 2 (HTLV-2 foram os primeiros retrovírus identificados em humanos, em 1980 e 1982, respectivamente. O HTLV-1 é associado à leucemia/linfoma de células T do adulto (ATL e mielopatia associada ao HTLV-1/ paraparesia espástica tropical (HAM/TSP. Tais vírus podem ser transmitidos por via vertical (mãe para criança principalmente pela amamentação; por via sexual e via parenteral (usuários de drogas e transfusão de sangue e componentes. Nas áreas endêmicas, as transmissões vertical e sexual têm sido as principais vias para a disseminação da infecção por HTLV-1. Porém, a hemotransfusão parece ter importante participação na introdução do HTLV em populações não endêmicas. A via mais eficaz de transmissão transfusional do HTLV-1 é através de componentes celulares do sangue contaminado. No passado, isso ocorria principalmente através da transfusão de sangue não testado para o HTLV-1/2. Eficiência de transmissão transfusional da ordem de 60% foi descrita nos primeiros trabalhos japoneses. Subseqüentemente, extremos de 13% a 80% foram descritos nos estudos retrospectivos realizados nos Estados Unidos. Tamanha variação na eficiência da transmissão transfusional foi influenciada pelos parâmetros: tipo do produto sangüíneo, tempo decorrido entre a coleta dos componentes celulares até seu uso transfusional e carga proviral do HTLV no doador. Estima-se que 4% a 8% dos receptores de unidades celulares infectados por HTLV-1 possam desenvolver HAM/TSP, sendo raros os casos descritos de ATL nestes receptores. "Look-back"é o termo usado em hemovigilância para um programa que notifica grupos de receptores de hemotransfusão, de seus riscos quanto à exposição a um agente infeccioso por ocasião de transfusão prévia. "Look-back targeted"é o programa para identificar receptores de unidades previamente doadas por doadores específicos e que subseq

  15. HLA-DP antigens and HTLV-1 antibody status among Japanese with multiple sclerosis: evidence for an increased frequency of HLA-DPw4

    DEFF Research Database (Denmark)

    Ødum, Niels; Saida, T; Ohta, M

    1989-01-01

    , personal communication). Sera from all 34 patients and 38 controls (both from the HTLV-1 nonendemic, Kyoto region) were examined for the presence of HTLV-1 reacting antibodies by a highly sensitive radioimmuno assay (RIA) using two sources of HTLV-1 antigens, namely total crude protein preparations from...... disrupted HTLV-1 virions and affinity purified p24 HTLV-1 core proteins. The frequency of DPw4 was significantly increased to 35.3% in Japanese MS patients compared to 16.5% in controls (Relative Risk, RR = 2.8, p = 1.9 x 10(-2)). 41.6% of the MS patients gave clear typing responses with a PLT reagent which...... recognized a Dw2+ related specificity, which is higher than the frequency of Dw2 (6.8%) in Japanese. Fourteen of the 34 patient sera contrasting to none of the sera from 38 controls contained antibodies of IgG and/or IgM subclasses reacting with the HTLV-1 derived antigens. This difference is highly...

  16. Niclosamide, an anti-helminthic molecule, downregulates the retroviral oncoprotein Tax and pro-survival Bcl-2 proteins in HTLV-1-transformed T lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Xiang, Di [Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA 17033 (United States); Yuan, Yunsheng [Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA 17033 (United States); Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai (China); Chen, Li [Pharmacy College, Fujian University of Traditional Chinese Medicine, Fuzhou (China); Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201 (United States); Liu, Xin; Belani, Chandra [Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA 17033 (United States); Cheng, Hua, E-mail: hcheng@ihv.umaryland.edu [Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201 (United States); Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201 (United States); Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201 (United States); Department Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201 (United States)

    2015-08-14

    Adult T cell leukemia and lymphoma (ATL) is a highly aggressive form of hematological malignancy and is caused by chronic infection of human T cell leukemia virus type 1 (HTLV-1). The viral genome encodes an oncogenic protein, Tax, which plays a key role in transactivating viral gene transcription and in deregulating cellular oncogenic signaling to promote survival, proliferation and transformation of virally infected T cells. Hence, Tax is a desirable therapeutic target, particularly at early stage of HTLV-1-mediated oncogenesis. We here show that niclosamide, an anti-helminthic molecule, induced apoptosis of HTLV-1-transformed T cells. Niclosamide facilitated degradation of the Tax protein in proteasome. Consistent with niclosamide-mediated Tax degradation, this compound inhibited activities of MAPK/ERK1/2 and IκB kinases. In addition, niclosamide downregulated Stat3 and pro-survival Bcl-2 family members such as Mcl-1 and repressed the viral gene transcription of HTLV-1 through induction of Tax degradation. Since Tax, Stat3 and Mcl-1 are crucial molecules for promoting survival and growth of HTLV-1-transformed T cells, our findings demonstrate a novel mechanism of niclosamide in inducing Tax degradation and downregulating various cellular pro-survival molecules, thereby promoting apoptosis of HTLV-1-associated leukemia cells. - Highlights: • Niclosamide is a promising therapeutic candidate for adult T cell leukemia. • Niclosamide employs a novel mechanism through proteasomal degradation of Tax. • Niclosamide downregulates certain cellular pro-survival molecules.

  17. Cardiovascular risk profile in patients with myelopathy associated with HTLV-1.

    Science.gov (United States)

    Prado, Fabio Luís Silva do; Prado, Renata; Ladeia, Ana Marice Teixeira

    HAM/TSP (HTLV-1-associated myelopathy/tropical spastic paraparesis) is a slowly progressive disease, characterized by a chronic spastic paraparesis. It is not known if the disease carries an independent risk for cardiovascular disease. The objective of this study was to evaluate the cardiovascular risk profile related to HAM/TSP and compare it with the general population. This was a cross-sectional study, with a control group. HAM/TSP patients were evaluated using cardiovascular risk scores (ASCVD RISK, SCORE and Framingham) and inflammatory markers (ultrasensitive CRP and IL-6), and compared with a control group of healthy individuals. We also evaluated the correlation between cardiovascular risk and the functional status of patients with HAM/TSP evaluated by the FIM scale. Eighty percent of patients in this study were females, mean age of 51 years (11.3). The control group showed an increased cardiovascular event risk in 10 years when ASCVD was analyzed (cardiovascular risk ≥7.5% in 10 years seen in 43% of patients in the control group vs. 23% of patients with HAM/TSP; p=0.037). There was no difference in ultrasensitive CRP or IL-6 values between the groups, even when groups were stratified into low and high risk. There was no correlation between the functional status of HAM/TSP patients and the cardiovascular risk. In this study, the cardiovascular risk profile of patients with HAM/TSP was better than the risk of the control group. Copyright © 2017 Sociedade Brasileira de Infectologia. Published by Elsevier Editora Ltda. All rights reserved.

  18. SMYD3 interacts with HTLV-1 Tax and regulates subcellular localization of Tax.

    Science.gov (United States)

    Yamamoto, Keiyu; Ishida, Takaomi; Nakano, Kazumi; Yamagishi, Makoto; Yamochi, Tadanori; Tanaka, Yuetsu; Furukawa, Yoichi; Nakamura, Yusuke; Watanabe, Toshiki

    2011-01-01

    HTLV-1 Tax deregulates signal transduction pathways, transcription of genes, and cell cycle regulation of host cells, which is mainly mediated by its protein-protein interactions with host cellular factors. We previously reported an interaction of Tax with a histone methyltransferase (HMTase), SUV39H1. As the interaction was mediated by the SUV39H1 SET domain that is shared among HMTases, we examined the possibility of Tax interaction with another HMTase, SMYD3, which methylates histone H3 lysine 4 and activates transcription of genes, and studied the functional effects. Expression of endogenous SMYD3 in T cell lines and primary T cells was confirmed by immunoblotting analysis. Co-immuno-precipitaion assays and in vitro pull-down assay indicated interaction between Tax and SMYD3. The interaction was largely dependent on the C-terminal 180 amino acids of SMYD3, whereas the interacting domain of Tax was not clearly defined, although the N-terminal 108 amino acids were dispensable for the interaction. In the cotransfected cells, colocalization of Tax and SMYD3 was indicated in the cytoplasm or nuclei. Studies using mutants of Tax and SMYD3 suggested that SMYD3 dominates the subcellular localization of Tax. Reporter gene assays showed that nuclear factor-κB activation promoted by cytoplasmic Tax was enhanced by the presence of SMYD3, and attenuated by shRNA-mediated knockdown of SMYD3, suggesting an increased level of Tax localization in the cytoplasm by SMYD3. Our study revealed for the first time Tax-SMYD3 direct interaction, as well as apparent tethering of Tax by SMYD3, influencing the subcellular localization of Tax. Results suggested that SMYD3-mediated nucleocytoplasmic shuttling of Tax provides one base for the pleiotropic effects of Tax, which are mediated by the interaction of cellular proteins localized in the cytoplasm or nucleus. © 2010 Japanese Cancer Association.

  19. PDZ domain-binding motif of Tax sustains T-cell proliferation in HTLV-1-infected humanized mice.

    Science.gov (United States)

    Pérès, Eléonore; Blin, Juliana; Ricci, Emiliano P; Artesi, Maria; Hahaut, Vincent; Van den Broeke, Anne; Corbin, Antoine; Gazzolo, Louis; Ratner, Lee; Jalinot, Pierre; Duc Dodon, Madeleine

    2018-03-01

    Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), an aggressive malignant proliferation of activated CD4+ T lymphocytes. The viral Tax oncoprotein is critically involved in both HTLV-1-replication and T-cell proliferation, a prerequisite to the development of ATLL. In this study, we investigated the in vivo contribution of the Tax PDZ domain-binding motif (PBM) to the lymphoproliferative process. To that aim, we examined T-cell proliferation in humanized mice (hu-mice) carrying a human hemato-lymphoid system infected with either a wild type (WT) or a Tax PBM-deleted (ΔPBM) provirus. We observed that the frequency of CD4+ activated T-cells in the peripheral blood and in the spleen was significantly higher in WT than in ΔPBM hu-mice. Likewise, human T-cells collected from WT hu-mice and cultivated in vitro in presence of interleukin-2 were proliferating at a higher level than those from ΔPBM animals. We next examined the association of Tax with the Scribble PDZ protein, a prominent regulator of T-cell polarity, in human T-cells analyzed either after ex vivo isolation or after in vitro culture. We confirmed the interaction of Tax with Scribble only in T-cells from the WT hu-mice. This association correlated with the presence of both proteins in aggregates at the leading edge of the cells and with the formation of long actin filopods. Finally, data from a comparative genome-wide transcriptomic analysis suggested that the PBM-PDZ association is implicated in the expression of genes regulating proliferation, apoptosis and cytoskeletal organization. Collectively, our findings suggest that the Tax PBM is an auxiliary motif that contributes to the sustained growth of HTLV-1 infected T-cells in vivo and in vitro and is essential to T-cell immortalization.

  20. Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1-infected T cells.

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    Watanabe, Toshiki

    2017-03-02

    Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) that develops through a multistep carcinogenesis process involving 5 or more genetic events. We provide a comprehensive overview of recently uncovered information on the molecular basis of leukemogenesis in ATL. Broadly, the landscape of genetic abnormalities in ATL that include alterations highly enriched in genes for T-cell receptor-NF-κB signaling such as PLCG1 , PRKCB , and CARD11 and gain-of function mutations in CCR4 and CCR7 Conversely, the epigenetic landscape of ATL can be summarized as polycomb repressive complex 2 hyperactivation with genome-wide H3K27 me3 accumulation as the basis of the unique transcriptome of ATL cells. Expression of H3K27 methyltransferase enhancer of zeste 2 was shown to be induced by HTLV-1 Tax and NF-κB. Furthermore, provirus integration site analysis with high-throughput sequencing enabled the analysis of clonal composition and cell number of each clone in vivo, whereas multicolor flow cytometric analysis with CD7 and cell adhesion molecule 1 enabled the identification of HTLV-1-infected CD4 + T cells in vivo. Sorted immortalized but untransformed cells displayed epigenetic changes closely overlapping those observed in terminally transformed ATL cells, suggesting that epigenetic abnormalities are likely earlier events in leukemogenesis. These new findings broaden the scope of conceptualization of the molecular mechanisms of leukemogenesis, dissecting them into immortalization and clonal progression. These recent findings also open a new direction of drug development for ATL prevention and treatment because epigenetic marks can be reprogrammed. Mechanisms underlying initial immortalization and progressive accumulation of these abnormalities remain to be elucidated. © 2017 by The American Society of Hematology.

  1. ATF3, an HTLV-1 bZip factor binding protein, promotes proliferation of adult T-cell leukemia cells

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    Ohshima Koichi

    2011-03-01

    Full Text Available Abstract Background Adult T-cell leukemia (ATL is an aggressive malignancy of CD4+ T-cells caused by human T-cell leukemia virus type 1 (HTLV-1. The HTLV-1 bZIP factor (HBZ gene, which is encoded by the minus strand of the viral genome, is expressed as an antisense transcript in all ATL cases. By using yeast two-hybrid screening, we identified activating transcription factor 3 (ATF3 as an HBZ-interacting protein. ATF3 has been reported to be expressed in ATL cells, but its biological significance is not known. Results Immunoprecipitation analysis confirmed that ATF3 interacts with HBZ. Expression of ATF3 was upregulated in ATL cell lines and fresh ATL cases. Reporter assay revealed that ATF3 could interfere with the HTLV-1 Tax's transactivation of the 5' proviral long terminal repeat (LTR, doing so by affecting the ATF/CRE site, as well as HBZ. Suppressing ATF3 expression inhibited proliferation and strongly reduced the viability of ATL cells. As mechanisms of growth-promoting activity of ATF3, comparative expression profiling of ATF3 knockdown cells identified candidate genes that are critical for the cell cycle and cell death, including cell division cycle 2 (CDC2 and cyclin E2. ATF3 also enhanced p53 transcriptional activity, but this activity was suppressed by HBZ. Conclusions Thus, ATF3 expression has positive and negative effects on the proliferation and survival of ATL cells. HBZ impedes its negative effects, leaving ATF3 to promote proliferation of ATL cells via mechanisms including upregulation of CDC2 and cyclin E2. Both HBZ and ATF3 suppress Tax expression, which enables infected cells to escape the host immune system.

  2. Lack of evidence to support the association of a single IL28B genotype SNP rs12979860 with the HTLV-1 clinical outcomes and proviral load

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    Sanabani Sabri Saeed

    2012-12-01

    Full Text Available Abstract Background The Interleukin 28B (IL28B rs12979860 polymorphisms was recently reported to be associated with the human T-cell leukemia virus type 1 (HTLV-1 proviral load (PvL and the development of the HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP. Methods In an attempt to examine this hypothesis, we assessed the association of the rs12979860 genotypes with HTLV-1 PvL levels and clinical status in 112 unrelated Brazilian subjects (81 HTLV-1 asymptomatic carriers, 24 individuals with HAM/TSP and 7 with Adult T cell Leukemia/Lymphoma (ATLL. Results All 112 samples were successfully genotyped and their PvLs compared. Neither the homozygote TT nor the heterozygote CT mutations nor the combination genotypes (TT/CT were associated with a greater PvL. We also observed no significant difference in allele distribution between asymptomatic carriers and patients with HTLV-1 associated HAM/TSP. Conclusions Our study failed to support the previously reported positive association between the IL28B rs12979860 polymorphisms and an increased risk of developing HAM/TSP in the Brazilian population.

  3. The transcription elongation factor ELL2 is specifically upregulated in HTLV-1-infected T-cells and is dependent on the viral oncoprotein Tax.

    Science.gov (United States)

    Mann, Melanie C; Strobel, Sarah; Fleckenstein, Bernhard; Kress, Andrea K

    2014-09-01

    The oncoprotein Tax of human T-cell leukemia virus type 1 (HTLV-1) is a potent transactivator of viral and cellular transcription. Here, we identified ELL2 as the sole transcription elongation factor to be specifically upregulated in HTLV-1-/Tax-transformed T-cells. Tax contributes to regulation of ELL2, since transient transfection of Tax increases ELL2 mRNA, Tax transactivates the ELL2 promoter, and repression of Tax results in decrease of ELL2 in transformed T-lymphocytes. However, we also measured upregulation of ELL2 in HTLV-1-transformed cells exhibiting undetectable amounts of Tax, suggesting that ELL2 can still be maintained independent of continuous Tax expression. We further show that Tax and ELL2 synergistically activate the HTLV-1 promoter, indicating that ELL2 cooperates with Tax in viral transactivation. This is supported by our findings that Tax and ELL2 accumulate in nuclear fractions and that they co-precipitate upon co-expression in transiently-transfected cells. Thus, upregulation of ELL2 could contribute to HTLV-1 gene regulation. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. HTLV-1 Tax mediated downregulation of miRNAs associated with chromatin remodeling factors in T cells with stably integrated viral promoter.

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    Saifur Rahman

    Full Text Available RNA interference (RNAi is a natural cellular mechanism to silence gene expression and is predominantly mediated by microRNAs (miRNAs that target messenger RNA. Viruses can manipulate the cellular processes necessary for their replication by targeting the host RNAi machinery. This study explores the effect of human T-cell leukemia virus type 1 (HTLV-1 transactivating protein Tax on the RNAi pathway in the context of a chromosomally integrated viral long terminal repeat (LTR using a CD4(+ T-cell line, Jurkat. Transcription factor profiling of the HTLV-1 LTR stably integrated T-cell clone transfected with Tax demonstrates increased activation of substrates and factors associated with chromatin remodeling complexes. Using a miRNA microarray and bioinformatics experimental approach, Tax was also shown to downregulate the expression of miRNAs associated with the translational regulation of factors required for chromatin remodeling. These observations were validated with selected miRNAs and an HTLV-1 infected T cells line, MT-2. miR-149 and miR-873 were found to be capable of directly targeting p300 and p/CAF, chromatin remodeling factors known to play critical role in HTLV-1 pathogenesis. Overall, these results are first in line establishing HTLV-1/Tax-miRNA-chromatin concept and open new avenues toward understanding retroviral latency and/or replication in a given cell type.

  5. Analysis of CTCL cell lines reveals important differences between mycosis fungoides/Sézary syndrome vs. HTLV-1+ leukemic cell lines

    DEFF Research Database (Denmark)

    Netchiporouk, Elena; Gantchev, Jennifer; Tsang, Matthew

    2017-01-01

    HTLV-1 is estimated to affect ~20 million people worldwide and in ~5% of carriers it produces Adult T-Cell Leukemia/Lymphoma (ATLL), which can often masquerade and present with classic erythematous pruritic patches and plaques that are typically seen in Mycosis Fungoides (MF) and Sézary Syndrome...... (SS), the most recognized variants of Cutaneous T-Cell Lymphomas (CTCL). For many years the role of HTLV- 1 in the pathogenesis of MF/SS has been hotly debated. In this study we analyzed CTCL vs. HTLV-1+ leukemic cells. We performed G-banding/spectral karyotyping, extensive gene expression analysis......, TP53 sequencing in the 11 patient-derived HTLV- 1+ (MJ and Hut102) vs. HTLV-1- (Myla, Mac2a, PB2B, HH, H9, Hut78, SZ4, Sez4 and SeAx) CTCL cell lines. We further tested drug sensitivities to commonly used CTCL therapies and studied the ability of these cells to produce subcutaneous xenograft tumors...

  6. ORIGIN AND PREVALENCE OF HUMAN T-LYMPHOTROPIC VIRUS TYPE 1 (HTLV-1 AND TYPE 2 (HTLV-2 AMONG INDIGENOUS POPULATIONS IN THE AMERICAS

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    Arthur Paiva

    2015-02-01

    Full Text Available Human T-lymphotropic virus type 1 (HTLV-1 is found in indigenous peoples of the Pacific Islands and the Americas, whereas type 2 (HTLV-2 is widely distributed among the indigenous peoples of the Americas, where it appears to be more prevalent than HTLV-1, and in some tribes of Central Africa. HTLV-2 is considered ancestral in the Americas and is transmitted to the general population and injection drug users from the indigenous population. In the Americas, HTLV-1 has more than one origin, being brought by immigrants in the Paleolithic period through the Bering Strait, through slave trade during the colonial period, and through Japanese immigration from the early 20th century, whereas HTLV-2 was only brought by immigrants through the Bering Strait. The endemicity of HTLV-2 among the indigenous people of Brazil makes the Brazilian Amazon the largest endemic area in the world for its occurrence. A review of HTLV-1 in all Brazilian tribes supports the African origin of HTLV-1 in Brazil. The risk of hyperendemicity in these epidemiologically closed populations and transmission to other populations reinforces the importance of public health interventions for HTLV control, including the recognition of the infection among reportable diseases and events.

  7. Interferon-γ Promotes Inflammation and Development of T-Cell Lymphoma in HTLV-1 bZIP Factor Transgenic Mice.

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    Yu Mitagami

    2015-08-01

    Full Text Available Human T-cell leukemia virus type 1 (HTLV-1 is an etiological agent of several inflammatory diseases and a T-cell malignancy, adult T-cell leukemia (ATL. HTLV-1 bZIP factor (HBZ is the only viral gene that is constitutively expressed in HTLV-1-infected cells, and it has multiple functions on T-cell signaling pathways. HBZ has important roles in HTLV-1-mediated pathogenesis, since HBZ transgenic (HBZ-Tg mice develop systemic inflammation and T-cell lymphomas, which are similar phenotypes to HTLV-1-associated diseases. We showed previously that in HBZ-Tg mice, HBZ causes unstable Foxp3 expression, leading to an increase in regulatory T cells (Tregs and the consequent induction of IFN-γ-producing cells, which in turn leads to the development of inflammation in the mice. In this study, we show that the severity of inflammation is correlated with the development of lymphomas in HBZ-Tg mice, suggesting that HBZ-mediated inflammation is closely linked to oncogenesis in CD4+ T cells. In addition, we found that IFN-γ-producing cells enhance HBZ-mediated inflammation, since knocking out IFN-γ significantly reduced the incidence of dermatitis as well as lymphoma. Recent studies show the critical roles of the intestinal microbiota in the development of Tregs in vivo. We found that even germ-free HBZ-Tg mice still had an increased number of Tregs and IFN-γ-producing cells, and developed dermatitis, indicating that an intrinsic activity of HBZ evokes aberrant T-cell differentiation and consequently causes inflammation. These results show that immunomodulation by HBZ is implicated in both inflammation and oncogenesis, and suggest a causal connection between HTLV-1-associated inflammation and ATL.

  8. Seroprevalencia del Virus Linfotrópico Humano de células T tipo 1 (HTLV-1 en pacientes con tiroiditis autoinmune.

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    Ricardo Mori

    2010-10-01

    Full Text Available Objetivo: Describir la seroprevalencia de infección por HTLV-1 en pacientes con tiroiditis autoinmune. Material y Métodos: Estudio transversal realizado en pacientes con tiroiditis autoinmune que acudieron al consultorio de Endocrinología del Hospital Nacional Cayetano Heredia entre octubre del 2008 y enero del 2010. Se usó un cuestionario estructurado para obtener datos epidemiológicos y clínicos, paralelamente, se revisaron las historias clínicas para obtener datos de laboratorio. A los participantes se les tomó una muestra de sangre para el diagnóstico de HTLV-1 mediante prueba de ELISA y confirmación por Western Blot, previa firma de consentimiento informado. Resultados: Durante el período de estudio, se atendieron 285 pacientes con tiroiditis autoinmune. Se incluyeron 145 pacientes (50,9%; la edad media fue 48,1 ± 15 años y 135 (93,1% fueron de sexo femenino. Tres pacientes tuvieron infección por HTLV-1, con una prevalencia estimada de 2,1% (IC 95%: 0-4,4%. Los seropositivos fueron de sexo femenino y tuvieron el diagnóstico de Enfermedad de Graves hipertiroidea. La frecuencia de infección por HTLV-1 en este grupo fue de 5% (3/60; IC 95%: 0-11%. No se encontró diferencia significativa entre los pacientes HTLV-1 positivos y negativos en cuanto a características demográficas, clínicas y de laboratorio. Conclusión: La prevalencia de infección por HTLV-1 en los pacientes con tiroiditis autoinmune fue similar a la prevalencia estimada para la población peruana en general.(Rev Med Hered 2010;21:180-186.

  9. Cytokine profile and proviral load among Japanese immigrants and non-Japanese infected with HTLV-1 in a non-endemic area of Brazil.

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    João Américo Domingos

    Full Text Available The lifetime risk of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP development differs among ethnic groups. To better understand these differences, this prospective cohort study was conducted to investigate the cytokine profile and the HTLV-1 proviral load (PVL in Japanese and non-Japanese populations with HAM/TSP and asymptomatic carriers (ACs. The serum IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α, and IFN-γ levels were quantified using the Cytometric Bead Array in 40 HTLV-1-infected patients (11 HAM/TSP and 29 ACs and 18 healthy controls (HCs in Brazil. Among ACs, 15 were Japanese descendants and 14 were non-Japanese. Of 11 patients with HAM/TSP, only one was a Japanese descendant. The HTLV-1 PVL was quantified by real-time PCR. The HTLV-1 PVL was 2.7-fold higher in HAM/TSP patients than ACs. Regardless of the clinical outcome, the PVL was significantly higher in patients younger than 60 years than older patients. The HAM/TSP and ACs had higher IL-10 serum concentrations than that of HCs. The ACs also showed higher IL-6 serum levels than those of HCs. According to age, the IL-10 and IL-6 levels were higher in ACs non-Japanese patients older than 60 years. HAM/TSP patients showed a positive correlation between IL-6 and IL-17 and a negative correlation between the PVL and IL-17 and IFN-γ. In the all ACs, a significant positive correlation was observed between IL-2 and IL-17 and a negative correlation was detected between IL-10 and TNF-α. Only 6.25% of the Japanese patients were symptomatic carriers, compared with 41.67% of the non-Japanese patients. In conclusion, this study showed that high levels of HTLV-1 PVL was intrinsicaly associated with the development of HAM/TSP. A higher HTLV-1 PVL and IL10 levels found in non-Japanese ACs over 60 years old, which compared with the Japanese group depicts that the ethnic background may interfere in the host immune status. More researches also need to be undertaken regarding the host

  10. HTLV-1 bZIP Factor Impairs Anti-viral Immunity by Inducing Co-inhibitory Molecule, T Cell Immunoglobulin and ITIM Domain (TIGIT.

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    Keiko Yasuma

    2016-01-01

    Full Text Available Human T-cell leukemia virus type 1 (HTLV-1 infects CD4+ T cells and induces proliferation of infected cells in vivo, which leads to the onset of adult T-cell leukemia (ATL in some infected individuals. The HTLV-1 bZIP factor (HBZ gene, which is encoded in the minus strand of HTLV-1, plays critical roles in pathogenesis. In this study, RNA-seq and ChIP-seq analyses using HBZ transduced T cells revealed that HBZ upregulates the expression and promoter acetylation levels of a co-inhibitory molecule, T cell immunoglobulin and ITIM domain (TIGIT, in addition to those of regulatory T cells related genes, Foxp3 and Ccr4. TIGIT was expressed on CD4+ T cells from HBZ-transgenic (HBZ-Tg mice, and on ATL cells and HTLV-1 infected CD4+ T cells of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP in vivo. Expression of Blimp1 and IL-10 was upregulated in TIGIT+CD4+ cells of HBZ-Tg mice compared with TIGIT-CD4+ T cells, suggesting the correlation between TIGIT expression and IL-10 production. When CD4+ T cells from HBZ-Tg mice were stimulated with TIGIT's ligand, CD155, their production of the inhibitory cytokine IL-10 was enhanced. Furthermore, dendritic cells from HBZ-Tg mice produced high levels of IL-10 after stimulation. These data suggest that HBZ alters immune system to suppressive state via TIGIT and IL-10. Importantly, TIGIT suppressed T-cell responses to another HTLV-1 virus protein, Tax, in vitro. Blocking of TIGIT and PD-1 slightly increased anti-Tax T-cell activity in some HAM/TSP patients. These results suggest that HBZ-induced TIGIT on HTLV-1 infected cells impairs T-cell responses to viral antigens. This study shows that HBZ-induced TIGIT plays a pivotal role in attenuating host immune responses and shaping a microenvironment favorable to HTLV-1.

  11. NF-kappaB in Lung Tumorigenesis

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    Cai, Zhenjian [Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, New York University School of Medicine, 462 First Avenue, NBV 7N24, New York, NY 10016 (United States); Tchou-Wong, Kam-Meng; Rom, William N., E-mail: william.rom@nyumc.org [Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, New York University School of Medicine, 462 First Avenue, NBV 7N24, New York, NY 10016 (United States); Department of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987 (United States)

    2011-12-14

    The development of lung cancer in humans can be divided into three steps initiation, promotion and progression. This process is driven by alterations in related signal transduction pathways. These pathways signal the aberrant activation of NF-kappaB, a transcription factor that regulates the expression of genes important for lung tumorigenesis. Our current knowledge about the role of the NF-kappaB signaling pathway in the development of lung cancer has been bolstered by animal models demonstrating the connection between K-ras and tobacco induced lung transformation with NF-kappaB. Activation of downstream genes leads to cell proliferation, inhibition of apoptosis, angiogenesis, inflammation, invasion, and metastasis.

  12. NF-kappaB in Lung Tumorigenesis

    International Nuclear Information System (INIS)

    Cai, Zhenjian; Tchou-Wong, Kam-Meng; Rom, William N.

    2011-01-01

    The development of lung cancer in humans can be divided into three steps initiation, promotion and progression. This process is driven by alterations in related signal transduction pathways. These pathways signal the aberrant activation of NF-kappaB, a transcription factor that regulates the expression of genes important for lung tumorigenesis. Our current knowledge about the role of the NF-kappaB signaling pathway in the development of lung cancer has been bolstered by animal models demonstrating the connection between K-ras and tobacco induced lung transformation with NF-kappaB. Activation of downstream genes leads to cell proliferation, inhibition of apoptosis, angiogenesis, inflammation, invasion, and metastasis

  13. PDZ domain-binding motif of Tax sustains T-cell proliferation in HTLV-1-infected humanized mice

    Science.gov (United States)

    Artesi, Maria; Jalinot, Pierre

    2018-01-01

    Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), an aggressive malignant proliferation of activated CD4+ T lymphocytes. The viral Tax oncoprotein is critically involved in both HTLV-1-replication and T-cell proliferation, a prerequisite to the development of ATLL. In this study, we investigated the in vivo contribution of the Tax PDZ domain-binding motif (PBM) to the lymphoproliferative process. To that aim, we examined T-cell proliferation in humanized mice (hu-mice) carrying a human hemato-lymphoid system infected with either a wild type (WT) or a Tax PBM-deleted (ΔPBM) provirus. We observed that the frequency of CD4+ activated T-cells in the peripheral blood and in the spleen was significantly higher in WT than in ΔPBM hu-mice. Likewise, human T-cells collected from WT hu-mice and cultivated in vitro in presence of interleukin-2 were proliferating at a higher level than those from ΔPBM animals. We next examined the association of Tax with the Scribble PDZ protein, a prominent regulator of T-cell polarity, in human T-cells analyzed either after ex vivo isolation or after in vitro culture. We confirmed the interaction of Tax with Scribble only in T-cells from the WT hu-mice. This association correlated with the presence of both proteins in aggregates at the leading edge of the cells and with the formation of long actin filopods. Finally, data from a comparative genome-wide transcriptomic analysis suggested that the PBM-PDZ association is implicated in the expression of genes regulating proliferation, apoptosis and cytoskeletal organization. Collectively, our findings suggest that the Tax PBM is an auxiliary motif that contributes to the sustained growth of HTLV-1 infected T-cells in vivo and in vitro and is essential to T-cell immortalization. PMID:29566098

  14. Identification of a subset of perpheral T-cell lymphoma, not otherwise specified, characterized by FOXP3-positive regulatory T-cell phenotype, HTLV-1 negativity and poor outcome

    DEFF Research Database (Denmark)

    Pedersen, Martin Bjerregård; Hamilton-Dutoit, Stephen Jacques; Bendix, Knud

    2014-01-01

    Identification of a subset of perpheral T-cell lymphoma, not otherwise specified, characterized by FOXP3-positive regulatory T-cell phenotype, HTLV-1 negativity and poor outcome.......Identification of a subset of perpheral T-cell lymphoma, not otherwise specified, characterized by FOXP3-positive regulatory T-cell phenotype, HTLV-1 negativity and poor outcome....

  15. Occurrence of strongyloidiasis among patients with HTLV-1/2 seen at the outpatient clinic of the Núcleo de Medicina Tropical, Belém, State of Pará, Brazil.

    Science.gov (United States)

    Furtado, Karen Cristini Yumi Ogawa; Costa, Carlos Araújo da; Ferreira, Louise de Souza Canto; Martins, Luisa Carício; Linhares, Alexandre da Costa; Ishikawa, Edna Aoba Yassui; Batista, Evander de Jesus Oliveira; Sousa, Maisa Silva de

    2013-01-01

    This study investigated the occurrence of Strongyloides stercoralis infestation and coinfection with HTLV-1/2 in Belém, Brazil. S. stercoralis was investigated in stool samples obtained from individuals infected with HTLV-1/2 and their uninfected relatives. The frequency of S. stercoralis was 9% (9/100), including six patients infected with HTLV-1 (14.3%), two patients infected with HTLV-2 (11.1%), and one uninfected relative. Two cases of hyperinfestation by S. stercoralis were characterized as HTLV-1. These results support the need for the routine investigation of S. stercoralis in patients with HTLV-1, in an attempt to prevent the development of severe forms of strongyloidiasis.

  16. Roles of viral and cellular proteins in the expression of alternatively spliced HTLV-1 pX mRNAs

    International Nuclear Information System (INIS)

    Princler, Gerald L.; Julias, John G.; Hughes, Stephen H.; Derse, David

    2003-01-01

    The human T cell leukemia virus type 1 (HTLV-1) genome contains a cluster of at least five open reading frames (ORFs) near the 3' terminus within the pX region. The pX ORFs are encoded by mono- or bicistronic mRNAs that are generated by alternative splicing. The various pX mRNAs result from skipping of the internal exon (2-exon versus 3-exon isofoms) or from the utilization of alternative splice acceptor sites in the terminal exon. The Rex and Tax proteins, encoded by ORFs X-III and X-IV, have been studied intensively and are encoded by the most abundant of the alternative 3-exon mRNAs. The protein products of the other pX ORFs have not been detected in HTLV-1-infected cell lines and the levels of the corresponding mRNAs have not been accurately established. We have used real-time RT-PCR with splice-site specific primers to accurately measure the levels of individual pX mRNA species in chronically infected T cell lines. We have asked whether virus regulatory proteins or ectopic expression of cellular factors influence pX mRNA splicing in cells that were transfected with HTLV-1 provirus clones. In chronically infected cell lines, the pX-tax/rex mRNA was present at 500- to 2500-fold higher levels than the pX-tax-orfII mRNA and at approximately 1000-fold higher levels than pX-rex-orfI mRNA. Chronically infected cell lines that contain numerous defective proviruses expressed 2-exon forms of pX mRNAs at significantly higher levels compared to cell lines that contain a single full-length provirus. Cells transfected with provirus expression plasmids expressed similar relative amounts of 3-exon pX mRNAs but lower levels of 2-exon mRNA forms compared to cells containing a single, full-length provirus. The pX mRNA expression patterns were nearly identical in cells transfected with wild-type, Tax-minus, or Rex-minus proviruses. Cotransfection of cells with HTLV-1 provirus in combination with SF2/ASF expression plasmid resulted in a relative increase in pX-tax/rex m

  17. Dermatomiositis y síndrome de evans asociado a infección por HTLV-1

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    David Loja-Oropeza

    2016-01-01

    Full Text Available Paciente mujer de 55 años de edad, natural de Ayacucho, con antecedente de dermatomiositis desde hace 3 años, recibió tratamiento irregular con prednisona. Dos meses antes del ingreso presenta anemia hemolítica autoinmune y púrpura trombocitopénica idiopática, recibió pulsos de metilprednisolona y transfusión de paquetes globulares. Al ingreso, soporosa, mal estado general, marcada pérdida ponderal, deshidratada, livedo reticularis en miembros inferiores, onicodistrofia y onicolisis múltiple en los dedos de ambos pies. Western Blot positivo para HTLV-1. Evoluciona con hipoglicemia recurrente. Reportamos un caso de dermatomiositis y síndrome de Evans presentados en el contexto de una infección por virus linfotrópico humano tipo 1.

  18. Prevalence of HTLV-1/2 infections in Spain: A cross-sectional hospital-based survey.

    Science.gov (United States)

    Treviño, Ana; García, Juan; de Mendoza, Carmen; Benito, Rafael; Aguilera, Antonio; Ortíz de Lejarazu, Raul; Ramos, José M; Trigo, Matilde; Eirós, Jose M; Rodríguez-Iglesias, Manuel; Torres, Alvaro; Calderón, Enrique; Hernandez, Araceli; Gomez, Cesar; Marcaida, Goizane; Soriano, Vincent

    2010-08-01

    The presence of antibodies to human T-lymphotropic virus (HTLV) types 1 and 2 was examined in 5742 sera belonging to consecutive adult outpatients attended during June 2008 at 13 different hospitals across Spain. Overall, 58.8% were female. Foreigners represented 8% of the study population. Seven individuals were seropositive for HTLV-2 (overall prevalence 0.12%). No cases of HTLV-1 infection were found. All HTLV-2(+) subjects were Spanish natives, of whom six were coinfected with HIV-1 and five with hepatitis C virus (HCV). Moreover, all but one of the HTLV-2(+) subjects had been intravenous drug users. In summary, this cross-sectional survey suggests that the rate of HTLV infection in Spain is low, and is mostly represented by HTLV-2. Infected individuals are generally Spanish natives with a prior history of intravenous drug use and are coinfected with HIV-1 and/or HCV.

  19. Regulation of HTLV-1 Tax Stability, Cellular Trafficking and NF-κB Activation by the Ubiquitin-Proteasome Pathway

    Science.gov (United States)

    Lavorgna, Alfonso; Harhaj, Edward William

    2014-01-01

    Human T-cell leukemia virus type 1 (HTLV-1) is a complex retrovirus that infects CD4+ T cells and causes adult T-cell leukemia/lymphoma (ATLL) in 3%–5% of infected individuals after a long latent period. HTLV-1 Tax is a trans-activating protein that regulates viral gene expression and also modulates cellular signaling pathways to enhance T-cell proliferation and cell survival. The Tax oncoprotein promotes T-cell transformation, in part via constitutive activation of the NF-κB transcription factor; however, the underlying mechanisms remain unknown. Ubiquitination is a type of post-translational modification that occurs in a three-step enzymatic cascade mediated by E1, E2 and E3 enzymes and regulates protein stability as well as signal transduction, protein trafficking and the DNA damage response. Emerging studies indicate that Tax hijacks the ubiquitin machinery to activate ubiquitin-dependent kinases and downstream NF-κB signaling. Tax interacts with the E2 conjugating enzyme Ubc13 and is conjugated on C-terminal lysine residues with lysine 63-linked polyubiquitin chains. Tax K63-linked polyubiquitination may serve as a platform for signaling complexes since this modification is critical for interactions with NEMO and IKK. In addition to NF-κB signaling, mono- and polyubiquitination of Tax also regulate its subcellular trafficking and stability. Here, we review recent advances in the diverse roles of ubiquitin in Tax function and how Tax usurps the ubiquitin-proteasome pathway to promote oncogenesis. PMID:25341660

  20. Lower numbers of circulating natural killer T (NK T) cells in individuals with human T lymphotropic virus type 1 (HTLV-1) associated neurological disease

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    Ndhlovu, L C; Snyder-Cappione, J E; Carvalho, K I; Leal, F E; Loo, C P; bruno, F R; Jha, A R; Devita, D; Hasenkrug, A M; Barbosa, H M R; Segurado, A C; Nixon, D F; Murphy, E L; Kallas, E G

    2009-01-01

    Human T lymphotropic virus type 1 (HTLV-1) infects 10–20 million people worldwide. The majority of infected individuals are asymptomatic; however, approximately 3% develop the debilitating neurological disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is also currently no cure, vaccine or effective therapy for HTLV-1 infection, and the mechanisms for progression to HAM/TSP remain unclear. NK T cells are an immunoregulatory T cell subset whose frequencies and effector functions are associated critically with immunity against infectious diseases. We hypothesized that NK T cells are associated with HAM/TSP progression. We measured NK T cell frequencies and absolute numbers in individuals with HAM/TSP infection from two cohorts on two continents: São Paulo, Brazil and San Francisco, CA, USA, and found significantly lower levels when compared with healthy subjects and/or asymptomatic carriers. Also, the circulating NK T cell compartment in HAM/TSP subjects is comprised of significantly more CD4+ and fewer CD8+ cells than healthy controls. These findings suggest that lower numbers of circulating NK T cells and enrichment of the CD4+ NK T subset are associated with HTLV-1 disease progression. PMID:19778295

  1. The need to accessorize: Molecular roles of HTLV-1 p30 and HTLV-2 p28 accessory proteins in the viral life cycle

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    Rajaneesh eAnupam

    2013-09-01

    Full Text Available Extensive studies of HTLV-1 and HTLV-2 over the last three decades have provided detailed knowledge on viral transformation, host-viral interactions and pathogenesis. HTLV-1 is the etiological agent of adult T cell leukemia (ATL and multiple neurodegenerative and inflammatory diseases while HTLV-2 disease association remains elusive, with few infected individuals displaying neurodegenerative diseases similar to HTLV-1. The HTLV group of oncoretroviruses has a genome that encodes structural and enzymatic proteins Gag, Pro and Env, regulatory proteins Tax and Rex, and several accessory proteins from the pX region. Of these proteins, HTLV-1 p30 and HTLV-2 p28 are encoded by the open reading frame (ORF II of the pX region. Like most other accessory proteins, p30 and p28 are dispensable for in vitro viral replication and transformation but are required for efficient viral replication and persistence in vivo. Both p30 and p28 regulate viral gene expression at the post-transcriptional level whereas p30 can also function at the transcriptional level. Recently, several reports have implicated p30 and p28 in multiple cellular processes, which provide novel insight into HTLV spread and survival and ultimately pathogenesis. In this review we summarize and compare what is known about p30 and p28, highlighting their roles in viral replication and viral pathogenesis.

  2. HTLV-1 Tax protects against CD95-mediated apoptosis by induction of the cellular FLICE-inhibitory protein (c-FLIP).

    Science.gov (United States)

    Krueger, Andreas; Fas, Stefanie C; Giaisi, Marco; Bleumink, Marc; Merling, Anette; Stumpf, Christine; Baumann, Sven; Holtkotte, Denise; Bosch, Valerie; Krammer, Peter H; Li-Weber, Min

    2006-05-15

    The HTLV-1 transactivator protein Tax is essential for malignant transformation of CD4 T cells, ultimately leading to adult T-cell leukemia/lymphoma (ATL). Malignant transformation may involve development of apoptosis resistance. In this study we investigated the molecular mechanisms by which HTLV-1 Tax confers resistance toward CD95-mediated apoptosis. We show that Tax-expressing T-cell lines derived from HTLV-1-infected patients express elevated levels of c-FLIP(L) and c-FLIP(S). The levels of c-FLIP correlated with resistance toward CD95-mediated apoptosis. Using an inducible system we demonstrated that both resistance toward CD95-mediated apoptosis and induction of c-FLIP are dependent on Tax. In addition, analysis of early cleavage of the BH3-only Bcl-2 family member Bid, a direct caspase-8 substrate, revealed that apoptosis is inhibited at a CD95 death receptor proximal level in Tax-expressing cells. Finally, using siRNA we directly showed that c-FLIP confers Tax-mediated resistance toward CD95-mediated apoptosis. In conclusion, our data suggest an important mechanism by which expression of HTLV-1 Tax may lead to immune escape of infected T cells and, thus, to persistent infection and transformation.

  3. WRN-targeted therapy using inhibitors NSC 19630 and NSC 617145 induce apoptosis in HTLV-1-transformed adult T-cell leukemia cells

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    R. Moles

    2016-11-01

    Full Text Available Abstract Background Human T-cell leukemia virus type 1 (HTLV-1 infection is associated with adult T-cell leukemia/lymphoma (ATLL, a lymphoproliferative malignancy with a dismal prognosis and limited therapeutic options. Recent evidence shows that HTLV-1-transformed cells present defects in both DNA replication and DNA repair, suggesting that these cells might be particularly sensitive to treatment with a small helicase inhibitor. Because the “Werner syndrome ATP-dependent helicase” encoded by the WRN gene plays important roles in both cellular proliferation and DNA repair, we hypothesized that inhibition of WRN activity could be used as a new strategy to target ATLL cells. Methods Our analysis demonstrates an apoptotic effect induced by the WRN helicase inhibitor in HTLV-1-transformed cells in vitro and ATL-derived cell lines. Inhibition of cellular proliferation and induction of apoptosis were demonstrated with cell cycle analysis, XTT proliferation assay, clonogenic assay, annexin V staining, and measurement of mitochondrial transmembrane potential. Results Targeted inhibition of the WRN helicase induced cell cycle arrest and apoptosis in HTLV-1-transformed leukemia cells. Treatment with NSC 19630 (WRN inhibitor induces S-phase cell cycle arrest, disruption of the mitochondrial membrane potential, and decreased expression of anti-apoptotic factor Bcl-2. These events were associated with activation of caspase-3-dependent apoptosis in ATL cells. We identified some ATL cells, ATL-55T and LMY1, less sensitive to NSC 19630 but sensitive to another WRN inhibitor, NSC 617145. Conclusions WRN is essential for survival of ATL cells. Our studies suggest that targeting the WRN helicase with small inhibitors is a novel promising strategy to target HTLV-1-transformed ATL cells.

  4. HTLV-1 Tax Oncoprotein Subverts the Cellular DNA Damage Response via Binding to DNA-dependent Protein Kinase*S⃞

    Science.gov (United States)

    Durkin, Sarah S.; Guo, Xin; Fryrear, Kimberly A.; Mihaylova, Valia T.; Gupta, Saurabh K.; Belgnaoui, S. Mehdi; Haoudi, Abdelali; Kupfer, Gary M.; Semmes, O. John

    2008-01-01

    Human T-cell leukemia virus type-1 is the causative agent for adult T-cell leukemia. Previous research has established that the viral oncoprotein Tax mediates the transformation process by impairing cell cycle control and cellular response to DNA damage. We showed previously that Tax sequesters huChk2 within chromatin and impairs the response to ionizing radiation. Here we demonstrate that DNA-dependent protein kinase (DNA-PK) is a member of the Tax·Chk2 nuclear complex. The catalytic subunit, DNA-PKcs, and the regulatory subunit, Ku70, were present. Tax-containing nuclear extracts showed increased DNA-PK activity, and specific inhibition of DNA-PK prevented Tax-induced activation of Chk2 kinase activity. Expression of Tax induced foci formation and phosphorylation of H2AX. However, Tax-induced constitutive signaling of the DNA-PK pathway impaired cellular response to new damage, as reflected in suppression of ionizing radiation-induced DNA-PK phosphorylation and γH2AX stabilization. Tax co-localized with phospho-DNA-PK into nuclear speckles and a nuclear excluded Tax mutant sequestered endogenous phospho-DNA-PK into the cytoplasm, suggesting that Tax interaction with DNA-PK is an initiating event. We also describe a novel interaction between DNA-PK and Chk2 that requires Tax. We propose that Tax binds to and stabilizes a protein complex with DNA-PK and Chk2, resulting in a saturation of DNA-PK-mediated damage repair response. PMID:18957425

  5. Comprehensive Antiretroviral Restriction Factor Profiling Reveals the Evolutionary Imprint of the ex Vivo and in Vivo IFN-β Response in HTLV-1-Associated Neuroinflammation

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    Fabio E. Leal

    2018-05-01

    Full Text Available HTLV-1-Associated Myelopathy (HAM/TSP is a progressive neuroinflammatory disorder for which no disease-modifying treatment exists. Modest clinical benefit from type I interferons (IFN-α/β in HAM/TSP contrasts with its recently identified IFN-inducible gene signature. In addition, IFN-α treatment in vivo decreases proviral load and immune activation in HAM/TSP, whereas IFN-β therapy decreases tax mRNA and lymphoproliferation. We hypothesize this “IFN paradox” in HAM/TSP might be explained by both cell type- and gene-specific effects of type I IFN in HTLV-1-associated pathogenesis. Therefore, we analyzed ex vivo transcriptomes of CD4+ T cells, PBMCs and whole blood in healthy controls, HTLV-1-infected individuals, and HAM/TSP patients. First, we used a targeted approach, simultaneously quantifying HTLV-1 mRNA (HBZ, Tax, proviral load and 42 host genes with known antiretroviral (anti-HIV activity in purified CD4+ T cells. This revealed two major clusters (“antiviral/protective” vs. “proviral/deleterious”, as evidenced by significant negative (TRIM5/TRIM22/BST2 vs. positive correlation (ISG15/PAF1/CDKN1A with HTLV-1 viral markers and clinical status. Surprisingly, we found a significant inversion of antiretroviral activity of host restriction factors, as evidenced by opposite correlation to in vivo HIV-1 vs. HTLV-1 RNA levels. The anti-HTLV-1 effect of antiviral cluster genes was significantly correlated to their adaptive chimp/human evolution score, for both Tax mRNA and PVL. Six genes of the proposed antiviral cluster underwent lentivirus-driven purifying selection during primate evolution (TRIM5/TRIM22/BST2/APOBEC3F-G-H, underscoring the cross-retroviral evolutionary imprint. Secondly, we examined the genome-wide type I IFN response in HAM/TSP patients, following short-term ex vivo culture of PBMCs with either IFN-α or IFN-β. Microarray analysis evidenced 12 antiretroviral genes (including TRIM5α/TRIM22/BST2 were significantly

  6. Comprehensive Antiretroviral Restriction Factor Profiling Reveals the Evolutionary Imprint of the ex Vivo and in Vivo IFN-β Response in HTLV-1-Associated Neuroinflammation.

    Science.gov (United States)

    Leal, Fabio E; Menezes, Soraya Maria; Costa, Emanuela A S; Brailey, Phillip M; Gama, Lucio; Segurado, Aluisio C; Kallas, Esper G; Nixon, Douglas F; Dierckx, Tim; Khouri, Ricardo; Vercauteren, Jurgen; Galvão-Castro, Bernardo; Saraiva Raposo, Rui Andre; Van Weyenbergh, Johan

    2018-01-01

    HTLV-1-Associated Myelopathy (HAM/TSP) is a progressive neuroinflammatory disorder for which no disease-modifying treatment exists. Modest clinical benefit from type I interferons (IFN-α/β) in HAM/TSP contrasts with its recently identified IFN-inducible gene signature. In addition, IFN-α treatment in vivo decreases proviral load and immune activation in HAM/TSP, whereas IFN-β therapy decreases tax mRNA and lymphoproliferation. We hypothesize this "IFN paradox" in HAM/TSP might be explained by both cell type- and gene-specific effects of type I IFN in HTLV-1-associated pathogenesis. Therefore, we analyzed ex vivo transcriptomes of CD4 + T cells, PBMCs and whole blood in healthy controls, HTLV-1-infected individuals, and HAM/TSP patients. First, we used a targeted approach, simultaneously quantifying HTLV-1 mRNA (HBZ, Tax), proviral load and 42 host genes with known antiretroviral (anti-HIV) activity in purified CD4 + T cells. This revealed two major clusters ("antiviral/protective" vs. "proviral/deleterious"), as evidenced by significant negative (TRIM5/TRIM22/BST2) vs. positive correlation (ISG15/PAF1/CDKN1A) with HTLV-1 viral markers and clinical status. Surprisingly, we found a significant inversion of antiretroviral activity of host restriction factors, as evidenced by opposite correlation to in vivo HIV-1 vs. HTLV-1 RNA levels. The anti-HTLV-1 effect of antiviral cluster genes was significantly correlated to their adaptive chimp/human evolution score, for both Tax mRNA and PVL. Six genes of the proposed antiviral cluster underwent lentivirus-driven purifying selection during primate evolution (TRIM5/TRIM22/BST2/APOBEC3F-G-H), underscoring the cross-retroviral evolutionary imprint. Secondly, we examined the genome-wide type I IFN response in HAM/TSP patients, following short-term ex vivo culture of PBMCs with either IFN-α or IFN-β. Microarray analysis evidenced 12 antiretroviral genes (including TRIM5α/TRIM22/BST2) were significantly up-regulated by IFN

  7. Increased expression of OX40 is associated with progressive disease in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis.

    Science.gov (United States)

    Saito, Mineki; Tanaka, Reiko; Arishima, Shiho; Matsuzaki, Toshio; Ishihara, Satoshi; Tokashiki, Takashi; Ohya, Yusuke; Takashima, Hiroshi; Umehara, Fujio; Izumo, Shuji; Tanaka, Yuetsu

    2013-05-07

    OX40 is a member of the tumor necrosis factor receptor family that is expressed primarily on activated CD4+ T cells and promotes the development of effector and memory T cells. Although OX40 has been reported to be a target gene of human T-cell leukemia virus type-1 (HTLV-1) viral transactivator Tax and is overexpressed in vivo in adult T-cell leukemia (ATL) cells, an association between OX40 and HTLV-1-associated inflammatory disorders, such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), has not yet been established. Moreover, because abrogation of OX40 signals ameliorates chronic inflammation in animal models of autoimmune disease, novel monoclonal antibodies against OX40 may offer a potential treatment for HTLV-1-associated diseases such as ATL and HAM/TSP. In this study, we showed that OX40 was specifically expressed in CD4+ T cells naturally infected with HTLV-1 that have the potential to produce pro-inflammatory cytokines along with Tax expression. We also showed that OX40 was overexpressed in spinal cord infiltrating mononuclear cells in a clinically progressive HAM/TSP patient with a short duration of illness. The levels of the soluble form of OX40 (sOX40) in the cerebrospinal fluid (CSF) from chronic progressive HAM/TSP patients or from patients with other inflammatory neurological diseases (OINDs) were not different. In contrast, sOX40 levels in the CSF of rapidly progressing HAM/TSP patients were higher than those in the CSF from patients with OINDs, and these patients showed higher sOX40 levels in the CSF than in the plasma. When our newly produced monoclonal antibody against OX40 was added to peripheral blood mononuclear cells in culture, HTLV-1-infected T cells were specifically removed by a mechanism that depends on antibody-dependent cellular cytotoxicity. Our study identified OX40 as a key molecule and biomarker for rapid progression of HAM/TSP. Furthermore, blocking OX40 may have potential in therapeutic intervention for

  8. Influence of human t-cell lymphotropic virus type 1 (HTLV-1 Infection on laboratory parameters of patients with chronic hepatitis C virus Influência da infecção pelo vírus linfotrópico humano tipo 1 (HTLV-1 em parâmetros laboratoriais de pacientes com hepatite C crônica

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    Daniela Fernandes Cardoso

    2009-12-01

    Full Text Available Hepatitis C virus (HCV and human T-cell lymphotropic virus type 1 (HTLV-1 share routes of transmission and some individuals have dual infection. Although some studies point to a worse prognosis of hepatitis C virus in patients co-infected with HTLV-1, the interaction between these two infections is poorly understood. This study evaluated the influence of HTLV-1 infection on laboratory parameters in chronic HCV patients. Twelve HTLV-1/HCV-coinfected patients were compared to 23 patients infected only with HCV, in regard to demographic data, risk factors for viral acquisition, HCV genotype, presence of cirrhosis, T CD4+ and CD8+ cell counts and liver function tests. There was no difference in regard to age, gender, alcohol consumption, smoking habits, HCV genotype or presence of cirrhosis between the groups. Intravenous drug use was the most common risk factor among individuals co-infected with HTLV-1. These patients showed higher TCD8+ counts (p = 0.0159 and significantly lower median values of AST and ALT (p = 0.0437 and 0.0159, respectively. In conclusion, we have shown that HCV/HTLV-1 co-infected patients differs in laboratorial parameters involving both liver and immunological patterns. The meaning of these interactions in the natural history of these infections is a matter that deserves further studies.O vírus da hepatite C (VHC e vírus linfotrópico humano tipo 1 (HTLV-1 compartilham formas de transmissão e algumas pessoas apresentam coinfecção. Embora alguns estudos apontem para um pior prognóstico da infecção pelo VHC em pacientes coinfectados com HTLV-1, a interação entre estas infecções é mal compreendida. Este estudo avaliou a influência da infecção pelo HTLV-1 em parâmetros laboratoriais de pacientes com VHC. 12 coinfectados VHC/HTLV-1 foram comparados com 23 pacientes monoinfectados com VHC, no que diz respeito aos dados demográficos, fatores de risco para aquisição viral, genótipo do VHC, presença de cirrose

  9. Effects of Physiotherapy in the Treatment of Neurogenic Bladder in Patients Infected with Human T-Lymphotropic Virus 1 (HTLV-1)

    Science.gov (United States)

    Andrade, Rosana C.P.; Neto, José A.; Andrade, Luciana; Oliveira, Tatiane S. S.; Santos, Dislene N.; Oliveira, Cassius J.V.; Prado, Márcio J.; Carvalho, Edgar M.

    2016-01-01

    Objective To evaluate the efficacy of physiotherapy for urinary manifestations in patients with HTLV-1-associated lower urinary tract dysfunction. Methods Open clinical trial with 21 patients attending the physiotherapy clinic of the Hospital Universitário, Bahia, Brazil. Combinations of behavioral therapy, perineal exercises and intravaginal/intra-anal electrical stimulation were used. Results The mean age was 54±12 years and 67% were female. After treatment, there was an improvement in symptoms of urinary urgency, frequency, incontinence, nocturia and in the sensation of incomplete emptying (pPhysiotherapy was effective in cases of HTLV-1-associated neurogenic bladder, reducing symptoms, increasing perineal muscle strength, improving urodynamic parameters and quality of life. PMID:26724409

  10. HTLV-1 Tax protein recruitment into IKKε and TBK1 kinase complexes enhances IFN-I expression.

    Science.gov (United States)

    Diani, Erica; Avesani, Francesca; Bergamo, Elisa; Cremonese, Giorgia; Bertazzoni, Umberto; Romanelli, Maria Grazia

    2015-02-01

    The Tax protein expressed by human T-cell leukemia virus type 1 (HTLV-1) plays a pivotal role in the deregulation of cellular pathways involved in the immune response, inflammation, cell survival, and cancer. Many of these effects derive from Tax multiple interactions with host factors, including the subunits of the IKK-complex that are required for NF-κB activation. IKKɛ and TBK1 are two IKK-related kinases that allow the phosphorylation of interferon regulatory factors that trigger IFN type I gene expression. We observed that IKKɛ and TBK1 recruit Tax into cellular immunocomplexes. We also found that TRAF3, which regulates cell receptor signaling effectors, forms complexes with Tax. Transactivation analyses revealed that expression of Tax, in presence of IKKɛ and TBK1, enhances IFN-β promoter activity, whereas the activation of NF-κB promoter is not modified. We propose that Tax may be recruited into the TBK1/IKKɛ complexes as a scaffolding-adaptor protein that enhances IFN-I gene expression. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. The Sumo-targeted ubiquitin ligase RNF4 regulates the localization and function of the HTLV-1 oncoprotein Tax

    Science.gov (United States)

    Fryrear, Kimberly A.; Guo, Xin

    2012-01-01

    The Really Interesting New Gene (RING) Finger Protein 4 (RNF4) represents a class of ubiquitin ligases that target Small Ubiquitin-like Modifier (SUMO)–modified proteins for ubiquitin modification. To date, the regulatory function of RNF4 appears to be ubiquitin-mediated degradation of sumoylated cellular proteins. In the present study, we show that the Human T-cell Leukemia Virus Type 1 (HTLV-1) oncoprotein Tax is a substrate for RNF4 both in vivo and in vitro. We mapped the RNF4-binding site to a region adjacent to the Tax ubiquitin/SUMO modification sites K280/K284. Interestingly, RNF4 modification of Tax protein results in relocalization of the oncoprotein from the nucleus to the cytoplasm. Overexpression of RNF4, but not the RNF4 RING mutant, resulted in cytoplasmic enrichment of Tax. The RNF4-induced nucleus-to-cytoplasm relocalization was associated with increased NF-κB–mediated and decreased cAMP Response Element-Binding (CREB)–mediated Tax activity. Finally, depletion of RNF4 by RNAi prevented the DNA damage–induced nuclear/cytoplasmic translocation of Tax. These results provide important new insight into STUbL-mediated pathways that regulate the subcellular localization and functional dynamics of viral oncogenes. PMID:22106342

  12. Sporadic on/off switching of HTLV-1 Tax expression is crucial to maintain the whole population of virus-induced leukemic cells.

    Science.gov (United States)

    Mahgoub, Mohamed; Yasunaga, Jun-Ichirou; Iwami, Shingo; Nakaoka, Shinji; Koizumi, Yoshiki; Shimura, Kazuya; Matsuoka, Masao

    2018-02-06

    Viruses causing chronic infection artfully manipulate infected cells to enable viral persistence in vivo under the pressure of immunity. Human T-cell leukemia virus type 1 (HTLV-1) establishes persistent infection mainly in CD4+ T cells in vivo and induces leukemia in this subset. HTLV-1-encoded Tax is a critical transactivator of viral replication and a potent oncoprotein, but its significance in pathogenesis remains obscure due to its very low level of expression in vivo. Here, we show that Tax is expressed in a minor fraction of leukemic cells at any given time, and importantly, its expression spontaneously switches between on and off states. Live cell imaging revealed that the average duration of one episode of Tax expression is ∼19 hours. Knockdown of Tax rapidly induced apoptosis in most cells, indicating that Tax is critical for maintaining the population, even if its short-term expression is limited to a small subpopulation. Single-cell analysis and computational simulation suggest that transient Tax expression triggers antiapoptotic machinery, and this effect continues even after Tax expression is diminished; this activation of the antiapoptotic machinery is the critical event for maintaining the population. In addition, Tax is induced by various cytotoxic stresses and also promotes HTLV-1 replication. Thus, it seems that Tax protects infected cells from apoptosis and increases the chance of viral transmission at a critical moment. Keeping the expression of Tax minimal but inducible on demand is, therefore, a fundamental strategy of HTLV-1 to promote persistent infection and leukemogenesis. Copyright © 2018 the Author(s). Published by PNAS.

  13. Magnetic resonance imaging for Human T-cell lymphotropic virus type 1 (HTLV1- associated myelopathy/tropical spastic paraparesis patients: a systematic review

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    Fariba Zemorshidi

    2015-06-01

    Full Text Available Introduction: Human T-cell lymphotropic virus type 1 (HTLV-1 associated myelopathy/tropical spastic paraparesis is a chronic progressive neurologic disease which might be associated by brain and spinal cord atrophy and lesions. Here we systematically reviewed the brain and spinal cord abnormalities reported by using magnetic resonance imaging modality on HTLV-1 associated myelopathy/tropical spastic paraparesis patients. Methods: PubMed was searched for all the relevant articles which used magnetic resonance imaging for patients with human HTLV-1 associated myelopathy/tropical spastic paraparesis disease. Included criteria were all the cohort and case series on with at least 10 patients. We had no time limitation for searched articles, but only English language articles were included in our systematic review. Exclusion criteria were none-English articles, case reports, articles with less than 10 patients, spastic paraparesis patients with unknown etiology, and patients with HTLVII. Results: Total of 14 relevant articles were extracted after studying title, abstracts, and full text of the irrelevant articles. Only 2/14 articles, reported brain atrophy incidence. 5/14 articles studied the brain lesions prevalence. Spinal cord atrophy and lesions, each were studied in 6/14 articles.Discussion: According to the extracted data, brain atrophy does not seem to happen frequently in patients with HTLV-1 associated myelopathy/tropical spastic paraparesis. None-specific brain lesions identified in articles are indicative of low specificity of magnetic resonance imaging technique despite its high sensitivity. Conclusion: Prevalence of spinal cord lesions and atrophy in these patients might be due to the degenerative processes associated with aging phenomenon. Further larger studies in endemic areas can more accurately reveal the specificity of magnetic resonance imaging for these patients.

  14. Western blot seroindeterminate individuals for Human T-lymphotropic Virus 1/2 (HTLV-1/2 in Fortaleza (Brazil: a serological and molecular diagnostic and epidemiological approach

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    Santos Terezinha de Jesus Teixeira

    2003-01-01

    Full Text Available How to handle Western blot (WB seroindeterminate individuals for Human T-lymphotropic Virus 1/2 (HTLV-1/2 constitutes a challenge for blood banks and fam ilies. We made a cross-sectional study of 191 enzyme linked immunoassay (EIA reactive individuals from the hematological center (HEMOCE of Fortaleza (Brazil, examining their serological (WB and molecular (PCR diagnosis, and demographic profiles, as well as a possible association of their condition with other infectious pathologies and risk factors. Ethical institutional approval and personal consent were obtained. Out of 191 EIA reactive individuals, 118 were WB seroindeterminate and 73 were seropositive for HTLV-1/2. In the PCR analysis of 41 WB seroindeterminate individuals, 9 (22% were positive and 32 (78% were negative for HTLV-1/2. The demographic analysis indicated a trend towards a predominance of males among the seroindeterminate individuals and females in the seropositive ones. The seroindeterminate individuals were younger than the seropositive ones. We did not find any association of these conditions with syphilis, Chagas disease or HIV or hepatitis, and with risk factors such as breast-feeding, blood transfusion, STD (syphilis and IDU.

  15. Western blot seroindeterminate individuals for Human T-lymphotropic Virus 1/2 (HTLV-1/2 in Fortaleza (Brazil: a serological and molecular diagnostic and epidemiological approach

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    Terezinha de Jesus Teixeira Santos

    Full Text Available How to handle Western blot (WB seroindeterminate individuals for Human T-lymphotropic Virus 1/2 (HTLV-1/2 constitutes a challenge for blood banks and fam ilies. We made a cross-sectional study of 191 enzyme linked immunoassay (EIA reactive individuals from the hematological center (HEMOCE of Fortaleza (Brazil, examining their serological (WB and molecular (PCR diagnosis, and demographic profiles, as well as a possible association of their condition with other infectious pathologies and risk factors. Ethical institutional approval and personal consent were obtained. Out of 191 EIA reactive individuals, 118 were WB seroindeterminate and 73 were seropositive for HTLV-1/2. In the PCR analysis of 41 WB seroindeterminate individuals, 9 (22% were positive and 32 (78% were negative for HTLV-1/2. The demographic analysis indicated a trend towards a predominance of males among the seroindeterminate individuals and females in the seropositive ones. The seroindeterminate individuals were younger than the seropositive ones. We did not find any association of these conditions with syphilis, Chagas disease or HIV or hepatitis, and with risk factors such as breast-feeding, blood transfusion, STD (syphilis and IDU.

  16. FoxP3+ regulatory T cells are distinct from leukemia cells in HTLV-1-associated adult T-cell leukemia.

    Science.gov (United States)

    Toulza, Frederic; Nosaka, Kisato; Takiguchi, Masafumi; Pagliuca, Tony; Mitsuya, Hiroaki; Tanaka, Yuetsu; Taylor, Graham P; Bangham, Charles R M

    2009-11-15

    Human T-lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATLL). It has been postulated that ATLL cells might act as regulatory T cells (T(regs)) which, in common with ATLL cells, express both CD25 and FoxP3, and so contribute to the severe immune suppression typical of ATLL. We report here that the frequency of CD25(+) cells varied independently of the frequency of FoxP3(+) cells in both a cross-sectional study and in a longitudinal study of 2 patients with chronic ATLL. Furthermore, the capacity of ATLL cells to suppress proliferation of heterologous CD4(+)CD25(-) cells correlated with the frequency of CD4(+) FoxP3(+) cells but was independent of CD25 expression. Finally, the frequency of CD4(+)FoxP3(+) cells was inversely correlated with the lytic activity of HTLV-1-specific CTLs in patients with ATLL. We conclude that ATLL is not a tumor of FoxP3(+) regulatory T cells, and that a population of FoxP3(+) cells distinct from ATLL cells has regulatory functions and may impair the cell-mediated immune response to HTLV-1 in patients with ATLL.

  17. Simultaneous RNA quantification of human and retroviral genomes reveals intact interferon signaling in HTLV-1-infected CD4+ T cell lines

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    Moens Britta

    2012-08-01

    Full Text Available Abstract Background IFN-α contributes extensively to host immune response upon viral infection through antiviral, pro-apoptotic, antiproliferative and immunomodulatory activities. Although extensively documented in various types of human cancers and viral infections, controversy exists in the exact mechanism of action of IFN-α in human immunodeficiency virus type 1 (HIV-1 and human T-lymphotropic virus type 1 (HTLV-1 retroviral infections. Results IFN-α displayed strong anti-HIV-1 effects in HIV-1/HTLV-1 co-infected MT-4 cells in vitro, demonstrated by the dose-dependent inhibition of the HIV-1-induced cytopathic effect (IC50 = 83.5 IU/ml, p 50 = 1.2 IU/ml, p  Conclusions Taken together, our results indicate that both the absence of in vitro antiproliferative and pro-apoptotic activity as well as the modest post-transcriptional antiviral activity of IFN-α against HTLV-1, were not due to a cell-intrinsic defect in IFN-α signalisation, but rather represents a retrovirus-specific phenomenon, considering the strong HIV-1 inhibition in co-infected cells.

  18. Role of adapter function in oncoprotein-mediated activation of NF-kappaB. Human T-cell leukemia virus type I Tax interacts directly with IkappaB kinase gamma.

    Science.gov (United States)

    Jin, D Y; Giordano, V; Kibler, K V; Nakano, H; Jeang, K T

    1999-06-18

    Mechanisms by which the human T-cell leukemia virus type I Tax oncoprotein activates NF-kappaB remain incompletely understood. Although others have described an interaction between Tax and a holo-IkappaB kinase (IKK) complex, the exact details of protein-protein contact are not fully defined. Here we show that Tax binds to neither IKK-alpha nor IKK-beta but instead complexes directly with IKK-gamma, a newly characterized component of the IKK complex. This direct interaction with IKK-gamma correlates with Tax-induced IkappaB-alpha phosphorylation and NF-kappaB activation. Thus, our findings establish IKK-gamma as a key molecule for adapting an oncoprotein-specific signaling to IKK-alpha and IKK-beta.

  19. Direct visualization of antigen-specific T cells: HTLV-1 Tax11-19- specific CD8(+) T cells are activated in peripheral blood and accumulate in cerebrospinal fluid from HAM/TSP patients.

    Science.gov (United States)

    Greten, T F; Slansky, J E; Kubota, R; Soldan, S S; Jaffee, E M; Leist, T P; Pardoll, D M; Jacobson, S; Schneck, J P

    1998-06-23

    Human T lymphotropic virus type 1 (HTLV-1) -associated myelopathy/tropic spastic paraparesis is a demyelinating inflammatory neurologic disease associated with HTLV-1 infection. HTLV-1 Tax11-19-specific cytotoxic T cells have been isolated from HLA-A2-positive patients. We have used a peptide-loaded soluble HLA-A2-Ig complex to directly visualize HTLV-1 Tax11-19-specific T cells from peripheral blood and cerebrospinal fluid without in vitro stimulation. Five of six HTLV-1-associated myelopathy/tropic spastic paraparesis patients carried a significant number (up to 13.87%) of CD8(+) lymphocytes specific for the HTLV-1 Tax11-19 peptide in their peripheral blood, which were not found in healthy controls. Simultaneous comparison of peripheral blood and cerebrospinal fluid from one patient revealed 2.5-fold more Tax11-19-specific T cells in the cerebrospinal fluid (23.7% vs. 9.4% in peripheral blood lymphocyte). Tax11-19-specific T cells were seen consistently over a 9-yr time course in one patient as far as 19 yrs after the onset of clinical symptoms. Further analysis of HTLV-1 Tax11-19-specific CD8(+) T lymphocytes in HAM/TSP patients showed different expression patterns of activation markers, intracellular TNF-alpha and gamma-interferon depending on the severity of the disease. Thus, visualization of antigen-specific T cells demonstrates that HTLV-1 Tax11-19-specific CD8(+) T cells are activated, persist during the chronic phase of the disease, and accumulate in cerebrospinal fluid, showing their pivotal role in the pathogenesis of this neurologic disease.

  20. Making the invisible visible: searching for human T-cell lymphotropic virus types 1 and 2 (HTLV-1 and HTLV-2 in Brazilian patients with viral hepatitis B and C

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    Adele Caterino-de-Araujo

    Full Text Available With this study, the authors hope to alert clinicians regarding the presence of human T-cell lymphotropic virus type 1 and 2 (HTLV-1/-2 infections in patients with viral hepatitis B and C in Brazil. HTLV-1/-2 were detected in 1.3% of hepatitis B virus (HBV- and 5.3% of hepatitis C virus (HCV-infected blood samples sent for laboratory viral load measurements. A partial association of human immunodeficiency virus (HIV-1 and HTLV-1/-2 infection was detected in patients with HCV (HIV+, 27.3%, whereas this association was almost 100% in HBV-infected patients (HIV+, all except one. The high prevalence of HTLV-1/-2 infection among patients with hepatitis C was of concern, as HTLV-1/-2 could change the natural course of subsequent liver disease. The authors suggest including HTLV-1/-2 serology in the battery of tests used when following patients with viral hepatitis in Brazil, regardless of the HIV status.

  1. Making the invisible visible: searching for human T-cell lymphotropic virus types 1 and 2 (HTLV-1 and HTLV-2) in Brazilian patients with viral hepatitis B and C.

    Science.gov (United States)

    Caterino-de-Araujo, Adele; Alves, Fabiana Aparecida; Campos, Karoline Rodrigues; Lemos, Marcílio Figueiredo; Moreira, Regina Célia

    2018-02-01

    With this study, the authors hope to alert clinicians regarding the presence of human T-cell lymphotropic virus type 1 and 2 (HTLV-1/-2) infections in patients with viral hepatitis B and C in Brazil. HTLV-1/-2 were detected in 1.3% of hepatitis B virus (HBV)- and 5.3% of hepatitis C virus (HCV)-infected blood samples sent for laboratory viral load measurements. A partial association of human immunodeficiency virus (HIV)-1 and HTLV-1/-2 infection was detected in patients with HCV (HIV+, 27.3%), whereas this association was almost 100% in HBV-infected patients (HIV+, all except one). The high prevalence of HTLV-1/-2 infection among patients with hepatitis C was of concern, as HTLV-1/-2 could change the natural course of subsequent liver disease. The authors suggest including HTLV-1/-2 serology in the battery of tests used when following patients with viral hepatitis in Brazil, regardless of the HIV status.

  2. Expansion in CD39+ CD4+ Immunoregulatory T Cells and Rarity of Th17 Cells in HTLV-1 Infected Patients Is Associated with Neurological Complications

    Science.gov (United States)

    Hasenkrug, Aaron M.; Bruno, Fernanda R.; Carvalho, Karina I.; Wynn-Williams, Harry; Neto, Walter K.; Sanabani, Sabri S.; Segurado, Aluisio C.; Nixon, Douglas F.; Kallas, Esper G.

    2013-01-01

    HTLV-1 infection is associated with several inflammatory disorders, including the neurodegenerative condition HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). It is unclear why a minority of infected subjects develops HAM/TSP. CD4+ T cells are the main target of infection and play a pivotal role in regulating immunity to HTLV and are hypothesized to participate in the pathogenesis of HAM/TSP. The CD39 ectonucleotidase receptor is expressed on CD4+ T cells and based on co-expression with CD25, marks T cells with distinct regulatory (CD39+CD25+) and effector (CD39+CD25−) function. Here, we investigated the expression of CD39 on CD4+ T cells from a cohort of HAM/TSP patients, HTLV-1 asymptomatic carriers (AC), and matched uninfected controls. The frequency of CD39+ CD4+ T cells was increased in HTLV-1 infected patients, regardless of clinical status. More importantly, the proportion of the immunostimulatory CD39+CD25− CD4+ T-cell subset was significantly elevated in HAM/TSP patients as compared to AC and phenotypically had lower levels of the immunoinhibitory receptor, PD-1. We saw no difference in the frequency of CD39+CD25+ regulatory (Treg) cells between AC and HAM/TSP patients. However, these cells transition from being anergic to displaying a polyfunctional cytokine response following HTLV-1 infection. CD39−CD25+ T cell subsets predominantly secreted the inflammatory cytokine IL-17. We found that HAM/TSP patients had significantly fewer numbers of IL-17 secreting CD4+ T cells compared to uninfected controls. Taken together, we show that the expression of CD39 is upregulated on CD4+ T cells HAM/TSP patients. This upregulation may play a role in the development of the proinflammatory milieu through pathways both distinct and separate among the different CD39 T cell subsets. CD39 upregulation may therefore serve as a surrogate diagnostic marker of progression and could potentially be a target for interventions to reduce the development of

  3. Seroprevalence and molecular epidemiology of HTLV-1 isolates from HIV-1 co-infected women in Feira de Santana, Bahia, Brazil.

    Science.gov (United States)

    de Almeida Rego, Filipe Ferreira; Mota-Miranda, Aline; de Souza Santos, Edson; Galvão-Castro, Bernardo; Alcantara, Luiz Carlos

    2010-12-01

    HTLV-1/HIV-1 co-infection is associated with severe clinical manifestations, marked immunodeficiency, and opportunistic pathogenic infections, as well as risk behavior. Salvador, the capital of the State of Bahia, Brazil, has the highest HTLV-1 prevalence (1.74%) found in Brazil. Few studies exist which describe this co-infection found in Salvador and its surrounding areas, much less investigate how these viruses circulate or assess the relationship between them. To describe the epidemiological and molecular features of HTLV in HIV co-infected women. To investigate the prevalence of HTLV/HIV co-infection in surrounding areas, as well as the molecular epidemiology of HTLV, a cross sectional study was carried out involving 107 women infected with HIV-1 from the STD/HIV/AIDS Reference Center located in the neighboring City of Feira de Santana. Patient samples were submitted to ELISA, and HTLV infection was confirmed using Western Blot and Polymerase Chain Reaction (PCR). Phylogenetic analysis using Neighbor-Joining (NJ) and Maximum Likelihood (ML) was performed on HTLV LTR sequences in order to gain further insights about molecular epidemiology and the origins of this virus in Bahia. Four out of five reactive samples were confirmed to be infected with HTLV-1, and one with HTLV-2. The seroprevalence of HTLV among HIV-1 co-infected women was 4.7%. Phylogenetic analysis of the LTR region from four HTLV-1 sequences showed that all isolates were clustered into the main Latin American group within the Transcontinental subgroup of the Cosmopolitan subtype. The HTLV-2 sequence was classified as the HTLV-2c subtype. It was also observed that four HTLV/HIV-1 co-infected women exhibited risk behavior with two having parenteral exposure, while another two were sex workers. This article describes the characteristics of co-infected patients. This co-infection is known to be severe and further studies should be conducted to confirm the suggestion that HTLV-1 is spreading from

  4. Characteristics of co-infections by HCV and HBV among Brazilian patients infected by HIV-1 and/or HTLV-1

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    Marcia Moreira

    Full Text Available BACKGROUND: The human retroviruses HIV-1 and HTLV-1 share the routes of infection with hepatitis viruses B and C. Co-infection by these agents are a common event, but we have scarce knowledge on co-infection by two or more of these agents. OBJECTIVE: To evaluate the characteristics and risk factors for co-infections by HBV and HCV in patients infected by HIV-1 or/and HTLV-1, in Salvador, Brazil. METHODS: In a case-control study we evaluated patients followed in the AIDS and HTLV clinics of Federal University of Bahia Hospital. Clinical and epidemiological characteristics were reviewed, and patients were tested for the presence of serological markers of HBV and HCV infections. HCV-infected patients were tested by PCR to evaluate the presence of viremia. RESULTS: A total of 200 HIV-1, 213 HTLV-1-infected, and 38 HIV-HTLV-co-infected individuals were included. HIV-infected patients were more likely to have had more sexual partners in the lifetime than other patients' groups. HIV-HTLV-co-infected subjects were predominantly male. Patients infected by HTLV or co-infected had a significantly higher frequency of previous syphilis or gonorrhea, while HIV infection was mainly associated with HPV infection. Co-infection was significantly associated to intravenous drug use (IVDU. HBV and/or HCV markers were more frequently found among co-infected patients. HBV markers were more frequently detected among HIV-infected patients, while HCV was clearly associated with IVDU across all groups. AgHBs was strongly associated with co-infection by HIV-HTLV (OR = 22.03, 95% CI: 2.69-469.7, as well as confirmed HCV infection (p = 0.001. Concomitant HCV and HBV infection was also associated with retroviral co-infection. Patients infected by HTLV-1 had a lower chance of detectable HCV viremia (OR = 0.04, 95% CI: 0.002-0.85. CONCLUSIONS: Infection by HCV and/or HBV is frequent among patients presenting retroviral infection, but risk factors and prevalence for each

  5. Acetylation of the c-MYC oncoprotein is required for cooperation with the HTLV-1 p30{sup II} accessory protein and the induction of oncogenic cellular transformation by p30{sup II}/c-MYC

    Energy Technology Data Exchange (ETDEWEB)

    Romeo, Megan M.; Ko, Bookyung; Kim, Janice; Brady, Rebecca; Heatley, Hayley C.; He, Jeffrey; Harrod, Carolyn K.; Barnett, Braden [Laboratory of Molecular Virology, Department of Biological Sciences, and The Dedman College Center for Drug Discovery, Design, and Delivery, Southern Methodist University, Dallas, TX 75275-0376 (United States); Ratner, Lee [Departments of Medicine and Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110 (United States); Lairmore, Michael D. [University of California-Davis, School of Veterinary Medicine, One Shields Avenue, Davis, CA 95618 (United States); Martinez, Ernest [Department of Biochemistry, University of California, Riverside, CA 92521 (United States); Lüscher, Bernhard [Institute of Biochemistry, Klinikum, RWTH Aachen University, Pauwelsstrasse 30, 52057 Aachen (Germany); Robson, Craig N. [Northern Institute for Cancer Research, Newcastle University, The Medical School, Newcastle upon Tyne, NE2 4HH (United Kingdom); Henriksson, Marie [Department of Microbiology, Cell and Tumor Biology, Karolinska Institutet, Stockholm (Sweden); Harrod, Robert, E-mail: rharrod@smu.edu [Laboratory of Molecular Virology, Department of Biological Sciences, and The Dedman College Center for Drug Discovery, Design, and Delivery, Southern Methodist University, Dallas, TX 75275-0376 (United States)

    2015-02-15

    The human T-cell leukemia retrovirus type-1 (HTLV-1) p30{sup II} protein is a multifunctional latency-maintenance factor that negatively regulates viral gene expression and deregulates host signaling pathways involved in aberrant T-cell growth and proliferation. We have previously demonstrated that p30{sup II} interacts with the c-MYC oncoprotein and enhances c-MYC-dependent transcriptional and oncogenic functions. However, the molecular and biochemical events that mediate the cooperation between p30{sup II} and c-MYC remain to be completely understood. Herein we demonstrate that p30{sup II} induces lysine-acetylation of the c-MYC oncoprotein. Acetylation-defective c-MYC Lys→Arg substitution mutants are impaired for oncogenic transformation with p30{sup II} in c-myc{sup −/−} HO15.19 fibroblasts. Using dual-chromatin-immunoprecipitations (dual-ChIPs), we further demonstrate that p30{sup II} is present in c-MYC-containing nucleoprotein complexes in HTLV-1-transformed HuT-102 T-lymphocytes. Moreover, p30{sup II} inhibits apoptosis in proliferating cells expressing c-MYC under conditions of genotoxic stress. These findings suggest that c-MYC-acetylation is required for the cooperation between p30{sup II}/c-MYC which could promote proviral replication and contribute to HTLV-1-induced carcinogenesis. - Highlights: • Acetylation of c-MYC is required for oncogenic transformation by HTLV-1 p30{sup II}/c-MYC. • Acetylation-defective c-MYC mutants are impaired for foci-formation by p30{sup II}/c-MYC. • The HTLV-1 p30{sup II} protein induces lysine-acetylation of c-MYC. • p30{sup II} is present in c-MYC nucleoprotein complexes in HTLV-1-transformed T-cells. • HTLV-1 p30{sup II} inhibits apoptosis in c-MYC-expressing proliferating cells.

  6. The HTLV-1 Tax protein binding domain of cyclin-dependent kinase 4 (CDK4 includes the regulatory PSTAIRE helix

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    Grassmann Ralph

    2005-09-01

    Full Text Available Abstract Background The Tax oncoprotein of human T-cell leukemia virus type 1 (HTLV-1 is leukemogenic in transgenic mice and induces permanent T-cell growth in vitro. It is found in active CDK holoenzyme complexes from adult T-cell leukemia-derived cultures and stimulates the G1- to-S phase transition by activating the cyclin-dependent kinase (CDK CDK4. The Tax protein directly and specifically interacts with CDK4 and cyclin D2 and binding is required for enhanced CDK4 kinase activity. The protein-protein contact between Tax and the components of the cyclin D/CDK complexes increases the association of CDK4 and its positive regulatory subunit cyclin D and renders the complex resistant to p21CIP inhibition. Tax mutants affecting the N-terminus cannot bind cyclin D and CDK4. Results To analyze, whether the N-terminus of Tax is capable of CDK4-binding, in vitro binding -, pull down -, and mammalian two-hybrid analyses were performed. These experiments revealed that a segment of 40 amino acids is sufficient to interact with CDK4 and cyclin D2. To define a Tax-binding domain and analyze how Tax influences the kinase activity, a series of CDK4 deletion mutants was tested. Different assays revealed two regions which upon deletion consistently result in reduced binding activity. These were isolated and subjected to mammalian two-hybrid analysis to test their potential to interact with the Tax N-terminus. These experiments concurrently revealed binding at the N- and C-terminus of CDK4. The N-terminal segment contains the PSTAIRE helix, which is known to control the access of substrate to the active cleft of CDK4 and thus the kinase activity. Conclusion Since the N- and C-terminus of CDK4 are neighboring in the predicted three-dimensional protein structure, it is conceivable that they comprise a single binding domain, which interacts with the Tax N-terminus.

  7. Ubiquitination and sumoylation of the HTLV-2 Tax-2B protein regulate its NF-κB activity: a comparative study with the HTLV-1 Tax-1 protein

    Science.gov (United States)

    2012-01-01

    Background Retroviruses HTLV-1 and HTLV-2 have homologous genomic structures but differ significantly in pathogenicity. HTLV-1 is associated with Adult T cell Leukemia (ATL), whereas infection by HTLV-2 has no association with neoplasia. Transformation of T lymphocytes by HTLV-1 is linked to the capacity of its oncoprotein Tax-1 to alter cell survival and cell cycle control mechanisms. Among these functions, Tax-1-mediated activation of cellular gene expression via the NF-κB pathway depends on Tax-1 post-translational modifications by ubiquitination and sumoylation. The Tax-2 protein of HTLV-2B (Tax-2B) is also modified by ubiquitination and sumoylation and activates the NF-κB pathway to a level similar to that of Tax-1. The present study aims to understand whether ubiquitination and sumoylation modifications are involved in Tax-2B-mediated activation of the NF-κB pathway. Results The comparison of Tax-1 and Tax-2B lysine to arginine substitution mutants revealed conserved patterns and levels of ubiquitination with notable difference in the lysine usage for sumoylation. Neither Tax-1 nor Tax-2B ubiquitination and sumoylation deficient mutants could activate the NF-κB pathway and fusion of ubiquitin or SUMO-1 to the C-terminus of the ubiquitination and sumoylation deficient Tax-2B mutant strikingly restored transcriptional activity. In addition, ubiquitinated forms of Tax-2B colocalized with RelA and IKKγ in prominent cytoplasmic structures associated with the Golgi apparatus, whereas colocalization of Tax-2B with the RelA subunit of NF-κB and the transcriptional coactivator p300 in punctate nuclear structures was dependent on Tax-2B sumoylation, as previously observed for Tax-1. Conclusions Both Tax-1 and Tax-2 activate the NF-κB pathway via similar mechanisms involving ubiquitination and sumoylation. Therefore, the different transforming potential of HTLV-1 and HTLV-2 is unlikely to be related to different modes of activation of the canonical NF-κB pathway

  8. HTLV-2B Tax oncoprotein is modified by ubiquitination and sumoylation and displays intracellular localization similar to its homologue HTLV-1 Tax

    International Nuclear Information System (INIS)

    Turci, Marco; Lodewick, Julie; Righi, Paola; Polania, Angela; Romanelli, Maria Grazia; Bex, Francoise; Bertazzoni, Umberto

    2009-01-01

    HTLV-1 is more pathogenic than HTLV-2B. The difference is generally attributed to the properties of their individual transactivating Tax proteins. By using internal Flag-6His tagged Tax-1 and Tax-2B, which display transcriptional activities comparable to the untagged proteins and can be recognized by a single anti-Flag antibody, we demonstrate that Tax-2B is modified by ubiquitination and sumoylation. In addition, Tax2B is distributed in punctuate nuclear structures that include the RelA subunit of NF-κB, as has been previously demonstrated for Tax-1

  9. Interference of HTLV-1 Tax Protein with Cell Polarity Regulators: Defining the Subcellular Localization of the Tax-DLG1 Interaction.

    Science.gov (United States)

    Marziali, Federico; Bugnon Valdano, Marina; Brunet Avalos, Clarisse; Moriena, Lucía; Cavatorta, Ana Laura; Gardiol, Daniela

    2017-11-23

    Human T cell leukemia virus (HTLV)-1 Tax (Tax) protein is very important in viral replication and cell transformation. Tax localizes in the nucleus and cytoplasm in association with organelles. Some activities of Tax depend on interactions with PDZ (PSD-95/Discs Large/Z0-1) domain-containing proteins such as Discs large protein 1 (DLG1) which is involved in cell polarity and proliferation. The DLG1 interaction results in a cytoplasmic co-localization pattern resembling vesicular aggregates, the nature of which is still unknown. To further explore the role of PDZ proteins in HTLV-1 cell transformation, we deeply investigated the Tax-DLG1 association. By fluorescence resonance energy transfer (FRET), we detected, for the first time, the direct binding of Tax to DLG1 within the cell. We showed that the interaction specifically affects the cellular distribution of not only DLG1, but also Tax. After studying different cell structures, we demonstrated that the aggregates distribute into the Golgi apparatus in spatial association with the microtubule-organizing center (MTOC). This study contributes to understand the biological significance of Tax-PDZ interactions.

  10. Common γ-chain blocking peptide reduces in vitro immune activation markers in HTLV-1-associated myelopathy/tropical spastic paraparesis.

    Science.gov (United States)

    Massoud, Raya; Enose-Akahata, Yoshimi; Tagaya, Yutaka; Azimi, Nazli; Basheer, Asjad; Jacobson, Steven

    2015-09-01

    Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive inflammatory myelopathy occurring in a subset of HTLV-1-infected individuals. Despite advances in understanding its immunopathogenesis, an effective treatment remains to be found. IL-2 and IL-15, members of the gamma chain (γc) family of cytokines, are prominently deregulated in HAM/TSP and underlie many of the characteristic immune abnormalities, such as spontaneous lymphocyte proliferation (SP), increased STAT5 phosphorylation in the lymphocytes, and increased frequency and cytotoxicity of virus-specific cytotoxic CD8(+) T lymphocytes (CTLs). In this study, we describe a novel immunomodulatory strategy consisting of selective blockade of certain γc family cytokines, including IL-2 and IL-15, with a γc antagonistic peptide. In vitro, a PEGylated form of the peptide, named BNZ132-1-40, reduced multiple immune activation markers such as SP, STAT5 phosphorylation, spontaneous degranulation of CD8(+) T cells, and the frequency of transactivator protein (Tax)-specific CD8(+) CTLs, thought to be major players in the immunopathogenesis of the disease. This strategy is thus a promising therapeutic approach to HAM/TSP with the potential of being more effective than single monoclonal antibodies targeting either IL-2 or IL-15 receptors and safer than inhibitors of downstream signaling molecules such as JAK1 inhibitors. Finally, selective cytokine blockade with antagonistic peptides might be applicable to multiple other conditions in which cytokines are pathogenic.

  11. [HSP90 inhibitor 17-AAG plays an important role in JAK3/STAT5 signaling pathways in HTLV-1 infection cell line HUT-102].

    Science.gov (United States)

    Yang, Q Q; Tan, H; Fu, Z P; Ma, Q; Song, J L

    2017-08-14

    Objective: To analyze whether heat-shock protein 90 (HSP90) be involved in a permanently abnormal activated JAK/STAT signaling in ATL cells in vitro. Methods: The effect of 17-AAG on proliferation of ATL cell lines HUT-102 was assessed using CCK8 at different time points. Cell apoptosis was measured by flow cytometry. The specific proteins HSP90, STAT5, p-STAT5 and JAK3 were detected by Western blotting. Results: Overexpression of HSP90 in HUT-102 cell lines was disclosed ( P AAG led to reduced cell proliferation, but there was no significant change in terms of cell proliferation when the concentration of 17-AAG between 2 000-8 000 nmol/L ( P >0.05) . 17-AAG induced cell apoptosis in different time-points and concentrations. 17-AAG don't affect the expression of JAK3 gene. Conclusion: This study indicated that JAK3 as HSP90 client protein was aberrantly activated in HTLV-1-infected T-cell lines, leading to constitutive activation of p-STAT5 in JAK/STAT signal pathway, which demonstrated that HSP90-inhibitors 17-AAG inhibited the growth of HTLV-1-infected T-cell lines by reducing cell proliferation and inducing cell apoptosis.

  12. Interference of HTLV-1 Tax Protein with Cell Polarity Regulators: Defining the Subcellular Localization of the Tax-DLG1 Interaction

    Directory of Open Access Journals (Sweden)

    Federico Marziali

    2017-11-01

    Full Text Available Human T cell leukemia virus (HTLV-1 Tax (Tax protein is very important in viral replication and cell transformation. Tax localizes in the nucleus and cytoplasm in association with organelles. Some activities of Tax depend on interactions with PDZ (PSD-95/Discs Large/Z0-1 domain–containing proteins such as Discs large protein 1 (DLG1 which is involved in cell polarity and proliferation. The DLG1 interaction results in a cytoplasmic co-localization pattern resembling vesicular aggregates, the nature of which is still unknown. To further explore the role of PDZ proteins in HTLV-1 cell transformation, we deeply investigated the Tax-DLG1 association. By fluorescence resonance energy transfer (FRET, we detected, for the first time, the direct binding of Tax to DLG1 within the cell. We showed that the interaction specifically affects the cellular distribution of not only DLG1, but also Tax. After studying different cell structures, we demonstrated that the aggregates distribute into the Golgi apparatus in spatial association with the microtubule-organizing center (MTOC. This study contributes to understand the biological significance of Tax-PDZ interactions.

  13. Direct binding of the N-terminus of HTLV-1 tax oncoprotein to cyclin-dependent kinase 4 is a dominant path to stimulate the kinase activity.

    Science.gov (United States)

    Li, Junan; Li, Hongyuan; Tsai, Ming-Daw

    2003-06-10

    The involvement of Tax oncoprotein in the INK4-CDK4/6-Rb pathway has been regarded as a key factor for immortalization and transformation of human T-cell leukemia virus 1 (HTLV-1) infected cells. In both p16 -/- and +/+ cells, expression of Tax has been correlated with an increase in CDK4 activity, which subsequently increases the phosphorylation of Rb and drives the infected cells into cell cycle progression. In relation to these effects, Tax has been shown to interact with two components of the INK4-CDK4/6-Rb pathway, p16 and cyclin D(s). While Tax competes with CDK4 for p16 binding, thus suppressing p16 inhibition of CDK4, Tax also binds to cyclin D(s) with concomitant increases in both CDK4 activity and the phosphorylation of cyclin D(s). Here we show that both Tax and residues 1-40 of the N-terminus of Tax, Tax40N, bind to and activate CDK4 in vitro. In the presence of INK4 proteins, binding of Tax and Tax40N to CDK4 counteracts against the inhibition of p16 and p18 and acts as the major path to regulate Tax-mediated activation of CDK4. We also report that Tax40N retains the transactivation ability. These results of in vitro studies demonstrate a potentially novel, p16-independent route to regulate CDK4 activity by the Tax oncoprotein in HTLV-1 infected cells.

  14. HTLV-1 Tax Stimulates Ubiquitin E3 Ligase, Ring Finger Protein 8, to Assemble Lysine 63-Linked Polyubiquitin Chains for TAK1 and IKK Activation.

    Science.gov (United States)

    Ho, Yik-Khuan; Zhi, Huijun; Bowlin, Tara; Dorjbal, Batsukh; Philip, Subha; Zahoor, Muhammad Atif; Shih, Hsiu-Ming; Semmes, Oliver John; Schaefer, Brian; Glover, J N Mark; Giam, Chou-Zen

    2015-08-01

    Human T lymphotropic virus type 1 (HTLV-1) trans-activator/oncoprotein, Tax, impacts a multitude of cellular processes, including I-κB kinase (IKK)/NF-κB signaling, DNA damage repair, and mitosis. These activities of Tax have been implicated in the development of adult T-cell leukemia (ATL) in HTLV-1-infected individuals, but the underlying mechanisms remain obscure. IKK and its upstream kinase, TGFβ-activated kinase 1 (TAK1), contain ubiquitin-binding subunits, NEMO and TAB2/3 respectively, which interact with K63-linked polyubiquitin (K63-pUb) chains. Recruitment to K63-pUb allows cross auto-phosphorylation and activation of TAK1 to occur, followed by TAK1-catalyzed IKK phosphorylation and activation. Using cytosolic extracts of HeLa and Jurkat T cells supplemented with purified proteins we have identified ubiquitin E3 ligase, ring finger protein 8 (RNF8), and E2 conjugating enzymes, Ubc13:Uev1A and Ubc13:Uev2, to be the cellular factors utilized by Tax for TAK1 and IKK activation. In vitro, the combination of Tax and RNF8 greatly stimulated TAK1, IKK, IκBα and JNK phosphorylation. In vivo, RNF8 over-expression augmented while RNF8 ablation drastically reduced canonical NF-κB activation by Tax. Activation of the non-canonical NF-κB pathway by Tax, however, is unaffected by the loss of RNF8. Using purified components, we further demonstrated biochemically that Tax greatly stimulated RNF8 and Ubc13:Uev1A/Uev2 to assemble long K63-pUb chains. Finally, co-transfection of Tax with increasing amounts of RNF8 greatly induced K63-pUb assembly in a dose-dependent manner. Thus, Tax targets RNF8 and Ubc13:Uev1A/Uev2 to promote the assembly of K63-pUb chains, which signal the activation of TAK1 and multiple downstream kinases including IKK and JNK. Because of the roles RNF8 and K63-pUb chains play in DNA damage repair and cytokinesis, this mechanism may also explain the genomic instability of HTLV-1-transformed T cells and ATL cells.

  15. Prácticas sexuales y seroprevalencia de infección por VIH, HTLV-1 sífilis en meretrices clandestinas de Lima

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    Luis Trujillo

    1996-10-01

    Full Text Available Objetivo: Investigar la prevalencia de prácticas sexuales de riesgo para infección por Enfermedades de Transmisión Sexual (ETS y la seroprevalencia de infección por VIH-1, HTLV-1 y Treponema pallidum en meretrices de los burdeles clandestinos de Lima. Material y métodos: Estudio de diseño transversal, descriptivo y no probabilístico. Se realizó una encuesta anónima por entrevista directa sobre prácticas sexuales y antecedentes de ETS y se tomó una muestra de sangre para análisis serológico de anticuerpos contra VIH-1, HTLV-1 y T. Pallidum de 158 meretrices voluntarias en 15 burdeles clandestinos de Lima Metropolitana entre marzo y junio de 1994. Resultados: Todas las muestras de suero fueron negativas para VIH-1 (IC 95%, 0.0 - 1.8 pero dos resultaron indeterminadas (ELISA positivo y WB banda p24 presente. Seis (3.8% positivas para HTLV-1 (IC 95%, 1.4 - 8.1. Cinco (3.2% fueron VDRL reactivas (IC 95%, 1.0 - 7.3. El uso consistente de condón con los clientes fue 75% (119/158. Sólo 3% (4/137 lo usan con su pareja sexual estable. Las prácticas sexuales de riesgo encontradas fueron: coito anal 7.6%, relaciones sexuales durante la menstruación 37%, felación 93%, relaciones sexuales con clientes portadores de úlceras genitales 19%; pero refirieron un mayor uso del condón en las mismas. El 25% tuvo antecedentes de alguna ETS en los últimos 5 años, siendo gonorrea, la más frecuente (22%. Conclusiones: La población de meretrices de los burdeles clandestinos de Lima tiene un elevado uso consistente del condón con clientes, y la prevalencia de infección retroviral y de sífilis es baja. (Rev Med Hered 1996; 7: 162-171.

  16. Clonagem e expressão da glicoproteína transmembrana do retrovírus HTLV-1 em células de mamíferos Cloning and transmembrane glycoprotein expression of the retrovirus HTLV-1 in mammals' cells

    Directory of Open Access Journals (Sweden)

    Flora Cristina Lobo Penteado

    2006-04-01

    Full Text Available O retrovírus linfotrópico de células T humanas tipo 1 é o agente etiológico da leucemia das células T do adulto e da paraparesia espástica tropical/mielopatia associada ao HTLV-1. O genoma proviral é composto por 9.032 pares de bases, contendo genes estruturais e regulatórios. A glicoproteína transmembrana gp 21 é codificada pelo gene estrutural env. O desenvolvimento de metodologias para a expressão heteróloga de proteínas, assim como a obtenção de uma linhagem celular que expresse a gp 21 recombinante constitutivamente são os principais objetivos do trabalho. O fragmento codificante da gp 21 foi amplificado por Nested-PCR e clonado no vetor pCR2.1-TOPO. Posteriormente, foi realizada a subclonagem no vetor de expressão pcDNA3.1+. A transfecção da linhagem celular de mamíferos HEK 293 foi realizada de maneira transitória e permanente. A produção da gp 21 recombinante foi confirmada por citometria de fluxo e a linhagem celular produtora será utilizada em ensaios de imunogenicidade.The retrovirus HTLV-1 is the etiological agent of the adult T-cell leukemia and HTLV-1 associated myelopathy/tropical spastic paraparesis. The proviral genome has 9,032 base pairs, showing regulatory and structural genes. The env gene encodes for the transmembrane glycoprotein gp 21. The development of methodologies for heterologous protein expression, as well as the acquisition of a cellular line that constituently expresses the recombinant, were the main goals of this work. The DNA fragment that encodes for gp 21 was amplified by nested-PCR and cloned into a pCR2.1-TOPO vector. After which, a sub-cloning was realized using the expressing vector pcDNA3.1+. The transfection of mammalian cells HEK 293 was performed transitorily and permanently. Production of the recombinant gp 21 was confirmed by flux cytometry experiments and the cell line producing protein will be used in immunogenicity assays.

  17. Implicações clínicas e imunológicas da associação entre o HTLV-1 e a estrongiloidíase

    OpenAIRE

    Porto, Maria Aurélia da Fonseca; Muniz, André Luís Nunes; Oliveira Júnior, Jamary; Carvalho Filho, Edgar Marcelino de

    2002-01-01

    P. 641-649,Nov-Dez. A estrongiloidíase é uma das mais importantes helmintíases em países tropicais e estudos epidemiológicos têm demonstrado associação desta parasitose com o vírus HTLV-1. Em regiões onde estes dois agentes são endêmicos a coinfecção pode resultar no desenvolvimento de formas disseminadas da estrongiloidíase assim como em estrongiloidíase recorrente. Enquanto que o vírus HTLV-1 está relacionado com uma alta produção de IFN-g e desvio da resposta imune para o tipo Th1, a pr...

  18. Implicações clínicas e imunológicas da associação entre o HTLV-1 e a estrongiloidíase

    OpenAIRE

    Porto,Maria Aurélia F.; Muniz,André; Oliveira Júnior,Jamary; Carvalho,Edgar Marcelino

    2002-01-01

    A estrongiloidíase é uma das mais importantes helmintíases em países tropicais e estudos epidemiológicos têm demonstrado associação desta parasitose com o vírus HTLV-1. Em regiões onde estes dois agentes são endêmicos a coinfecção pode resultar no desenvolvimento de formas disseminadas da estrongiloidíase assim como em estrongiloidíase recorrente. Enquanto que o vírus HTLV-1 está relacionado com uma alta produção de IFN-γ e desvio da resposta imune para o tipo Th1, a proteção contra helm...

  19. Seroprevalencia del virus linfotropo T humano tipo 1 (HTLV-1 en gestantes y grupos de elevada prevalencia para enfermedades de transmisión sexual de Ayacucho, Perú

    Directory of Open Access Journals (Sweden)

    Zoraida Juscamaita P

    2004-10-01

    Full Text Available Mediante encuestas sero-epidemiológicas se determinó la prevalencia de HTLV-1 en gestantes que acudieron a control prenatal al Hospital Regional de Ayacucho, ciudad andina del Perú, y en grupos de alta prevalencia para enfermedades de transmisión sexual (GEPETS. Las muestras séricas fueron tamizadas con el método de ELISA y finalmente confirmadas con el método de inmunoensayo en línea (INNO-LIA. Se enroló a 602 gestantes de las cuales 3 fueron positivas (0,5% y 3 indeterminadas (0,5. Todas las 85 trabajadoras sexuales fueron negativas, mientras que 2 de 74 homo/bisexuales (2,7% fueron indeterminados. En conclusión, la seroprevalencia de HTLV-1 en gestantes de Huamanga fue baja. La ausencia de casos positivos en los GEPETS contrasta con lo informado en nuestro país.

  20. Hiv/hbv, hiv/hcv and hiv/htlv-1 co infection among injecting drug user patients hospitalized at the infectious disease ward of a training hospital in iran

    International Nuclear Information System (INIS)

    Alavi, S.M.; Etemadi, A.

    2007-01-01

    To assess the prevalence and risk factors for HBV, HCV and HTLV-I co-infection in the Iranian HIV positive Injecting Drug Users (IDU) patients admitted in hospital. Analyses were based on 154 male IDU patients admitted in Infectious disease ward of Razi Hospital, Ahwaz, Iran, from April 2001 to March 2003. All of them had been tested for HIV infection (Elisa-antibody and Western blot), HBV surface antigen, HCV antibody and HTLV-1 antibody. One hundred and four patients (67.53%) were identified as HIV infected. Among HIV infected, HB surface antigen, HCV antibody and HTLV-I antibody were positive in 44.23% and 74.04% and 16.33% patients respectively. HCV/HBV/HIV and HCV/HBV/HIV/HTLV-1 co-infection were 20.20% and 8.65% respectively. Co-infection with HBV or HCV or HTLV-1 is common among hospitalized HIV-infected IDU patients in the region of study. HIV disease outcomes appear to be adversely affected by HBV/HCV/HTLV-I co-infection, so identification of these viral infections is recommended as routine tests for this population. (author)

  1. Expansion in CD39⁺ CD4⁺ immunoregulatory t cells and rarity of Th17 cells in HTLV-1 infected patients is associated with neurological complications.

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    Fabio E Leal

    Full Text Available HTLV-1 infection is associated with several inflammatory disorders, including the neurodegenerative condition HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP. It is unclear why a minority of infected subjects develops HAM/TSP. CD4⁺ T cells are the main target of infection and play a pivotal role in regulating immunity to HTLV and are hypothesized to participate in the pathogenesis of HAM/TSP. The CD39 ectonucleotidase receptor is expressed on CD4⁺ T cells and based on co-expression with CD25, marks T cells with distinct regulatory (CD39⁺CD25⁺ and effector (CD39⁺CD25⁻ function. Here, we investigated the expression of CD39 on CD4⁺ T cells from a cohort of HAM/TSP patients, HTLV-1 asymptomatic carriers (AC, and matched uninfected controls. The frequency of CD39⁺ CD4⁺ T cells was increased in HTLV-1 infected patients, regardless of clinical status. More importantly, the proportion of the immunostimulatory CD39⁺CD25⁻ CD4⁺ T-cell subset was significantly elevated in HAM/TSP patients as compared to AC and phenotypically had lower levels of the immunoinhibitory receptor, PD-1. We saw no difference in the frequency of CD39⁺CD25⁺ regulatory (Treg cells between AC and HAM/TSP patients. However, these cells transition from being anergic to displaying a polyfunctional cytokine response following HTLV-1 infection. CD39⁻CD25⁺ T cell subsets predominantly secreted the inflammatory cytokine IL-17. We found that HAM/TSP patients had significantly fewer numbers of IL-17 secreting CD4⁺ T cells compared to uninfected controls. Taken together, we show that the expression of CD39 is upregulated on CD4⁺ T cells HAM/TSP patients. This upregulation may play a role in the development of the proinflammatory milieu through pathways both distinct and separate among the different CD39 T cell subsets. CD39 upregulation may therefore serve as a surrogate diagnostic marker of progression and could potentially be a target for

  2. Diclofenac sodium inhibits NFkappaB transcription in osteoclasts.

    Science.gov (United States)

    Karakawa, A; Fukawa, Y; Okazaki, M; Takahashi, K; Sano, T; Amano, H; Yamamoto, M; Yamada, S

    2009-11-01

    A non-steroidal anti-inflammatory drug, diclofenac, acts efficiently against inflammation; however, down-regulation of diclofenac on bone remodeling has raised concerns. The inhibitory mechanisms of diclofenac are poorly understood. We hypothesized that diclofenac down-regulates osteoclast differentiation and activation via inhibition of the translocation of phosphorylated nuclear factor kappa B (NFkappaB). When osteoclasts prepared from mouse hematopoietic stem cells were treated with diclofenac, tartrateresistant acid phosphatase-positive multinucleated cells decreased in a concentration-dependent manner. Pit formation assay revealed the abolition of osteoclastic bone resorption; levels of cathepsin K transcripts, an osteoclastic resorption marker, were down-regulated time-dependently. Diclofenac induced the accumulation of the inhibitor of kappa B in cytosol, which led to suppression of the nuclear translocation of NFkappaB and phosphorylated NFkappaB. These results suggest that the novel mechanism of diclofenac for bone remodeling is associated with phosphorylated NFkappaB reduction, which regulates osteoclast differentiation and activation.

  3. Human T-cell leukemia virus type 1 (HTLV-1 tax requires CADM1/TSLC1 for inactivation of the NF-κB inhibitor A20 and constitutive NF-κB signaling.

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    Rajeshree Pujari

    2015-03-01

    Full Text Available Persistent activation of NF-κB by the Human T-cell leukemia virus type 1 (HTLV-1 oncoprotein, Tax, is vital for the development and pathogenesis of adult T-cell leukemia (ATL and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP. K63-linked polyubiquitinated Tax activates the IKK complex in the plasma membrane-associated lipid raft microdomain. Tax also interacts with TAX1BP1 to inactivate the NF-κB negative regulatory ubiquitin-editing A20 enzyme complex. However, the molecular mechanisms of Tax-mediated IKK activation and A20 protein complex inactivation are poorly understood. Here, we demonstrated that membrane associated CADM1 (Cell adhesion molecule1 recruits Ubc13 to Tax, causing K63-linked polyubiquitination of Tax, and IKK complex activation in the membrane lipid raft. The c-terminal cytoplasmic tail containing PDZ binding motif of CADM1 is critical for Tax to maintain persistent NF-κB activation. Finally, Tax failed to inactivate the NF-κB negative regulator ubiquitin-editing enzyme A20 complex, and activate the IKK complex in the lipid raft in absence of CADM1. Our results thus indicate that CADM1 functions as a critical scaffold molecule for Tax and Ubc13 to form a cellular complex with NEMO, TAX1BP1 and NRP, to activate the IKK complex in the plasma membrane-associated lipid rafts, to inactivate NF-κB negative regulators, and maintain persistent NF-κB activation in HTLV-1 infected cells.

  4. Características epidemiológicas de los pacientes con paraparesia espástica tropical (PET asociada a infección por HTLV-1 en Lima, Perú.

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    César De las Casas

    1996-04-01

    Full Text Available Objetivo: Describir las características epidemiológicas de la paraparesia espástica tropical asociada a infección por HTLV-1. Material y métodos: Se realizó un estudio descriptivo de 61 pacientes consecutivos con paraparesia espástica tropical (PET asociada a HTLV1. Los casos fueron evaluados prospectivamente en dos instituciones de Lima (Instituto de Medicina Tropical "Alexander Von Humboldt" y el Servicio de Neurología del Hospital Nacional Guillermo Almenara Irigoyen entre agosto de 1989 y noviembre de 1995. Fueron incluidos 61 pacientes con diagnóstico clínico de PET y confirmación sexológica de HTLV-1 mediante ELISA y Western Blot. Resultados y conclusiones: Se observó una preponderancia del sexo femenino, con una relación mujer a hombre de 1.91:1. La edad promedio fue de 51.7 años (rango: 21 a 76 años. El 50.5% había residido en regiones andinas, siendo éste el lugar de nacimiento para el 54.1%. Sólo el 6.6% fue referido desde hospitales de esa región. No se identificaron adictos a drogas endovenosas, aunque un 23% tenía antecedente de transfusiones. Enfermedades de transmisión sexual fueron admitidas por el 35% de los hombres que respondieron, en los que la falta de empleo del condón fue un evento frecuente. Otros factores de riesgo fueron también evaluados. (Rev Med Hered 1996; 7: 68-74.

  5. Universal cytotoxic activity of a HTLV-1 Tax-specific T cell clone from an HLA-A*24:02⁺ patient with adult T-cell leukemia against a variety of HTLV-I-infected T-cells.

    Science.gov (United States)

    Tanaka, Yukie; Yamazaki, Rie; Terasako-Saito, Kiriko; Nakasone, Hideki; Akahoshi, Yu; Nakano, Hirofumi; Ugai, Tomotaka; Wada, Hidenori; Yamasaki, Ryoko; Ishihara, Yuko; Kawamura, Koji; Sakamoto, Kana; Ashizawa, Masahiro; Sato, Miki; Kimura, Shun-ichi; Kikuchi, Misato; Kako, Shinichi; Kanda, Junya; Tanihara, Aki; Nishida, Junji; Kanda, Yoshinobu

    2014-01-01

    Adult T cell leukemia/lymphoma (ATL) is an aggressive mature T cell malignancy that is causally associated with human T cell lymphotropic virus type 1 (HTLV-1) infection. The HTLV-1 regulatory protein Tax aggressively accelerates the proliferation of host cells and is also an important target antigen for CD8(+) cytotoxic T cells (CTLs). We previously reported that several predominant HLA-A*24:02-restricted HTLV-1 Tax301-309-specific CTL clones commonly expressed a particular amino acid sequence motif (P-D-R) in complementarity-determining region 3 of T-cell receptor (TCR)-β chain among unrelated ATL patients who underwent allogeneic stem cell transplantation (allo-HSCT). Furthermore, a PDR-motif(+) CTL clone persistently existed in a long-term survivor as a central CTL clone with strong CTL activities after HSCT. Although a larger analysis of the relationship between PDR-motif(+) CTLs and the clinical course is required, the expression of PDR-motif(+) TCR on CD8(+) T cells may play a critical role in the management of anti-HTLV-1 activities for HLA-A24:02(+) ATL patients. Therefore, in this study, we prepared an HTLV-1 Tax301-309 peptide-specific CTL clone (HT-9) expressing PDR-motif(+) TCR isolated from a long-term survivor after HSCT, and evaluated its CTL activity against a variety of HTLV-1-infected T-cells from HLA-A*24:02(+) ATL patients. Before the assay of CTL function, we confirmed that HT-9 expressed less-differentiated effector-memory phenotypes (CD45RA(-)CCR7(-)CD27(+)CD28(+/-)CD57(+/-)) and T-cell exhaustion marker PD-1(+). In assays of CTL function, HT-9 recognized HTLV-1 Tax in an HLA-restricted fashion and demonstrated strong CTL activities against a variety of HTLV-1-infected T-cells from HLA-A*24:02(+) ATL patients regardless of whether the sources were autologous or allogeneic, but not normal cells. These data indicate that PDR-motif(+) TCR could be an important TCR candidate for TCR-gene immunotherapy for HLA-A24:02(+) ATL patients, provided

  6. DMPD: New insights into NF-kappaB regulation and function. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18775672 New insights into NF-kappaB regulation and function. Sun SC, Ley SC. Trend...ction. PubmedID 18775672 Title New insights into NF-kappaB regulation and function....s Immunol. 2008 Oct;29(10):469-78. Epub 2008 Sep 3. (.png) (.svg) (.html) (.csml) Show New insights into NF-kappaB regulation and fun

  7. Virus linfotrópico humano de células T tipo 1 (HTLV-1: Una infección endémica en el Perú

    Directory of Open Access Journals (Sweden)

    Eduardo Gotuzzo H

    2004-10-01

    Full Text Available El artículo tiene como objetivo presentar una revisión de aspectos clínicos de la infección por el virus linfotrópico humano de células T tipo 1 (HTLV-1, poniendo énfasis en información relevante para los médicos en el Perú. Luego de presentar algunos aspectos virológicos y epidemiológicos, tratamos los temas de la transmisión y de las enfermedades asociadas con el virus. Se discute específicamente las siguientes enfermedades asociadas: leucemia linfoma de células T del adulto, paraparesia espástica tropical, estrongiloidiasis, sarna, tuberculosis, dermatitis infectiva y coinfección con VIH. En conclusión, HTLV-1 es una infección endémica en el Perú. El espectro de enfermedades asociadas comprende síndromes inflamatorios, enfermedades linfoproliferativas e infecciones oportunistas.

  8. DMPD: Ubiquitin: tool and target for intracellular NF-kappaB inhibitors. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 16982211 Ubiquitin: tool and target for intracellular NF-kappaB inhibitors. Wullaer...vg) (.html) (.csml) Show Ubiquitin: tool and target for intracellular NF-kappaB inhibitors. PubmedID 1698221...1 Title Ubiquitin: tool and target for intracellular NF-kappaB inhibitors. Author

  9. DMPD: NF-kappaB activation by reactive oxygen species: fifteen years later. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 16723122 NF-kappaB activation by reactive oxygen species: fifteen years later. Gloi...svg) (.html) (.csml) Show NF-kappaB activation by reactive oxygen species: fifteen years later. PubmedID 167...23122 Title NF-kappaB activation by reactive oxygen species: fifteen years later.

  10. NF-kappaB signaling: a tale of two pathways in skeletal myogenesis.

    Science.gov (United States)

    Bakkar, Nadine; Guttridge, Denis C

    2010-04-01

    NF-kappaB is a ubiquitiously expressed transcription factor that plays vital roles in innate immunity and other processes involving cellular survival, proliferation, and differentiation. Activation of NF-kappaB is controlled by an IkappaB kinase (IKK) complex that can direct either canonical (classical) NF-kappaB signaling by degrading the IkappaB inhibitor and releasing p65/p50 dimers to the nucleus, or causes p100 processing and nuclear translocation of RelB/p52 via a noncanonical (alternative) pathway. Under physiological conditions, NF-kappaB activity is transiently regulated, whereas constitutive activation of this transcription factor typically in the classical pathway is associated with a multitude of disease conditions, including those related to skeletal muscle. How NF-kappaB functions in muscle diseases is currently under intense investigation. Insight into this role of NF-kappaB may be gained by understanding at a more basic level how this transcription factor contributes to skeletal muscle cell differentiation. Recent data from knockout mice support that the classical NF-kappaB pathway functions as an inhibitor of skeletal myogenesis and muscle regeneration acting through multiple mechanisms. In contrast, alternative NF-kappaB signaling does not appear to be required for myofiber conversion, but instead functions in myotube homeostasis by regulating mitochondrial biogenesis. Additional knowledge of these signaling pathways in skeletal myogenesis should aid in the development of specific inhibitors that may be useful in treatments of muscle disorders.

  11. Colorectal cancer: can nutrients modulate NF-kappaB and apoptosis?

    Science.gov (United States)

    Ravasco, Paula; Aranha, Márcia M; Borralho, Pedro M; Moreira da Silva, Isabel B; Correia, Luís; Fernandes, Afonso; Rodrigues, Cecília M P; Camilo, Maria

    2010-02-01

    NF-kappaB may promote carcinogenesis by altering cell cycle, inflammatory responses and apoptosis-related gene expression, though cell mechanisms relating diet and colorectal cancer (CRC) remain unveiled in humans. This study in patients with CRC aimed to explore potential interactions between the dietary pattern, nutrient intake, expression of NF-kappaB, apoptosis and tumour histological aggressiveness. Usual diet was assessed by diet history; nutrient composition was determined by DIETPLAN software. Histologically classified patient tissue samples (adenoma, adenocarcinoma and normal surrounding mucosa) were obtained via biopsies during colonoscopy (n=16) or surgery (n=8). NF-kappaB expression was determined by immunohistochemistry and apoptosis by TUNEL assay. NF-kappaB expression and apoptosis were higher in tumours (p<0.01), greater along with histological aggressiveness (p<0.01). Highest intake terciles of animal protein, refined carbohydrates, saturated fat, n-6 fatty acids and alcohol were associated with higher NF-kappaB, apoptosis and histological aggressiveness (p<0.01); the opposite tissue characteristics were associated with highest intake terciles of n-3 fatty acids, fibre, vitamin E, flavonoids, isoflavones, beta-carotene and selenium (p<0.002). Additionally, higher n-6:n-3 fatty acids ratio (median 26:1) was associated with higher NF-kappaB (p<0.006) and apoptosis (p<0.01), and more aggressive histology (p<0.01). Conversely, lower n-6:n-3 fatty acids ratio (median 6:1) was associated with lower NF-kappaB (p<0.002) and apoptosis (p<0.002), and less aggressive histology (p<0.002). NF-kappaB expression and apoptosis increased from adenoma to poorly differentiated adenocarcinoma. This degenerative transition, recognized as key in carcinogenesis, appear to have been influenced by a diet promoting a pro-inflammatory milieu that can trigger NF-kappaB. Copyright 2009 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  12. Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls.

    Science.gov (United States)

    Baud, Véronique; Karin, Michael

    2009-01-01

    Nuclear factor kappaB (NF-kappaB) transcription factors have a key role in many physiological processes such as innate and adaptive immune responses, cell proliferation, cell death, and inflammation. It has become clear that aberrant regulation of NF-kappaB and the signalling pathways that control its activity are involved in cancer development and progression, as well as in resistance to chemotherapy and radiotherapy. This article discusses recent evidence from cancer genetics and cancer genome studies that support the involvement of NF-kappaB in human cancer, particularly in multiple myeloma. The therapeutic potential and benefit of targeting NF-kappaB in cancer, and the possible complications and pitfalls of such an approach, are explored.

  13. The effect of Taiwan's tax-induced increases in cigarette prices on brand-switching and the consumption of cigarettes.

    Science.gov (United States)

    Tsai, Yi-Wen; Yang, Chung-Lin; Chen, Chin-Shyan; Liu, Tsai-Ching; Chen, Pei-Fen

    2005-06-01

    The effect of raising cigarette taxes to reduce smoking has been the subject of several studies, which often treat the price of cigarettes as an exogenous factor given to smokers who respond to it by adjusting their smoking behavior. However, cigarette prices vary with brand and quality, and smokers can and do switch to lower-priced brands to reduce the impact of the tax on the cost of cigarettes as they try to consume the same number of cigarettes as they had before a tax hike. Using data from a two-year follow-up interview survey conducted before and after a new cigarette tax scheme was imposed in Taiwan in 2002, this study examines three behavioral changes smokers may make to respond to tax-induced cigarette price increase: brand-switching, amount consumed, and amount spent on smoking. These changes were studied in relation to smoker income, before-tax cigarette price, level of addiction, exposure to advertizing, and consumer loyalty. We found that smokers, depending upon exposure to advertizing, level of consumer loyalty and initial price of cigarettes, switched brands to maintain current smoking habits and control costs. We also found that the initial amount smoked and level of addiction, not price, at least not at the current levels in Taiwan, determined whether a smoker reduced the number of cigarettes he consumed. Copyright 2005 John Wiley & Sons, Ltd.

  14. NF-kappaB mediates FGF signal regulation of msx-1 expression.

    Science.gov (United States)

    Bushdid, P B; Chen, C L; Brantley, D M; Yull, F; Raghow, R; Kerr, L D; Barnett, J V

    2001-09-01

    The nuclear factor-kappaB (NF-kappaB) family of transcription factors is involved in proliferation, differentiation, and apoptosis in a stage- and cell-dependent manner. Recent evidence has shown that NF-kappaB activity is necessary for both chicken and mouse limb development. We report here that the NF-kappaB family member c-rel and the homeodomain gene msx-1 have partially overlapping expression patterns in the developing chick limb. In addition, inhibition of NF-kappaB activity resulted in a decrease in msx-1 mRNA expression. Sequence analysis of the msx-1 promoter revealed three potential kappaB-binding sites similar to the interferon-gamma (IFN-gamma) kappaB-binding site. These sites bound to c-Rel, as shown by electrophoretic mobility shift assay (EMSA). Furthermore, inhibition of NF-kappaB activity significantly reduced transactivation of the msx-1 promoter in response to FGF-2/-4, known stimulators of msx-1 expression. These results suggest that NF-kappaB mediates the FGF-2/-4 signal regulation of msx-1 gene expression. Copyright 2001 Academic Press.

  15. Modulation of the NF-kappaB pathway by Bordetella pertussis filamentous hemagglutinin.

    Directory of Open Access Journals (Sweden)

    Tzvia Abramson

    Full Text Available Filamentous hemagglutinin (FHA is a cell-associated and secreted adhesin produced by Bordetella pertussis with pro-apoptotic and pro-inflammatory activity in host cells. Given the importance of the NF-kappaB transcription factor family in these host cell responses, we examined the effect of FHA on NF-kappaB activation in macrophages and bronchial epithelial cells, both of which are relevant cell types during natural infection.Exposure to FHA of primary human monocytes and transformed U-937 macrophages, but not BEAS-2B epithelial cells, resulted in early activation of the NF-kappaB pathway, as manifested by the degradation of cytosolic IkappaB alpha, by NF-kappaB DNA binding, and by the subsequent secretion of NF-kappaB-regulated inflammatory cytokines. However, exposure of macrophages and human monocytes to FHA for two hours or more resulted in the accumulation of cytosolic IkappaB alpha, and the failure of TNF-alpha to activate NF-kappaB. Proteasome activity was attenuated following exposure of cells to FHA for 2 hours, as was the nuclear translocation of RelA in BEAS-2B cells.These results reveal a complex temporal dynamic, and suggest that despite short term effects to the contrary, longer exposures of host cells to this secreted adhesin may block NF-kappaB activation, and perhaps lead to a compromised immune response to this bacterial pathogen.

  16. Prácticas sexuales de riesgo y seroprevalencia de infección por VIH-1. HTLV-1, sífilis y hepatitis B en varones drogadictos no endovenosos de Lima.

    Directory of Open Access Journals (Sweden)

    Dany MUÑOZ

    1997-07-01

    Full Text Available Objetivo: Investigar la prevalencia de prácticas sexuales de riesgo para infección por Enfermedades de Transmisión Sexual (ETS y la seroprevalencia de infección por VIH-1, HTLV-1, Hepatitis B y Sífilis en varones Drogadictos no Endovenosos (DNEV de Lima e identificar si ellos podrían ser considerados como grupo de alto riesgo de infección para HIV. Material y métodos: Encuesta anónima por entrevista directa sobre practicas sexuales y antecedentes de ETS, y análisis serológico para anticuerpos contra VIH, HTLV-1, HBc y T pallidum de 298 DNEV voluntarios del Instituto de Salud Mental "Honorio Delgado - Hideyo Noguchi" y de 10 Organizaciones No Gubernamentales ("Comunidades Terapéuticas" de Lima Metropolitana entre Abril y Agosto de 1996. Resultados: Cinco (1.7% muestras fueron positivas para VIH y una resultó indeterminada (ELISA positivo y WB banda gp 160 presente. Siete (2.3% positivas para HTLV- 1, treinta y cuatro (11.4% positivas para Ab Anti-HBc; y una (0.3% fue RPR y FTA-Abs positiva. El promedio de edad fué 28.8 ± 8.1 años. El promedio de tiempo de consumo de drogas más frecuente fue 6.9 ± 6.2 años con el 80% más de un año. Durante la etapa de consumo: el promedio del número de parejas sexuales fue 53.9 ± 243 con una mediana de 15. De los DNEV mantuvieron relaciones sexuales con Parejas Sexuales Estables el 79%, con Encuentros Casuales el 82%, con Meretrices el 62.4% y con Homosexuales el 60%; el uso consistente de condón es bajo con todos los tipos de parejas sexuales y en todos los tipos de relaciones sexuales pero aumenta significativamente en las relaciones sexuales con meretrices. Con el uso de drogas existe un aumento en el número de parejas sexuales y mayor frecuencia de algunas prácticas sexuales de riesgo tal como el coito anal con todos los tipos de parejas sexuales, así mismo un elevado porcentaje (75% mantienen relaciones sexuales estando drogados, y el 32.9% intercambian drogas por sexo. El 43

  17. Memory extinction entails the inhibition of the transcription factor NF-kappaB.

    Directory of Open Access Journals (Sweden)

    Emiliano Merlo

    Full Text Available In contextual memories, an association between a positive or negative reinforcement and the contextual cues where the reinforcement occurs is formed. The re-exposure to the context without reinforcement can lead to memory extinction or reconsolidation, depending on the number of events or duration of a single event of context re-exposure. Extinction involves the temporary waning of the previously acquired conditioned response. The molecular processes underlying extinction and the mechanisms which determine if memory will reconsolidate or extinguish after retrieval are not well characterized, particularly the role of transcription factors and gene expression. Here we studied the participation of a transcription factor, NF-kappaB, in memory extinction. In the crab context-signal memory, the activation of NF-kappaB plays a critical role in consolidation and reconsolidation, memory processes that are well characterized in this model. The administration of a NF-kappaB inhibitor, sulfasalazine prior to extinction session impeded spontaneous recovery. Moreover, reinstatement experiments showed that the original memory was not affected and that NF-kappaB inhibition by sulfasalazine impaired spontaneous recovery strengthening the ongoing memory extinction process. Interestingly, in animals with fully consolidated memory, a brief re-exposure to the training context induced neuronal NF-kappaB activation and reconsolidation, while prolonged re-exposure induced NF-kappaB inhibition and memory extinction. These data constitutes a novel insight into the molecular mechanisms involved in the switch between memory reconsolidation and extinction. Moreover, we propose the inhibition of NF-kappaB as the engaged mechanism underlying extinction, supporting a novel approach for the pharmacological enhancement of this memory process. The accurate description of the molecular mechanisms that support memory extinction is potentially useful for developing new strategies

  18. Effects of protein-energy malnutrition on NF-kappaB signalling in murine peritoneal macrophages.

    Science.gov (United States)

    Fock, Ricardo Ambrósio; Rogero, Marcelo Macedo; Vinolo, Marco Aurélio Ramirez; Curi, Rui; Borges, Maria Carolina; Borelli, Primavera

    2010-04-01

    Protein-energy malnutrition (PEM) is an important public health problem affecting millions of people worldwide. PEM decreases resistance to infection, impairing a number of physiological processes. In unstimulated cells, NF-kappaB is kept from binding to its consensus sequence by the inhibitor I kappaB alpha, which retains NF-kappaB in the cytoplasm. Upon various signals, such as lipopolysaccharide (LPS), I kappaB alpha is rapidly degraded and NF-kappaB is induced to translocate into the nucleus, where it activates expression of various genes that participate in the inflammatory response, including those involved in the synthesis of TNF-alpha. TRAF-6 is a cytoplasmic adapter protein that links the stimulatory signal from Toll like receptor-4 to NF-kappaB. The aim of this study was to evaluate the effect of malnutrition on induction of TNF-alpha by LPS in murine peritoneal macrophages. We evaluated peritoneal cellularity, the expression of MyD88, TRAF-6, IKK, I kappaB alpha and NF-kappaB, NF-kappaB activation and TNF-alpha mRNA and protein synthesis in macrophages. Two-month-old male BALB/C mice were submitted to PEM with a low-protein diet that contained 2% protein, compared to 12% protein in the control diet. When the experimental group had lost about 20% of the original body weight, it was used in the subsequent experiments. Malnourished animals presented anemia, leucopenia and severe reduction in peritoneal cavity cellularity. TNF-alpha mRNA and protein levels of macrophages stimulated with LPS were significantly lower in malnourished animals. PEM also decreased TRAF-6 expression and NF-kappaB activation after LPS stimulation. These results led us to conclude that PEM changes NF-kB signalling pathway in macrophages to LPS stimulus.

  19. The MHC-II transactivator CIITA, a restriction factor against oncogenic HTLV-1 and HTLV-2 retroviruses: similarities and differences in the inhibition of Tax-1 and Tax-2 viral transactivators

    Science.gov (United States)

    Forlani, Greta; Abdallah, Rawan; Accolla, Roberto S.; Tosi, Giovanna

    2013-01-01

    The activation of CD4+ T helper cells is strictly dependent on the presentation of antigenic peptides by MHC class II (MHC-II) molecules. MHC-II expression is primarily regulated at the transcriptional level by the AIR-1 gene product CIITA (class II transactivator). Thus, CIITA plays a pivotal role in the triggering of the adaptive immune response against pathogens. Besides this well known function, we recently found that CIITA acts as an endogenous restriction factor against HTLV-1 (human T cell lymphotropic virus type 1) and HTLV-2 oncogenic retroviruses by targeting their viral transactivators Tax-1 and Tax-2, respectively. Here we review our findings on CIITA-mediated inhibition of viral replication and discuss similarities and differences in the molecular mechanisms by which CIITA specifically counteracts the function of Tax-1 and Tax-2 molecules. The dual function of CIITA as a key regulator of adaptive and intrinsic immunity represents a rather unique example of adaptation of host-derived factors against pathogen infections during evolution. PMID:23986750

  20. TLR4 activates NF-{kappa}B in human ovarian granulosa tumor cells

    Energy Technology Data Exchange (ETDEWEB)

    Woods, Dori C., E-mail: dwoods2@partners.org [Vincent Center for Reproductive Biology, Vincent Obstetrics and Gynecology Service, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02114 (United States); White, Yvonne A.R. [Vincent Center for Reproductive Biology, Vincent Obstetrics and Gynecology Service, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02114 (United States); Dau, Caroline [University of California, San Francisco, School of Dentistry, San Francisco, CA 94143 (United States); Johnson, A.L. [Center for Reproductive Biology and Health, The Pennsylvania State University, University Park, PA 16802 (United States)

    2011-06-17

    Highlights: {yields} TLR4 is expressed in human ovarian granulosa tumor cells. {yields} Acting through TLR4, LPS and HSP60 induce a NF{kappa}B signaling cascade in human ovarian granulosa tumor cells. {yields} NF{kappa}B activation or inhibition did not alter chemosensitivity to TRAIL or cisplatin. -- Abstract: Previous studies have demonstrated expression of Toll-like receptors (TLRs) in the surface epithelium of normal ovaries (OSE) and in epithelial ovarian tumors. Most notably, OSE-derived cancers express TLR4, which activates the nuclear factor-kappa B (NF-{kappa}B) signaling cascade as a mediator of inflammatory response. Currently, there is considerable interest in elucidating the role of TLR-mediated signaling in cancers. Nevertheless, the expression of TLRs in granulosa cell tumors (GCTs) of the ovary, and the extent to which GCT expression of TLRs may influence cell-signaling pathways and/or modulate the efficacy of chemotherapeutics, has yet to be determined. In the present study, human GCT lines (COV434 and KGN) were utilized to evaluate expression of functional TLR4. TLR4 is expressed in GCT cell lines and ligation of TLR4 with bacterial lipopolysaccharide (LPS) led to I{kappa}B degradation and activation of NF-{kappa}B. NF-{kappa}B activation was confirmed by nuclear localization of NF-{kappa}B p65 following treatment with LPS and the naturally occurring ligand, HSP60. Notably, immunoneutralization of TLR4 blocked nuclear localization, and inhibition of NF-{kappa}B signaling attenuated LPS-induced TNF{alpha} plus increased doubling time in both cell lines. Contradictory to reports using human OSE cell lines, inhibition of NF-{kappa}B signaling failed to sensitize GCT lines to TRAIL or cisplatin. In summary, findings herein are the first to demonstrate a functional TLR-signaling pathway specifically in GCTs, and indicate that in contrast to OSE-derived cancers, inhibition of NF-{kappa}B does not sensitize GCTs to TRAIL or cisplatin.

  1. DMPD: Signaling to NF-kappaB by Toll-like receptors. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available l Med. 2007 Nov;13(11):460-9. Epub 2007 Oct 29. (.png) (.svg) (.html) (.csml) Show Signaling to NF-kappaB by Toll-like receptors. Pub...medID 18029230 Title Signaling to NF-kappaB by Toll-like receptors. Authors Kawai T

  2. Pim-2 activates API-5 to inhibit the apoptosis of hepatocellular carcinoma cells through NF-kappaB pathway.

    Science.gov (United States)

    Ren, Ke; Zhang, Wei; Shi, Yujun; Gong, Jianping

    2010-06-01

    Pim-2 is proved to be relevant to the tumorigenesis of hepatocellular carcinoma (HCC), but the mechanism is unclear. We studied the relationship among Pim-2, NF-kappaB and API-5. In our experiment, expression level of the three factors and phosphorylation level of API-5, as well as NF-kappaB activity, were detected in HCC tissues and the nontumorous controls. Then Pim-2 gene was transfected into nontumorous liver cells L02, and Pim-2 SiRNA was transfected into hepatoblastoma cell line HepG2. Parthenolide was added as NF-kappaB inhibitor. The same detections as above were repeated in the cells, along with the apoptosis analysis. We found the levels of Pim-2, NF-kappaB and API-5, as well as NF-kappaB activity, were significantly higher in HCC tissues. Pim-2 level was increased in L02 cells after the transfection of Pim-2 gene, but decreased in HepG2 cells after the transfection of Pim-2 SiRNA. The levels of NF-kappaB and API-5, as well as NF-kappaB activity and API-5 phosphorylation level, were in accordance with Pim-2 level, but could be reversed by Parthenolide. Cell apoptosis rates were negatively correlated with API-5 phosphorylation level. Therefore, we infer that Pim-2 could activate API-5 to inhibit the apoptosis of liver cells, and NF-kappaB is the key regulator.

  3. Purinergic signaling is required for fluid shear stress-induced NF-{kappa}B translocation in osteoblasts

    Energy Technology Data Exchange (ETDEWEB)

    Genetos, Damian C., E-mail: dgenetos@ucdavis.edu [Department of Anatomy, Cell Biology, and Physiology, School of Veterinary Medicine, University of California, Davis, CA (United States); Karin, Norman J. [Cell Biology and Biochemistry, Pacific Northwest National Laboratory, Richland, WA (United States); Geist, Derik J. [Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN (United States); Donahue, Henry J. [Division of Musculoskeletal Sciences, Department of Orthopaedics and Rehabilitation, Pennsylvania State College of Medicine, Hershey, PA (United States); Duncan, Randall L. [Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN (United States)

    2011-04-01

    Fluid shear stress regulates gene expression in osteoblasts, in part by activation of the transcription factor NF-{kappa}B. We examined whether this process was under the control of purinoceptor activation. MC3T3-E1 osteoblasts under static conditions expressed the NF-{kappa}B inhibitory protein I{kappa}B{alpha} and exhibited cytosolic localization of NF-{kappa}B. Under fluid shear stress, I{kappa}B{alpha} levels decreased, and concomitant nuclear localization of NF-{kappa}B was observed. Cells exposed to fluid shear stress in ATP-depleted medium exhibited no significant reduction in I{kappa}B{alpha}, and NF-{kappa}B remained within the cytosol. Similar results were found using oxidized ATP or Brilliant Blue G, P2X{sub 7} receptor antagonists, indicating that the P2X{sub 7} receptor is responsible for fluid shear-stress-induced I{kappa}B{alpha} degradation and nuclear accumulation of NF-{kappa}B. Pharmacologic blockage of the P2Y6 receptor also prevented shear-induced I{kappa}B{alpha} degradation. These phenomena involved neither ERK1/2 signaling nor autocrine activation by P2X{sub 7}-generated lysophosphatidic acid. Our results suggest that fluid shear stress regulates NF-{kappa}B activity through the P2Y{sub 6} and P2X{sub 7} receptor.

  4. Effect of apple extracts on NF-kappaB activation in human umbilical vein endothelial cells

    Czech Academy of Sciences Publication Activity Database

    Davis, P.A.; Polagruto, J.A.; Valacchi, G.; Phung, A.; Souček, Karel; Keen, C.L.; Gershwin, M.E.

    2006-01-01

    Roč. 231, č. 5 (2006), s. 594-598 ISSN 1535-3702 Institutional research plan: CEZ:AV0Z50040507 Keywords : human umbilical vascular endothelial cells * NF-kappaB * antioxidants Subject RIV: BO - Biophysics Impact factor: 2.845, year: 2006

  5. Insulin receptor substrate-3, interacting with Bcl-3, enhances p50 NF-{kappa}B activity

    Energy Technology Data Exchange (ETDEWEB)

    Kabuta, Tomohiro [Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo 113-8657 (Japan); Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502 (Japan); Hakuno, Fumihiko; Cho, Yoshitake; Yamanaka, Daisuke; Chida, Kazuhiro [Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo 113-8657 (Japan); Asano, Tomoichiro [Graduate School of Biomedical Science, Hiroshima University, Hiroshima 734-8551 (Japan); Wada, Keiji [Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502 (Japan); Takahashi, Shin-Ichiro, E-mail: atkshin@mail.ecc.u-tokyo.ac.jp [Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo 113-8657 (Japan)

    2010-04-09

    The insulin receptor substrate (IRS) proteins are major substrates of both insulin receptor and insulin-like growth factor (IGF)-I receptor tyrosine kinases. Previously, we reported that IRS-3 is localized to both cytosol and nucleus, and possesses transcriptional activity. In the present study, we identified Bcl-3 as a novel binding protein to IRS-3. Bcl-3 is a nuclear protein, which forms a complex with the homodimer of p50 NF-{kappa}B, leading to enhancement of transcription through p50 NF-{kappa}B. We found that Bcl-3 interacts with the pleckstrin homology domain and the phosphotyrosine binding domain of IRS-3, and that IRS-3 interacts with the ankyrin repeat domain of Bcl-3. In addition, IRS-3 augmented the binding activity of p50 to the NF-{kappa}B DNA binding site, as well as the tumor necrosis factor (TNF)-{alpha}-induced transcriptional activity of NF-{kappa}B. Lastly, IRS-3 enhanced NF-{kappa}B-dependent anti-apoptotic gene induction and consequently inhibited TNF-{alpha}-induced cell death. This series of results proposes a novel function for IRS-3 as a transcriptional regulator in TNF-{alpha} signaling, distinct from its function as a substrate of insulin/IGF receptor kinases.

  6. Induction of oncogene addiction shift to NF-{kappa}B by camptothecin in solid tumor cells

    Energy Technology Data Exchange (ETDEWEB)

    Togano, Tomiteru; Sasaki, Masataka; Watanabe, Mariko; Nakashima, Makoto [Department of Hematology, School of Medicine, Kitasato University, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555 (Japan); Tsuruo, Takashi [Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Umezawa, Kazuo [Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-0061 (Japan); Higashihara, Masaaki [Department of Hematology, School of Medicine, Kitasato University, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555 (Japan); Watanabe, Toshiki [Laboratory of Tumor Cell Biology, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639 (Japan); Horie, Ryouichi, E-mail: rhorie@med.kitasato-u.ac.jp [Department of Hematology, School of Medicine, Kitasato University, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555 (Japan)

    2009-12-04

    The biological basis of the resistance of solid tumor cells to chemotherapy is not well understood. While addressing this problem, we found that gastric cancer cell line St-4/CPT, lung cancer cell line A549/CPT, and colon cancer cell line HT-29/CPT, all of which are resistant to camptothecin (CPT), showed strong and constitutive nuclear factor (NF)-{kappa}B activity driven by I{kappa}B kinase compared with their parental cell lines St-4, A549, and HT-29. A new NF-{kappa}B inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), reduced viability and induced apoptosis in St-4/CPT, A549/CPT, and HT-29/CPT cell lines, while their parental cell lines were resistant to DHMEQ. The results in this study present an example of the shift in signals that support the survival of solid tumor cells to NF-{kappa}B during the acquisition of resistance to CPT. The results also indicate that solid tumor cells that become resistant to chemotherapy may be more easily treated by NF-{kappa}B inhibitors.

  7. Role of NFkappaB in an animal model of complex regional pain syndrome-type I (CRPS-I).

    Science.gov (United States)

    de Mos, Marissa; Laferrière, André; Millecamps, Magali; Pilkington, Mercedes; Sturkenboom, Miriam C J M; Huygen, Frank J P M; Coderre, Terence J

    2009-11-01

    NFkappaB is involved in several pathogenic mechanisms that are believed to underlie the complex regional pain syndrome (CRPS), including ischemia, inflammation and sensitization. Chronic postischemia pain (CPIP) has been developed as an animal model that mimics the symptoms of CRPS-I. The possible involvement of NFkappaB in CRPS-I was studied using CPIP rats. Under sodium pentobarbital anesthesia, a tourniquet was placed around the rat left ankle joint, producing 3 hours of ischemia, followed by rapid reperfusion (IR injury). NFkappaB was measured in nuclear extracts of muscle and spinal cord tissue using ELISA. Moreover, the anti-allodynic (mechanical and cold) effect was tested for systemic, intrathecal, or intraplantar treatment with the NFkappaB inhibitor pyrrolidine dithiocarbamate (PDTC). At 2 and 48 hours after IR injury, NFkappaB was elevated in muscle and spinal cord of CPIP rats compared to shams. At 7 days, NFkappaB levels were normalized in muscle, but still elevated in spinal cord tissue. Systemic PDTC treatment relieved mechanical and cold allodynia in a dose-dependent manner, lasting for at least 3 hours. Intrathecal-but not intraplantar-administration also relieved mechanical allodynia. The results suggest that muscle and spinal NFkappaB plays a role in the pathogenesis of CPIP and potentially of human CRPS. Using the CPIP model, we demonstrate that NFkappaB is involved in the development of allodynia after a physical injury (ischemia and reperfusion) without direct nerve trauma. Since CPIP animals exhibit many features of human CRPS-I, this observation indicates a potential role for NFkappaB in human CRPS.

  8. Evaluation of the use of real-time PCR for human T cell lymphotropic virus 1 and 2 as a confirmatory test in screening for blood donors Análise do uso da PCR em tempo real para HTLV-1 e 2 como teste confirmatório na triagem de doadores de sangue

    Directory of Open Access Journals (Sweden)

    Rafaela Gomes Andrade

    2010-04-01

    Full Text Available INTRODUCTION: HTLV-1/2 screening among blood donors commonly utilizes an enzyme-linked immunosorbent assay (EIA, followed by a confirmatory method such as Western blot (WB if the EIA is positive. However, this algorithm yields a high rate of inconclusive results, and is expensive. METHODS: Two qualitative real-time PCR assays were developed to detect HTLV-1 and 2, and a total of 318 samples were tested (152 blood donors, 108 asymptomatic carriers, 26 HAM/TSP patients and 30 seronegative individuals. RESULTS: The sensitivity and specificity of PCR in comparison with WB results were 99.4% and 98.5%, respectively. PCR tests were more efficient for identifying the virus type, detecting HTLV-2 infection and defining inconclusive cases. CONCLUSIONS: Because real-time PCR is sensitive and practical and costs much less than WB, this technique can be used as a confirmatory test for HTLV in blood banks, as a replacement for WB.INTRODUÇÃO: A triagem para HTLV-1/2 em doadores de sangue geralmente utiliza imunoensaio enzimático, seguido de um método confirmatório como Western blot quando o EIA é positivo, mas este algoritmo mostra alta taxa de resultados inconclusivos, e elevado custo. MÉTODOS: Dois ensaios qualitativos de PCR em tempo real foram desenvolvidos para detectar HTLV-1 e 2 e um total de 318 amostras foram testadas por PCR (152 de doadores de sangue, 108 de portadores assintomáticos, 26 de pacientes HAM/TSP e 30 de indivíduos soronegativos. RESULTADOS: A sensibilidade e especificidade das PCR em relação aos resultados de WB foram de 99,4% e 98,5%, respectivamente. As PCR foram mais eficientes em identificar o tipo viral, a infecção pelo HTLV-2 e úteis para definir casos inconclusivos. CONCLUSÕES: Por serem sensíveis, práticas e de custo muito inferior ao do WB, as técnicas de PCR em tempo real podem ser usadas como teste confirmatório do HTLV em bancos de sangue, em substituição ao WB.

  9. Human T Cell Leukemia Virus Type I Tax-Induced IκB-ζ Modulates Tax-Dependent and Tax-Independent Gene Expression in T Cells

    Directory of Open Access Journals (Sweden)

    Ryuichiro Kimura

    2013-09-01

    Full Text Available Human T cell leukemia virus type I (HTLV-I is the etiologic agent of adult T cell leukemia (ATL and various inflammatory disorders including HTLV-I-associated myelopathy/tropical spastic paraparesis. HTLV-I oncoprotein Tax is known to cause permanent activation of many cellular transcription factors including nuclear factor-κB (NF-κB, cyclic adenosine 3′,5′-monophosphate response element-binding protein, and activator protein 1 (AP-1. Here, we show that NF-κB-binding cofactor inhibitor of NF-κB-ζ (IκB-ζ is constitutively expressed in HTLV-I-infected T cell lines and ATL cells, and Tax transactivates the IκB-ζ gene, mainly through NF-κB. Microarray analysis of IκB-ζ-expressing uninfected T cells demonstrated that IκB-ζ induced the expression of NF-κB. and interferon-regulatory genes such as B cell CLL/lymphoma 3 (Bcl3, guanylate-binding protein 1, and signal transducer and activator of transcription 1. The transcriptional activation domain, nuclear localization signal, and NF-κB-binding domain of IκB-ζ were required for Bcl3 induction, and IκB-ζ synergistically enhanced Tax-induced Bcl3 transactivation in an NF-κB-dependent manner. Interestingly, IκB-ζ inhibited Tax-induced NF-κB, AP-1 activation, and HTLV-I transcription. Furthermore, IκB-ζ interacted with Tax in vitro and this interaction was also observed in an HTLV-I-transformed T cell line. These results suggest that IκB-ζ modulates Tax-dependent and Tax-independent gene transcription in T cells. The function of IκB-ζ may be of significance in ATL genesis and pathogenesis of HTLV-I-associated diseases.

  10. Human T Cell Leukemia Virus Type I Tax-Induced IκB-ζ Modulates Tax-Dependent and Tax-Independent Gene Expression in T Cells1

    Science.gov (United States)

    Kimura, Ryuichiro; Senba, Masachika; Cutler, Samuel J; Ralph, Stephen J; Xiao, Gutian; Mori, Naoki

    2013-01-01

    Human T cell leukemia virus type I (HTLV-I) is the etiologic agent of adult T cell leukemia (ATL) and various inflammatory disorders including HTLV-I-associated myelopathy/tropical spastic paraparesis. HTLV-I oncoprotein Tax is known to cause permanent activation of many cellular transcription factors including nuclear factor-κB (NF-κB), cyclic adenosine 3′,5′-monophosphate response element-binding protein, and activator protein 1 (AP-1). Here, we show that NF-κB-binding cofactor inhibitor of NF-κB-ζ (IκB-ζ) is constitutively expressed in HTLV-I-infected T cell lines and ATL cells, and Tax transactivates the IκB-ζ gene, mainly through NF-κB. Microarray analysis of IκB-ζ-expressing uninfected T cells demonstrated that IκB-ζ induced the expression of NF-κB. and interferon-regulatory genes such as B cell CLL/lymphoma 3 (Bcl3), guanylate-binding protein 1, and signal transducer and activator of transcription 1. The transcriptional activation domain, nuclear localization signal, and NF-κB-binding domain of IκB-ζ were required for Bcl3 induction, and IκB-ζ synergistically enhanced Tax-induced Bcl3 transactivation in an NF-κB-dependent manner. Interestingly, IκB-ζ inhibited Tax-induced NF-κB, AP-1 activation, and HTLV-I transcription. Furthermore, IκB-ζ interacted with Tax in vitro and this interaction was also observed in an HTLV-I-transformed T cell line. These results suggest that IκB-ζ modulates Tax-dependent and Tax-independent gene transcription in T cells. The function of IκB-ζ may be of significance in ATL genesis and pathogenesis of HTLV-I-associated diseases. PMID:24027435

  11. Persistent activation of NF-kappaB related to IkappaB's degradation profiles during early chemical hepatocarcinogenesis

    Directory of Open Access Journals (Sweden)

    García-Román Rebeca

    2007-04-01

    Full Text Available Abstract Background To define the NF-kappaB activation in early stages of hepatocarcinogenesis and its IkappaB's degradation profiles in comparison to sole liver regeneration. Methods Western-blot and EMSA analyses were performed for the NF-kappaB activation. The transcriptional activity of NF-kappaB was determined by RT-PCR of the IkappaB-α mRNA. The IkappaB's degradation proteins were determined by Western-blot assay. Results We demonstrated the persistent activation of NF-kappaB during early stages of hepatocarcinogenesis, which reached maximal level 30 min after partial hepatectomy. The DNA binding and transcriptional activity of NF-kappaB, were sustained during early steps of hepatocarcinogenesis in comparison to only partial hepatectomy, which displayed a transitory NF-kappaB activation. In early stages of hepatocarconogenesis, the IkappaB-α degradation turned out to be acute and transitory, but the low levels of IkappaB-β persisted even 15 days after partial hepatectomy. Interestingly, IkappaB-β degradation is not induced after sole partial hepatectomy. Conclusion We propose that during liver regeneration, the transitory stimulation of the transcription factor response, assures blockade of NF-kappaB until recovery of the total mass of the liver and the persistent NF-kappaB activation in early hepatocarcinogenesis may be due to IkappaB-β and IkappaB-α degradation, mainly IkappaB-β degradation, which contributes to gene transcription related to proliferation required for neoplasic progression.

  12. Spironolactone induces apoptosis and inhibits NF-kappaB independent of the mineralocorticoid receptor

    DEFF Research Database (Denmark)

    Sønder, Søren Ulrik Salling; Woetmann, Anders; Odum, Niels

    2006-01-01

    mononuclear cells (MNC). To elucidate the mechanism behind SPIR's apoptotic effect, we investigated the relation between apoptosis and cytokine suppression for SPIR along with the apoptosis-inducing and antiinflammatory drug sulfasalazine (SFZ). Using human MNC, we found that SPIR and SFZ, at concentrations...... 10 and 1000 muM, respectively, significantly increased both apoptosis and cell death. Production of inflammatory cytokines was significantly reduced by 3 to 30 muM SPIR and by 300 to 1000 muM SFZ. We also found that 0.4 muM SPIR and 300 muM SFZ significantly reduced the activity of NF......-kappaB, a transcription factor involved in both apoptosis and immunoinflammation. ALDO, the MR antagonist, eplerenone, and the SPIR metabolite, 7alpha-thiomethyl-spironolactone, slightly reduced NF-kappaB activity, but they did not interfere with SPIR's effect, showing that MR binding is not involved in SPIR...

  13. Analysis and Quantitation of NF-[kappa]B Nuclear Translocation in Tumor Necrosis Factor Alpha (TNF-[alpha]) Activated Vascular Endothelial Cells

    Science.gov (United States)

    Fuseler, John W.; Merrill, Dana M.; Rogers, Jennifer A.; Grisham, Matthew B.; Wolf, Robert E.

    2006-07-01

    Nuclear factor kappa B (NF-[kappa]B) is a heterodimeric transcription factor typically composed of p50 and p65 subunits and is a pleiotropic regulator of various inflammatory and immune responses. In quiescent cells, p50/p65 dimers are sequestered in the cytoplasm bound to its inhibitors, the I-[kappa]Bs, which prevent entry into the nucleus. Following cellular stimulation, the I-[kappa]Bs are rapidly degraded, activating NF-[kappa]B. The active form of NF-[kappa]B rapidly translocates into the nucleus, binding to consensus sequences in the promoter/enhancer region of various genes, promoting their transcription. In human vascular endothelial cells activated with tumor necrosis factor-alpha, the activation and translocation of NF-[kappa]B is rapid, reaching maximal nuclear localization by 30 min. In this study, the appearance of NF-[kappa]B (p65 subunit, p65-NF-[kappa]B) in the nucleus visualized by immunofluorescence and quantified by morphometric image analysis (integrated optical density, IOD) is compared to the appearance of activated p65-NF-[kappa]B protein in the nucleus determined biochemically. The appearance of p65-NF-[kappa]B in the nucleus measured by fluorescence image analysis and biochemically express a linear correlation (R2 = 0.9477). These data suggest that localization and relative protein concentrations of NF-[kappa]B can be reliably determined from IOD measurements of the immunofluorescent labeled protein.

  14. TWEAK activates the non-canonical NFkappaB pathway in murine renal tubular cells: modulation of CCL21.

    Directory of Open Access Journals (Sweden)

    Ana B Sanz

    2010-01-01

    Full Text Available TWEAK is a member of the TNF superfamily of cytokines that contribute to kidney tubulointerstitial injury. It has previously been reported that TWEAK induces transient nuclear translocation of RelA and expression of RelA-dependent cytokines in renal tubular cells. Additionally, TWEAK induced long-lasting NFkappaB activation suggestive of engagement of the non-canonical NFkappaB pathway. We now explore TWEAK-induced activation of NFkappaB2 and RelB, as well as expression of CCL21, a T-cell chemotactic factor, in cultured murine tubular epithelial cells and in healthy kidneys in vivo. In cultured tubular cells, TWEAK and TNFalpha activated different DNA-binding NFkappaB complexes. TWEAK-induced sustained NFkappaB activation was associated with NFkappaB2 p100 processing to p52 via proteasome and nuclear translocation and DNA-binding of p52 and RelB. TWEAK, but not TNFalpha used as control, induced a delayed increase in CCL21a mRNA (3.5+/-1.22-fold over control and CCL21 protein (2.5+/-0.8-fold over control, which was prevented by inhibition of the proteasome, or siRNA targeting of NIK or RelB, but not by RelA inhibition with parthenolide. A second NFkappaB2-dependent chemokine, CCL19, was upregulates by TWEAK, but not by TNFalpha. However, both cytokines promoted chemokine RANTES expression (3-fold mRNA at 24 h. In vivo, TWEAK induced nuclear NFkappaB2 and RelB translocation and CCL21a mRNA (1.5+/-0.3-fold over control and CCL21 protein (1.6+/-0.5-fold over control expression in normal kidney. Increased tubular nuclear RelB and tubular CCL21 expression in acute kidney injury were decreased by neutralization (2+/-0.9 vs 1.3+/-0.6-fold over healthy control or deficiency of TWEAK (2+/-0.9 vs 0.8+/-0.6-fold over healthy control. Moreover, anti-TWEAK treatment prevented the recruitment of T cells to the kidney in this model (4.1+/-1.4 vs 1.8+/-1-fold over healthy control. Our results thus identify TWEAK as a regulator of non-canonical NFkappaB

  15. Regulation of NF-{kappa}B activity in astrocytes: effects of flavonoids at dietary-relevant concentrations

    Energy Technology Data Exchange (ETDEWEB)

    Spilsbury, Alison [Reading School of Pharmacy, University of Reading, Reading RG6 6UB (United Kingdom); Vauzour, David; Spencer, Jeremy P.E. [Molecular Nutrition Group, Centre for Integrative Neuroscience and Neurodynamics, School of Chemistry, Food and Pharmacy, University of Reading, Reading RG6 6AP (United Kingdom); Rattray, Marcus, E-mail: m.a.n.rattray@reading.ac.uk [Reading School of Pharmacy, University of Reading, Reading RG6 6UB (United Kingdom)

    2012-02-17

    Highlights: Black-Right-Pointing-Pointer We tested the hypothesis that low concentrations of flavonoids inhibit NF-{kappa}B in astrocytes. Black-Right-Pointing-Pointer Primary cultured astrocytes possess a functional {kappa}B-system, measured using luciferase assays. Black-Right-Pointing-Pointer Seven flavonoids (100 nM-1 {mu}M) failed to reduce NF-{kappa}B activity in astrocytes. Black-Right-Pointing-Pointer Four flavonoids (100 nM-1 {mu}M) failed to reduce TNFa-stimulated NF-{kappa}B activity in astrocytes. Black-Right-Pointing-Pointer (-)-Epicatechin did not regulate nuclear translocation of the NF-{kappa}B subunit, p65. -- Abstract: Neuroinflammation plays an important role in the progression of neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Sustained activation of nuclear transcription factor {kappa}B (NF-{kappa}B) is thought to play an important role in the pathogenesis of neurodegenerative disorders. Flavonoids have been shown to possess antioxidant and anti-inflammatory properties and we investigated whether flavonoids, at submicromolar concentrations relevant to their bioavailability from the diet, were able to modulate NF-{kappa}B signalling in astrocytes. Using luciferase reporter assays, we found that tumour necrosis factor (TNF{alpha}, 150 ng/ml) increased NF-{kappa}B-mediated transcription in primary cultures of mouse cortical astrocytes, which was abolished on co-transfection of a dominant-negative I{kappa}B{alpha} construct. In addition, TNF{alpha} increased nuclear localisation of p65 as shown by immunocytochemistry. To investigate potential flavonoid modulation of NF-{kappa}B activity, astrocytes were treated with flavonoids from different classes; flavan-3-ols ((-)-epicatechin and (+)-catechin), flavones (luteolin and chrysin), a flavonol (kaempferol) or the flavanones (naringenin and hesperetin) at dietary-relevant concentrations (0.1-1 {mu}M) for 18 h. None of the flavonoids modulated constitutive or

  16. p38 mitogen-activated protein kinase up-regulates NF-{kappa}B transcriptional activation through RelA phosphorylation during stretch-induced myogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Ji, Guoping [Department of Orthodontics, College of Stomatology, Ninth People' s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Research Institute of Stomatology, Shanghai 200011 (China); Liu, Dongxu [Department of Orthodontics, College of Stomatology, Shandong University, Jinan, Shandong Province 250012 (China); Liu, Jing [Department of Orthodontics, The Affiliated Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong Province 266075 (China); Gao, Hui [Department of Orthodontics, Tianjin Stomatological Hospital, Tianjin 300041 (China); Yuan, Xiao, E-mail: yuanxiaoqd@163.com [Department of Orthodontics, The Affiliated Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong Province 266075 (China); Shen, Gang, E-mail: ganshen2007@163.com [Department of Orthodontics, College of Stomatology, Ninth People' s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Research Institute of Stomatology, Shanghai 200011 (China)

    2010-01-01

    p38 MAPK and nuclear factor-B (NF-B) signaling pathways play an indispensable role in the control of skeletal myogenesis. The specific contribution of these signaling pathways to the response of myoblast to the mechanical stimulation and the molecular mechanisms underlying this response remain unresolved. Using an established in vitro model, we now show that p38 MAP kinase activity regulates the transcriptional activation of NF-{kappa}B in response to mechanical stimulation of myoblasts. Furthermore, SB203580 blocked stretch-induced NF-{kappa}B activation during myogenesis, not through down-regulation of degradation of I{kappa}B-{alpha}, and consequent translocation of the p65 subunit of NF-{kappa}B to the nucleus. It is likely that stretch-induced NF-{kappa}B activation by phosphorylation of p65 NF-{kappa}B. Moreover, depletion of p38{alpha} using siRNA significantly reduces stretch-induced phosphorylation of RelA and NF-{kappa}B activity. These results provides the first evidence of a cross-talk between p38 MAPK and NF-{kappa}B signaling pathways during stretch-induced myogenesis, with phosphorylation of RelA being one of the effectors of this promyogenic mechanism. The {alpha} isoform of p38MAP kinase regulates the transcriptional activation of NF-{kappa}B following stimulation with cyclic stretch.

  17. New treatment of periodontal diseases by using NF-kappaB decoy oligodeoxynucleotides via prevention of bone resorption and promotion of wound healing.

    Science.gov (United States)

    Shimizu, Hideo; Nakagami, Hironori; Morita, Shosuke; Tsukamoto, Ikuyo; Osako, Mariana Kiomy; Nakagami, Futoshi; Shimosato, Takashi; Minobe, Noriko; Morishita, Ryuichi

    2009-09-01

    Nuclear factor-kappa B (NF-kappaB) is involved in osteoclast differentiation and activation. Thus, the blockade of the NF-kappaB pathway might be a novel therapeutic strategy for treating bone metabolic diseases. Periodontitis is subgingival inflammation caused by bacterial infection; this disease also is thought to be a chronic focal point responsible for systemic diseases. In this study, NF-kappaB decoy oligodeoxynucleotides (ODNs) were topically applied for experimental periodontitis in a debris-accumulation model and wound healing in a bone-defect model of beagle dogs to investigate the effect of decoy ODN on bone metabolism. Application of NF-kappaB decoy ODN significantly reduced interleukin-6 activity in crevicular fluid and improved alveolar bone loss in the analysis of dental radiographs and DEXA. Direct measurement of exposed root that lost alveolar bone support revealed that NF-kappaB decoy treatment dramatically protected bone from loss. In a bone-defect model, NF-kappaB decoy ODN promoted the healing process as compared with control scrambled decoy in micro-CT analysis. Overall, inhibition of NF-kappaB by decoy strategy prevented the progression of bone loss in periodontitis and promoted the wound healing in bone defects through the inhibition of osteoclastic bone resorption. Targeting of NF-kappaB might be a potential therapy in various bone metabolic diseases.

  18. DMPD: Toll-like receptors: from the discovery of NFkappaB to new insights intotranscriptional regulations in innate immunity. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 16930560 Toll-like receptors: from the discovery of NFkappaB to new insights intotr...2-13. Epub 2006 Aug 22. (.png) (.svg) (.html) (.csml) Show Toll-like receptors: from the discovery of NFkapp...6930560 Title Toll-like receptors: from the discovery of NFkappaB to new insights intotranscriptional regula

  19. DMPD: Convergence of the NF-kappaB and IRF pathways in the regulation of the innateantiviral response. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17706453 Convergence of the NF-kappaB and IRF pathways in the regulation of the innatea... (.png) (.svg) (.html) (.csml) Show Convergence of the NF-kappaB and IRF pathways in the regulation of the innatea... IRF pathways in the regulation of the innateantiviral response. Authors Hiscott J. Publication Cytokine Gro

  20. Effects of age and sedentary lifestyle on skeletal muscle NF-kappaB signaling in men.

    Science.gov (United States)

    Buford, Thomas W; Cooke, Matthew B; Manini, Todd M; Leeuwenburgh, Christiaan; Willoughby, Darryn S

    2010-05-01

    Nuclear factor kappa B (NF-kappaB) is a critical signaling molecule of disuse-induced skeletal muscle atrophy. However, few studies have carefully investigated whether similar pathways are modulated with physical activity and age. The present study examined lean mass, maximal force production, and skeletal muscle NF-kappaB signaling in 41 men categorized as sedentary (OS, N = 13, 63.85 +/- 6.59 year), physically active (OA, N = 14, 60.71 +/- 5.54 year), or young and sedentary (YS, N = 14, 21.35 +/- 3.84 year). Muscle tissue from the vastus lateralis was assayed for messenger RNA (mRNA) expression of the beta subunit of IkB kinase (IKKbeta), cytosolic protein content of phosphorylated inhibitor of kappa B alpha (pIKBalpha), and nuclear content of NF-kappaB subunits p50 and p65. When compared with YS, OS demonstrated age-related muscle atrophy and reduced isokinetic knee extension torque. Physical activity in older individuals preserved maximal isokinetic knee extension torque. OS muscle contained 50% more pIKBalpha than OA and 61% more pIKBalpha than YS. Furthermore, nuclear p65 was significantly elevated in OS compared with YS. OS muscle did not differ from either of the other two groups for nuclear p50 or for mRNA expression of IKKbeta. These results indicate that skeletal muscle content of nuclear-bound p65 is elevated by age in humans. The elevation in nuclear-bound p65 appears to be at least partially due to significant increases in pIKBalpha. A sedentary lifestyle appears to play some role in increased IKBalpha; however, further research is needed to identify downstream effects of this increase.

  1. Contribution of TRPV1 to microglia-derived IL-6 and NFkappaB translocation with elevated hydrostatic pressure.

    Science.gov (United States)

    Sappington, Rebecca M; Calkins, David J

    2008-07-01

    The authors investigated the contributions of the transient receptor potential vanilloid-1 receptor (TRPV1) and Ca(2+) to microglial IL-6 and nuclear factor kappa B (NFkappaB) translocation with elevated hydrostatic pressure. The authors first examined IL-6 colocalization with the microglia marker Iba-1 in the DBA/2 mouse model of glaucoma to establish relevance. They isolated microglia from rat retina and maintained them at ambient or elevated (+70 mm Hg) hydrostatic pressure in vitro and used ELISA and immunocytochemistry to measure changes in the IL-6 concentration and NFkappaB translocation induced by the Ca(2+) chelator EGTA, the broad-spectrum Ca(2+) channel inhibitor ruthenium red, and the TRPV1 antagonist iodo-resiniferatoxin (I-RTX). They applied the Ca(2+) dye Fluo-4 AM to measure changes in intracellular Ca(2+) at elevated pressure induced by I-RTX and confirmed TRPV1 expression in microglia using PCR and immunocytochemistry. In DBA/2 retina, elevated intraocular pressure increased microglial IL-6 in the ganglion cell layer. Elevated hydrostatic pressure (24 hours) increased microglial IL-6 release, cytosolic NFkappaB, and NFkappaB translocation in vitro. These effects were reduced substantially by EGTA and ruthenium red. Antagonism of TRPV1 in microglia partially inhibited pressure-induced increases in IL-6 release and NFkappaB translocation. Brief elevated pressure (1 hour) induced a significant increase in microglial intracellular Ca(2+) that was partially attenuated by TRPV1 antagonism. Elevated pressure induces an influx of extracellular Ca(2+) in retinal microglia that precedes the activation of NFkappaB and the subsequent production and release of IL-6 and is at least partially dependent on the activation of TRPV1 and other ruthenium red-sensitive channels.

  2. 1,25-dihydroxyvitamin D{sub 3} impairs NF-{kappa}B activation in human naive B cells

    Energy Technology Data Exchange (ETDEWEB)

    Geldmeyer-Hilt, Kerstin, E-mail: kerstin.hilt@charite.de [Allergie-Centrum-Charite, CCM, Klinik fuer Dermatologie und Allergologie, Charite - Universitaetsmedizin Berlin, Chariteplatz 1, 10117 Berlin (Germany); Heine, Guido, E-mail: guido.heine@charite.de [Allergie-Centrum-Charite, CCM, Klinik fuer Dermatologie und Allergologie, Charite - Universitaetsmedizin Berlin, Chariteplatz 1, 10117 Berlin (Germany); Deutsches Rheuma-Forschungszentrum Berlin, Chariteplatz 1, 10117 Berlin (Germany); Hartmann, Bjoern, E-mail: bjoern.hartmann@charite.de [Allergie-Centrum-Charite, CCM, Klinik fuer Dermatologie und Allergologie, Charite - Universitaetsmedizin Berlin, Chariteplatz 1, 10117 Berlin (Germany); Baumgrass, Ria, E-mail: baumgrass@drfz.de [Deutsches Rheuma-Forschungszentrum Berlin, Chariteplatz 1, 10117 Berlin (Germany); Radbruch, Andreas, E-mail: radbruch@drfz.de [Deutsches Rheuma-Forschungszentrum Berlin, Chariteplatz 1, 10117 Berlin (Germany); Worm, Margitta, E-mail: margitta.worm@charite.de [Allergie-Centrum-Charite, CCM, Klinik fuer Dermatologie und Allergologie, Charite - Universitaetsmedizin Berlin, Chariteplatz 1, 10117 Berlin (Germany)

    2011-04-22

    Highlights: {yields} In naive B cells, VDR activation by calcitriol results in reduced NF-{kappa}B p105 and p50 protein expression. {yields} Ligating the VDR with calcitriol causes reduced nuclear translocation of NF-{kappa}B p65. {yields} Reduced nuclear amount of p65 after calcitriol incubation results in reduced binding of p65 on the p105 promoter. {yields} Thus, vitamin D receptor signaling may reduce or prevent activation of B cells and unwanted immune responses, e.g. in IgE dependent diseases such as allergic asthma. -- Abstract: 1{alpha},25-dihydroxyvitamin D{sub 3} (calcitriol), the bioactive metabolite of vitamin D, modulates the activation and inhibits IgE production of anti-CD40 and IL-4 stimulated human peripheral B cells. Engagement of CD40 results in NF-{kappa}B p50 activation, which is essential for the class switch to IgE. Herein, we investigated by which mechanism calcitriol modulates NF-{kappa}B mediated activation of human naive B cells. Naive B cells were predominantly targeted by calcitriol in comparison with memory B cells as shown by pronounced induction of the VDR target gene cyp24a1. Vitamin D receptor activation resulted in a strongly reduced p105/p50 protein and mRNA expression in human naive B cells. This effect is mediated by impaired nuclear translocation of p65 and consequently reduced binding of p65 to its binding site in the p105 promoter. Our data indicate that the vitamin D receptor reduces NF-{kappa}B activation by interference with NF-{kappa}B p65 and p105. Thus, the vitamin D receptor inhibits costimulatory signal transduction in naive B cells, namely by reducing CD40 signaling.

  3. Cirhin up-regulates a canonical NF-{kappa}B element through strong interaction with Cirip/HIVEP1

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Bin; Mitchell, Grant A. [Genetique Medicale, Centre de Recherche CHU Sainte-Justine, Departement de Pediatrie, Universite de Montreal, Montreal, QC (Canada); Richter, Andrea, E-mail: andrea.richter@umontreal.ca [Genetique Medicale, Centre de Recherche CHU Sainte-Justine, Departement de Pediatrie, Universite de Montreal, Montreal, QC (Canada)

    2009-11-01

    North American Indian childhood cirrhosis (NAIC/CIRH1A) is a severe autosomal recessive intrahepatic cholestasis. All NAIC patients have a homozygous mutation in CIRH1A that changes conserved Arg565 to Trp (R565W) in Cirhin, a nucleolar protein of unknown function. Subcellular localization is unaffected by the mutation. Yeast two-hybrid screening identified Cirip (Cirhin interaction protein) and found that interaction between Cirip and R565W-Cirhin was weakened. Co-immunoprecipitation of the two proteins from nuclear extracts of HeLa cells strongly supports the yeast two hybrid results. Cirip has essentially the same sequence as the C-terminal of HIVEP1, a regulator of a canonical NF-{kappa}B sequence. Since Cirip has the zinc fingers required for this interaction, we developed an in vitro assay based on this element in mammalian cells to demonstrate functional Cirhin-Cirip interaction. The strong positive effect of Cirip on the NF-{kappa}B sequence was further increased by both Cirhin and R565W-Cirhin. Importantly, the effect of R565W-Cirhin was weaker than that of the wild type protein. We observed increased levels of Cirhin-Cirip complex in nuclear extracts in the presence of this NF-{kappa}B sequence. Our hypothesis is that Cirhin is a transcriptional regulatory factor of this NF-{kappa}B sequence and could be a participant in the regulation of other genes with NF-{kappa}B responsive elements. Since the activities of genes regulated through NF-{kappa}B responsive elements are especially important during development, this interaction may be a key to explain the perinatal appearance of NAIC.

  4. Nuclear IL-33 is a transcriptional regulator of NF-{kappa}B p65 and induces endothelial cell activation

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Yeon-Sook; Park, Jeong Ae; Kim, Jihye; Rho, Seung-Sik; Park, Hyojin [Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Kim, Young-Myeong [Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon (Korea, Republic of); Kwon, Young-Guen, E-mail: ygkwon@yonsei.ac.kr [Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of)

    2012-05-04

    Highlights: Black-Right-Pointing-Pointer IL-33 as nuclear factor regulated expression of ICAM-1 and VCAM-1. Black-Right-Pointing-Pointer Nuclear IL-33 increased the transcription of NF-{kappa}B p65 by binding to the p65 promoter. Black-Right-Pointing-Pointer Nuclear IL-33 controls NF-{kappa}B-dependent inflammatory responses. -- Abstract: Interleukin (IL)-33, an IL-1 family member, acts as an extracellular cytokine by binding its cognate receptor, ST2. IL-33 is also a chromatin-binding transcriptional regulator highly expressed in the nuclei of endothelial cells. However, the function of IL-33 as a nuclear factor is poorly defined. Here, we show that IL-33 is a novel transcriptional regulator of the p65 subunit of the NF-{kappa}B complex and is involved in endothelial cell activation. Quantitative reverse transcriptase PCR and Western blot analyses indicated that IL-33 mediates the expression of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 in endothelial cells basally and in response to tumor necrosis factor-{alpha}-treatment. IL-33-induced ICAM-1/VCAM-1 expression was dependent on the regulatory effect of IL-33 on the nuclear factor (NF)-{kappa}B pathway; NF-{kappa}B p65 expression was enhanced by IL-33 overexpression and, conversely, reduced by IL-33 knockdown. Moreover, NF-{kappa}B p65 promoter activity and chromatin immunoprecipitation analysis revealed that IL-33 binds to the p65 promoter region in the nucleus. Our data provide the first evidence that IL-33 in the nucleus of endothelial cells participates in inflammatory reactions as a transcriptional regulator of NF-{kappa}B p65.

  5. Proteasome and NF-kappaB inhibiting phaeophytins from the green alga Cladophora fascicularis.

    Science.gov (United States)

    Huang, Xinping; Li, Min; Xu, Bo; Zhu, Xiaobin; Deng, Zhiwei; Lin, Wenhan

    2007-03-21

    Chemical examination of the green alga Cladophora fascicularis resulted in the isolation and characterization of a new porphyrin derivative, porphyrinolactone (1), along with five known phaeophytins 2-6 and fourteen sterols and cycloartanes. The structure of 1 was determined on the basis of spectroscopic analyses and by comparison of its NMR data with those of known phaeophytins. Compounds 1-6 displayed moderate inhibition of tumor necrosis factor alpha (TNF-alpha) induced nuclear factor-kappaB (NF-kappaB) activation, while 2 and 4 displayed potential inhibitory activity toward proteasome chymotripsin-like activation. The primary structure-activity relationship was also discussed.

  6. Introducing spatial information into predictive NF-kappaB modelling--an agent-based approach.

    Directory of Open Access Journals (Sweden)

    Mark Pogson

    2008-06-01

    Full Text Available Nature is governed by local interactions among lower-level sub-units, whether at the cell, organ, organism, or colony level. Adaptive system behaviour emerges via these interactions, which integrate the activity of the sub-units. To understand the system level it is necessary to understand the underlying local interactions. Successful models of local interactions at different levels of biological organisation, including epithelial tissue and ant colonies, have demonstrated the benefits of such 'agent-based' modelling. Here we present an agent-based approach to modelling a crucial biological system--the intracellular NF-kappaB signalling pathway. The pathway is vital to immune response regulation, and is fundamental to basic survival in a range of species. Alterations in pathway regulation underlie a variety of diseases, including atherosclerosis and arthritis. Our modelling of individual molecules, receptors and genes provides a more comprehensive outline of regulatory network mechanisms than previously possible with equation-based approaches. The method also permits consideration of structural parameters in pathway regulation; here we predict that inhibition of NF-kappaB is directly affected by actin filaments of the cytoskeleton sequestering excess inhibitors, therefore regulating steady-state and feedback behaviour.

  7. Lentiviral-mediated targeted NF-kappaB blockade in dorsal spinal cord glia attenuates sciatic nerve injury-induced neuropathic pain in the rat.

    Science.gov (United States)

    Meunier, Alice; Latrémolière, Alban; Dominguez, Elisa; Mauborgne, Annie; Philippe, Stéphanie; Hamon, Michel; Mallet, Jacques; Benoliel, Jean-Jacques; Pohl, Michel

    2007-04-01

    Neuropathic pain developing after peripheral nerve injury is associated with altered neuronal and glial cell functions in the spinal cord. Activated glia produces algogenic mediators, exacerbating pain. Among the different intracellular pathways possibly involved in the modified glial function, the nuclear factor kappaB (NF-kappaB) system is of particular interest, as numerous genes encoding inflammation- and pain-related molecules are controlled by this transcription factor. NF-kappaB is a pleiotropic factor also involved in central nervous system homeostasy. To study its role in chronic pain, it is thus essential to inhibit the NF-kappaB pathway selectively in activated spinal glial cells. Here, we show that when restricted to spinal cord and targeted to glial cells, lentiviral vector-mediated delivery of NF-kappaB super- repressor IkappaBalpha resulted in an inhibition of the NF-kappaB pathway activated in the rat spinal cord after sciatic nerve injury (chronic constriction injury, CCI). Concomitantly, IkappaBalpha overproduction prevented the enhanced expression of interleukin-6 and of inducible nitric oxide synthase associated with chronic constriction injury and resulted in prolonged antihyperalgesic and antiallodynic effects. These data show that targeted blockade of NF-kappaB activity in spinal glia efficiently alleviates pain behavior in CCI rats, demonstrating the active participation of the glial NF-kappaB pathway in the development of neuropathic pain after peripheral nerve injury.

  8. NF-kappaB signaling mediates vascular smooth muscle endothelin type B receptor expression in resistance arteries

    DEFF Research Database (Denmark)

    Zheng, Jian-Pu; Zhang, Yaping; Edvinsson, Lars

    2010-01-01

    Vascular smooth muscle cells (SMC) endothelin type B (ET(B)) receptor upregulation results in strong vasoconstriction and reduction of local blood flow. We hypothesizes that the underlying molecular mechanisms involve transcriptional factor nuclear factor-kappaB (NF-kappaB) pathway. ET(B) recepto...

  9. NIK and IKKbeta interdependence in NF-kappaB signalling--flux analysis of regulation through metabolites.

    Science.gov (United States)

    Kim, Hong-Bum; Evans, Iona; Smallwood, Rod; Holcombe, Mike; Qwarnstrom, Eva E

    2010-02-01

    Activation of the transcription factor NF-kappaB is central to control of immune and inflammatory responses. Cytokine induced activation through the classical or canonical pathway relies on degradation of the inhibitor, IkappaBalpha and regulation by the IKKbeta kinase. In addition, the NF-kappaB is activated through the NF-kappaB-inducing kinase, NIK. Analysis of the IKK/NIK inter-relationship and its impact on NF-kappaB control, were analysed by mathematical modelling, using matrix formalism and stoichiometrically balanced reactions. The analysis considered a range of bio-reactions and core metabolites and their role in relation to kinase activation and in control of specific steps of the NF-kappaB pathway. The model predicts a growth-rate and time-dependent transfer of the primary kinase activity from IKKbeta to NIK. In addition, it suggests that NIK/IKKbeta interdependence is controlled by intermediates of phosphoribosylpyrophosphate (PRPP) within the glycolysis pathway, and thus, identifies a link between specific metabolic events and kinase activation in inflammatory signal transduction. Subsequent in vitro experiments, carried out to validate the impact of IKK/NIK interdependence, confirmed signal amplification at the level of the NF-kappaB/IkappaBalpha complex control in the presence of both kinases. Further, they demonstrate that the induced potentiation is due to synergistic enhancement of relA-dependent activation. Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.

  10. Inhibition of NFkappaB by the natural product Withaferin A in cellular models of Cystic Fibrosis inflammation.

    Science.gov (United States)

    Maitra, Rangan; Porter, Melissa A; Huang, Shan; Gilmour, Brian P

    2009-05-13

    Cystic Fibrosis (CF) is one of the most common autosomal genetic disorders in humans. This disease is caused by mutations within a single gene, coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The phenotypic hallmark of CF is chronic lung infection and associated inflammation from opportunistic microbes such as Pseudomonas aeruginosa (PA), Haemophilus influenzae, and Staphylococcus aureus. This eventually leads to deterioration of lung function and death in most CF patients. Unfortunately, there is no approved therapy for correcting the genetic defect causal to the disease. Hence, controlling inflammation and infection in CF patients are critical to disease management. Accordingly, anti-inflammatory agents and antibiotics are used to manage chronic inflammation and infection in CF patients. However, most of the anti-inflammatory agents in CF have severe limitations due to adverse side effects, and resistance to antibiotics is becoming an even more prominent problem. Thus, new agents that can be used to control chronic inflammation in CF are needed in the absence of a cure for the disease. Activation of the transcription factor NFkappaB through Toll-like receptors (TLR) following bacterial infection is principally involved in regulating lung inflammation in CF. NFkappaB regulates the transcription of several genes that are involved in inflammation, anti-apoptosis and anti-microbial activity, and hyper-activation of this transcription factor leads to a potent inflammatory response. Thus, NFkappaB is a potential anti-inflammatory drug target in CF. Screening of several compounds from natural sources in an in vitro model of CF-related inflammation wherein NFkappaB is activated by filtrates of a clinically isolated strain of PA (PAF) led us to Withaferin A (WFA), a steroidal lactone from the plant Withania Somnifera L. Dunal. Our data demonstrate that WFA blocks PAF-induced activation of NFkappaB as determined using reporter assays, IL

  11. Inhibition of NFkappaB activation and IL-8 expression in human bronchial epithelial cells by acrolein.

    Science.gov (United States)

    Valacchi, Giuseppe; Pagnin, Elisa; Phung, Anh; Nardini, Mirella; Schock, Bettina C; Cross, Carroll E; van der Vliet, Albert

    2005-01-01

    Lipid oxidation and environmental pollutants are major sources of alpha,beta-unsaturated aldehydes such as acrolein and 4-hydroxynonenal. Acrolein (2-propenal), a major product of organic combustion such as tobacco smoke, represents the most reactive alpha,beta-unsaturated aldehyde, with high reactivity toward nucleophilic targets such as sulfhydryl groups. To investigate how acrolein affects respiratory tract cell activation, we exposed either primary (NHBE) or immortalized human bronchial epithelial cells (HBE1) to 0-25 microM acrolein, and determined effects on basal and tumor necrosis factor-alpha (TNFalpha)-induced production of the chemokine interleukin (IL)-8. Cell exposure to acrolein dose-dependently suppressed IL-8 mRNA levels in HBE1 cells (26, 40, and 79% at 5, 10, and 25 microM acrolein concentrations, respectively) and resulted in corresponding decreases in IL-8 production. Studies of nuclear factor-kappaB (NFkappaB) activation, an essential event in IL-8 production, showed decreased TNFalpha-induced NFkappaB activation by acrolein, illustrated by inhibition of nuclear translocation of NFkappaB and reduced IkappaBalpha degradation. Immunochemical analysis of IkappaB kinase (IKK), a redox-sensitive regulator of NFkappaB activation, indicated direct modification of the IKK beta-subunit by acrolein, suggesting that acrolein may act directly on IKK. In summary, our results demonstrate that acrolein can suppress inflammatory processes in the airways by inhibiting epithelial IL-8 production through direct or indirect inhibitory effects on NFkappaB activation.

  12. Commensal-induced regulatory T cells mediate protection against pathogen-stimulated NF-kappaB activation.

    Directory of Open Access Journals (Sweden)

    Caitlin O'Mahony

    Full Text Available Host defence against infection requires a range of innate and adaptive immune responses that may lead to tissue damage. Such immune-mediated pathologies can be controlled with appropriate T regulatory (Treg activity. The aim of the present study was to determine the influence of gut microbiota composition on Treg cellular activity and NF-kappaB activation associated with infection. Mice consumed the commensal microbe Bifidobacterium infantis 35624 followed by infection with Salmonella typhimurium or injection with LPS. In vivo NF-kappaB activation was quantified using biophotonic imaging. CD4+CD25+Foxp3+ T cell phenotypes and cytokine levels were assessed using flow cytometry while CD4+ T cells were isolated using magnetic beads for adoptive transfer to naïve animals. In vivo imaging revealed profound inhibition of infection and LPS induced NF-kappaB activity that preceded a reduction in S. typhimurium numbers and murine sickness behaviour scores in B. infantis-fed mice. In addition, pro-inflammatory cytokine secretion, T cell proliferation, and dendritic cell co-stimulatory molecule expression were significantly reduced. In contrast, CD4+CD25+Foxp3+ T cell numbers were significantly increased in the mucosa and spleen of mice fed B. infantis. Adoptive transfer of CD4+CD25+ T cells transferred the NF-kappaB inhibitory activity. Consumption of a single commensal micro-organism drives the generation and function of Treg cells which control excessive NF-kappaB activation in vivo. These cellular interactions provide the basis for a more complete understanding of the commensal-host-pathogen trilogue that contribute to host homeostatic mechanisms underpinning protection against aberrant activation of the innate immune system in response to a translocating pathogen or systemic LPS.

  13. Gnotobiotic IL-10; NF-kappaB mice develop rapid and severe colitis following Campylobacter jejuni infection.

    Directory of Open Access Journals (Sweden)

    Elisabeth Lippert

    2009-10-01

    Full Text Available Limited information is available on the molecular mechanisms associated with Campylobacter jejuni (C. jejuni induced food-borne diarrheal illnesses. In this study, we investigated the function of TLR/NF-kappaB signaling in C. jejuni induced pathogenesis using gnotobiotic IL-10(-/-; NF-kappaB(EGFP mice. In vitro analysis showed that C. jejuni induced IkappaB phosphorylation, followed by enhanced NF-kappaB transcriptional activity and increased IL-6, MIP-2alpha and NOD2 mRNA accumulation in infected-mouse colonic epithelial cells CMT93. Importantly, these events were blocked by molecular delivery of an IkappaB inhibitor (Ad5IkappaBAA. NF-kappaB signalling was also important for C.jejuni-induced cytokine gene expression in bone marrow-derived dendritic cells. Importantly, C. jejuni associated IL-10(-/-; NF-kappaB(EGFP mice developed mild (day 5 and severe (day 14 ulcerating colonic inflammation and bloody diarrhea as assessed by colonoscopy and histological analysis. Macroscopic analysis showed elevated EGFP expression indicating NF-kappaB activation throughout the colon of C. jejuni associated IL-10(-/-; NF-kappaB(EGFP mice, while fluorescence microscopy revealed EGFP positive cells to be exclusively located in lamina propria mononuclear cells. Pharmacological NF-kappaB inhibition using Bay 11-7085 did not ameliorate C. jejuni induced colonic inflammation. Our findings indicate that C. jejuni induces rapid and severe intestinal inflammation in a susceptible host that correlates with enhanced NF-kappaB activity from lamina propria immune cells.

  14. Vergleichende Analyse der Expression des Glukokortikoid-Rezeptors und der NF-kappaB Untereinheit p50 in Lymphozyten von Patienten mit rheumatoider Arthritis und Gesunden

    OpenAIRE

    Klüter, Andreas

    2003-01-01

    Zielstellung: Es wurden die Expression des antiinflammatorisch wirkenden Transkriptionsfaktors Glukokortikoid-Rezeptor (GR) und der Untereinheit p50 des proinflammatorischen Transkriptionsfaktor NF-kappaB in peripheren mononuklearen Blutzellen (PBMC) von Patienten mit rheumatoider Arthritis (RA) untersucht. Methode: Es wurden unbehandelte und mit Glukokortikoiden vorbehandelte RA-Patienten sowie gesunde Probanden verglichen. Die Expressionsanalyse von GR und der NF-kappaB Untereinheit p50 ...

  15. Corneal NF-kappaB activity is necessary for the retention of transparency in the cornea of UV-B-exposed transgenic reporter mice.

    Science.gov (United States)

    Alexander, George; Carlsen, Harald; Blomhoff, Rune

    2006-04-01

    To determine the dynamics of Nuclear Factor-kappaB (NF-kappaB) in murine corneal pathology and the role of NF-kappaB in maintaining corneal clarity after ultraviolet B radiation insult, transgenic mice containing NF-kappaB-luciferase reporter were exposed to LPS (bacterial lipopolysaccharide), TNF-alpha (Tumor Necrosis Factor-alpha) or 4 kJ m(-2) UV-B radiation. NF-kappaB decoy oligonucleotides were also administered in some of the UV-B experiments. Following various exposure times, the mice were sacrificed and whole eyes or corneal tissues were obtained. Whole eyes were examined for scattering using a point-source optical imaging technique. Tissue homogenates were examined for luciferase activity using a luminometer. TNF-alpha and LPS-injected NF-kappaB-luciferase transgenic mice demonstrated 3-10-fold increases in cornea NF-kappaB with peak activities at 4 and 6 hr post-injection, respectively. Mice exposed to 4 kJ m(-2) UV-B exhibited a 3-fold increase in NF-kappaB activity 4 hr post-exposure. The administration of NF-kappaB-decoy oligonucleotides to mice had the effect of reducing UV-B-induced NF-kappaB activity in the cornea and significantly increasing the amount of light scattering in UV-B exposed corneas 7 days post-UV-B exposure when compared to sham injected mice. These results indicate that NF-kappaB is activated in cornea in pathologies that involves increased plasma levels of LPS and TNF-alpha, as well as direct UV-B exposure, and suggest that NF-kappaB activation play an essential part in the corneal healing process.

  16. NF-kappaB specifically activates BMP-2 gene expression in growth plate chondrocytes in vivo and in a chondrocyte cell line in vitro.

    Science.gov (United States)

    Feng, Jian Q; Xing, Lianping; Zhang, Jiang-Hong; Zhao, Ming; Horn, Diane; Chan, Jeannie; Boyce, Brendan F; Harris, Stephen E; Mundy, Gregory R; Chen, Di

    2003-08-01

    Bone morphogenetic protein-2 (BMP-2) regulates growth plate chondrogenesis during development and postnatal bone growth, but the control mechanisms of BMP-2 expression in growth plate chondrocytes are unknown. Here we have used both in vitro and in vivo approaches to demonstrate that transcription factor, NF-kappaB, regulates BMP-2 gene expression in chondrocytes. Two putative NF-kappaB response elements were found in the -2712/+165 region of the BMP-2 gene. Cotransfection of mutant I-kappaBalpha expression plasmids with BMP-2 promoter-luciferase reporters into TMC-23 chondrocyte cell line suppressed BMP-2 transcription. Mutations in NF-kappaB response elements in the BMP-2 gene lead to decreases in BMP-2 promoter activity. Electrophoretic mobility shift assay using nuclear extracts from TMC-23 chondrocytic cells revealed that the NF-kappaB subunits p50 and p65 bound to the NF-kappaB response elements of the BMP-2 gene. Thus, NF-kappaB may positively regulate BMP-2 gene transcription. Consistent with these findings, expression of BMP-2 mRNA was significantly reduced in growth plate chondrocytes in NF-kappaB p50/p52 dKO mice, which associated with decreased numbers of 5-bromo-2'-deoxyuridine (BrdUrd)-positive cells in the proliferating zone of growth plate in these mice. Therefore, in postnatal growth plate chondrocytes, expression of BMP-2 is regulated by NF-kappaB, which may play an important role in chondrogenesis.

  17. 20-Hydroxycholecalciferol, product of vitamin D3 hydroxylation by P450scc, decreases NF-kappaB activity by increasing IkappaB alpha levels in human keratinocytes.

    Directory of Open Access Journals (Sweden)

    Zorica Janjetovic

    Full Text Available The side chain of vitamin D3 is hydroxylated in a sequential manner by cytochrome P450scc (CYP11A1 to form 20-hydroxycholecalciferol, which can induce growth arrest and differentiation of both primary and immortalized epidermal keratinocytes. Since nuclear factor-kappaB (NF-kappaB plays a pivotal role in the regulation of cell proliferation, differentiation and apoptosis, we examined the capability of 20-hydroxycholecalciferol to modulate the activity of NF-kappaB, using 1,25-dihydroxycholecalciferol (calcitriol as a positive control. 20-hydroxycholecalciferol inhibits the activation of NFkappaB DNA binding activity as well as NF-kappaB-driven reporter gene activity in keratinocytes. Also, 20-hydroxycholecalciferol induced significant increases in the mRNA and protein levels of the NF-kappaB inhibitor protein, IkappaB alpha, in a time dependent manner, while no changes in total NF-kappaB-p65 mRNA or protein levels were observed. Another measure of NF-kappaB activity, p65 translocation from the cytoplasm into the nucleus was also inhibited in extracts of 20-hydroxycholecalciferol treated keratinocytes. Increased IkappaB alpha was concomitantly observed in cytosolic extracts of 20-hydroxycholecalciferol treated keratinocytes, as determined by immunoblotting and immunofluorescent staining. In keratinocytes lacking vitamin D receptor (VDR, 20-hydroxycholecalciferol did not affect IkappaB alpha mRNA levels, indicating that it requires VDR for its action on NF-kappaB activity. Comparison of the effects of calcitrol, hormonally active form of vitamin D3, with 20-hydrocholecalciferol show that both agents have a similar potency in inhibiting NF-kappaB. Since NF-kappaB is a major transcription factor for the induction of inflammatory mediators, our findings indicate that 20-hydroxycholecalciferol may be an effective therapeutic agent for inflammatory and hyperproliferative skin diseases.

  18. Induction of cyclooxygenase-2 in macrophages by catalase: role of NF-kappaB and PI3K signaling pathways.

    Science.gov (United States)

    Jang, Byeong-Churl; Kim, Do-Hyun; Park, Jong-Wook; Kwon, Taeg Kyu; Kim, Sang-Pyo; Song, Dae-Kyu; Park, Jong-Gu; Bae, Jae-Hoon; Mun, Kyo-Chul; Baek, Won-Ki; Suh, Min-Ho; Hla, Timothy; Suh, Seong-Il

    2004-04-02

    Induction of COX-2 by catalase in smooth muscle cells, endothelial cells, and neuronal cells has been previously reported. However, the mechanism by which catalase up-regulates COX-2 remains poorly understood. In this study, we investigated the effect of catalase on induction of COX-2 in macrophages. The addition of catalase into Raw 264.7 macrophages induced COX-2 expression that was correlated with increased COX-2 transcription and mRNA stability. Catalase also induced activation of NF-kappaB, PI3K, ERKs, p38s, or JNKs. Catalase-induced COX-2 expression was abrogated by treatment of MG-132 (a NF-kappaB inhibitor) or LY294002 (a PI3K inhibitor), but not by treatment of PD98059 (an ERK inhibitor), SB203580 (a p38 inhibitor), or SP600125 (a JNK inhibitor). Moreover, inhibition of PI3K by LY294002 caused partial decrease of catalase-induced COX-2 transcription and steady-state COX-2 transcript levels, but not COX-2 mRNA stability. Together, these results suggest that catalase induces the expression of COX-2 in Raw 264.7 macrophages, and the induction is related with activation of NF-kappaB transcription factor and PI3K signaling pathway.

  19. Bacterial effector binding to ribosomal protein s3 subverts NF-kappaB function.

    Directory of Open Access Journals (Sweden)

    Xiaofei Gao

    2009-12-01

    Full Text Available Enteric bacterial pathogens cause food borne disease, which constitutes an enormous economic and health burden. Enterohemorrhagic Escherichia coli (EHEC causes a severe bloody diarrhea following transmission to humans through various means, including contaminated beef and vegetable products, water, or through contact with animals. EHEC also causes a potentially fatal kidney disease (hemolytic uremic syndrome for which there is no effective treatment or prophylaxis. EHEC and other enteric pathogens (e.g., enteropathogenic E. coli (EPEC, Salmonella, Shigella, Yersinia utilize a type III secretion system (T3SS to inject virulence proteins (effectors into host cells. While it is known that T3SS effectors subvert host cell function to promote diarrheal disease and bacterial transmission, in many cases, the mechanisms by which these effectors bind to host proteins and disrupt the normal function of intestinal epithelial cells have not been completely characterized. In this study, we present evidence that the E. coli O157:H7 nleH1 and nleH2 genes encode T3SS effectors that bind to the human ribosomal protein S3 (RPS3, a subunit of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB transcriptional complexes. NleH1 and NleH2 co-localized with RPS3 in the cytoplasm, but not in cell nuclei. The N-terminal region of both NleH1 and NleH2 was required for binding to the N-terminus of RPS3. NleH1 and NleH2 are autophosphorylated Ser/Thr protein kinases, but their binding to RPS3 is independent of kinase activity. NleH1, but not NleH2, reduced the nuclear abundance of RPS3 without altering the p50 or p65 NF-kappaB subunits or affecting the phosphorylation state or abundance of the inhibitory NF-kappaB chaperone IkappaBalpha NleH1 repressed the transcription of a RPS3/NF-kappaB-dependent reporter plasmid, but did not inhibit the transcription of RPS3-independent reporters. In contrast, NleH2 stimulated RPS3-dependent transcription, as well

  20. Insights into iron and nuclear factor-kappa B (NF-kappaB) involvement in chronic inflammatory processes in peritoneal endometriosis.

    Science.gov (United States)

    Defrère, Sylvie; González-Ramos, Reinaldo; Lousse, Jean-Christophe; Colette, Sébastien; Donnez, Olivier; Donnez, Jacques; Van Langendonckt, Anne

    2011-08-01

    Endometriosis is a chronic pelvic inflammatory process. Local inflammation is known to play a role in pain and infertility associated with the disease, and may be extensively involved in molecular and cellular processes leading to endometriosis development. In this review, we focus on two inflammatory mediators clearly implicated in the pathogenesis of endometriosis, iron and NF-kappaB, and their potential association. Iron is essential for all living organisms, but excess iron results in toxicity and is linked to pathological disorders. In endometriosis patients, iron overload has been demonstrated in the different compartments of the peritoneal cavity (peritoneal fluid, endometriotic lesions, peritoneum and macrophages). This iron overload affects numerous mechanisms involved in endometriosis development. Moreover, iron can generate free radical species able to react with a wide range of cellular constituents, inducing cellular damage. Overproduction of reactive oxygen species also impairs cellular function by altering gene expression via regulation of redox-sensitive transcription factors such as NF-kappaB, which is clearly implicated in endometriosis. Indeed, NF-kappaB is activated in endometriotic lesions and peritoneal macrophages of endometriosis patients, which stimulates synthesis of proinflammatory cytokines, generating a positive feedback loop in the NF-kappaB pathway. NF-kappaB-mediated gene transcription promotes a variety of processes, including endometriotic lesion establishment, maintenance and development. In conclusion, iron and NF-kappaB appear to be linked and both are clearly involved in endometriosis development, making these pathways an attractive target for future treatment and prevention of this disease.

  1. Cdc25A promotes cell survival by stimulating NF-{kappa}B activity through I{kappa}B-{alpha} phosphorylation and destabilization

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Hey-Young; Choi, Jiyeon [Department of Biochemistry, College of Natural Sciences, Kangwon National University, 192-1 Hyoja-2-dong, Chuncheon 200-701 (Korea, Republic of); Cho, Young-Wook [Korea Basic Science Institute, Chuncheon Center, Gangwondaehak-gil 1, Chuncheon 200-701 (Korea, Republic of); Kim, Byung-Chul, E-mail: bckim@kangwon.ac.kr [Department of Biochemistry, College of Natural Sciences, Kangwon National University, 192-1 Hyoja-2-dong, Chuncheon 200-701 (Korea, Republic of)

    2012-04-06

    Highlights: Black-Right-Pointing-Pointer We examine the antiapoptotic mechanisms of Cdc25A. Black-Right-Pointing-Pointer Smad7 decreases the phosphorylation of I{kappa}B-alpha at Ser-32. Black-Right-Pointing-Pointer Smad7 positively regulates NF-{kappa}B activity through I{kappa}B-alpha ubiquitination. -- Abstract: Cell division cycle 25A (Cdc25A), a dual specificity protein phosphatase, exhibits anti-apoptotic activity, but the underlying molecular mechanisms are poorly characterized. Here we report that Cdc25A inhibits cisplatin-induced apoptotic cell death by stimulating nuclear factor-kappa B (NF-{kappa}B) activity. In HEK-293 cells, Cdc25A decreased protein level of inhibitor subunit kappa B alpha (I{kappa}-B{alpha}) in association with increased serine 32-phosphorylation, followed by stimulation of transcriptional activity of NF-{kappa}B. Inhibition of NF-{kappa}B activity by chemical inhibitor or overexpression of I{kappa}-B{alpha} in Cdc25A-elevated cancer cells resistant to cisplatin improved their sensitivity to cisplatin-induced apoptosis. Our data show for the first time that Cdc25A has an important physiological role in NF-{kappa}B activity regulation and it may be an important survival mechanism of cancer cells.

  2. Stimulation of the human immunodeficiency virus type 1 enhancer by the human T-cell leukemia virus type I tax gene product involves the action of inducible cellular proteins.

    Science.gov (United States)

    Böhnlein, E; Siekevitz, M; Ballard, D W; Lowenthal, J W; Rimsky, L; Bogérd, H; Hoffman, J; Wano, Y; Franza, B R; Greene, W C

    1989-04-01

    The human immunodeficiency virus type 1 (HIV-1) preferentially infects CD4+ T lymphocytes and may exist as a latent provirus within these cells for extended periods. The transition to a productive retroviral infection results in T-cell death and clinically may lead to the acquired immune deficiency syndrome. Accelerated production of infectious HIV-1 virions appears to be closely linked to a heightened state of T-cell activation. The transactivator (Tax) protein of the type I human T-cell leukemia virus (HTLV-I) can produce such an activated T-cell phenotype and augments activity of the HIV-1 long terminal repeat. One Tax-responsive region within the HIV-1 long terminal repeat has been mapped to a locus composed of two 10-base-pair direct repeats sharing homology with the binding site for the eucaryotic transcription factor NF-kappaB (GGGACTTTCC). Tax-expressing Jurkat T cells contain one or more inducible cellular proteins that specifically associate with the HIV-1 enhancer at these binding sites. Microscale DNA affinity precipitation assays identified a Tax-inducible 86-kilodalton protein, HIVEN86A, as one of these HIV-1 enhancer-binding factors. The interaction of HIVEN86A, and presumably other cellular proteins, with the HIV-1 enhancer appears functionally important as oligonucleotides corresponding to this enhancer were sufficient to impart Tax inducibility to an unresponsive heterologous promoter. These findings suggest that the Tax-inducible cellular protein HIVEN86A plays an important role in the transcriptional activation of the HIV-1 enhancer. These specific protein-DNA interactions may also be important for the transition of HIV-1 from a latent to a productive mode of infection. Furthermore, these findings highlight an intriguing biological interplay between HTLV-1 and HIV-1 through a cellular transcriptional pathway that is normally involved in T-cell activation and growth.

  3. SIRT1 overexpression decreases cisplatin-induced acetylation of NF-{kappa}B p65 subunit and cytotoxicity in renal proximal tubule cells

    Energy Technology Data Exchange (ETDEWEB)

    Jung, Yu Jin; Lee, Jung Eun; Lee, Ae Sin [Department of Internal Medicine, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Kang, Kyung Pyo; Lee, Sik; Park, Sung Kwang [Department of Internal Medicine, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Lee, Sang Yong [Department of Diagnostic Radiology, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Han, Myung Kwan [Department of Microbiology, Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Kim, Duk Hoon [Division of Forensic Medicine, National Forensic Service, Seoul (Korea, Republic of); Kim, Won, E-mail: kwon@jbnu.ac.kr [Department of Internal Medicine, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju (Korea, Republic of)

    2012-03-09

    Highlights: Black-Right-Pointing-Pointer Cisplatin increases acetylation of NF-{kappa}B p65 subunit in HK2 cells. Black-Right-Pointing-Pointer SIRT1 overexpression decreases cisplatin-induced p65 acetylation and -cytotoxicity. Black-Right-Pointing-Pointer Resveratrol decreased cisplatin-induced cell viability through deacetylation of p65. -- Abstract: As the increased acetylation of p65 is linked to nuclear factor-{kappa}B (NF-{kappa}B) activation, the regulation of p65 acetylation can be a potential target for the treatment of inflammatory injury. Cisplatin-induced nephrotoxicity is an important issue in chemotherapy of cancer patients. SIRT1, nicotinamide adenine dinucleotide (NAD{sup +})-dependent protein deacetylase, has been implicated in a variety of cellular processes such as inflammatory injury and the control of multidrug resistance in cancer. However, there is no report on the effect of SIRT1 overexpression on cisplatin-induced acetylation of p65 subunit of NF-{kappa}B and cell injury. To investigate the effect of SIRT1 in on cisplatin-induced acetylation of p65 subunit of NF-{kappa}B and cell injury, HK2 cells were exposed with SIRT1 overexpression, LacZ adenovirus or dominant negative adenovirus after treatment with cisplatin. While protein expression of SIRT1 was decreased by cisplatin treatment compared with control buffer treatment, acetylation of NF-{kappa}B p65 subunit was significantly increased after treatment with cisplatin. Overexpression of SIRT1 ameliorated the increased acetylation of p65 of NF-{kappa}B during cisplatin treatment and cisplatin-induced cytotoxicity. Further, treatment of cisplatin-treated HK2 cells with resveratrol, a SIRT1 activator, also decreased acetylation of NF-{kappa}B p65 subunit and cisplatin-induced increase of the cell viability in HK2 cells. Our findings suggests that the regulation of acetylation of p65 of NF-{kappa}B through SIRT1 can be a possible target to attenuate cisplatin-induced renal cell damage.

  4. (HTLV1) in different patients in the north of Iran

    African Journals Online (AJOL)

    Administrator

    2011-09-12

    Sep 12, 2011 ... disorders including neurologic (such as multiple sclerosis, paralysis and tumor), gastrointestinal disorders (ulcer, inflammatory bowel diseases and tumors), hematology and oncology disorders (chronic anemia and malig- nancies), urologic disorders (renal stone, malig-nancies and urinary tract infection), ...

  5. Quantification of HTLV-1 Clonality and TCR Diversity

    Science.gov (United States)

    Laydon, Daniel J.; Melamed, Anat; Sim, Aaron; Gillet, Nicolas A.; Sim, Kathleen; Darko, Sam; Kroll, J. Simon; Douek, Daniel C.; Price, David A.; Bangham, Charles R. M.; Asquith, Becca

    2014-01-01

    Estimation of immunological and microbiological diversity is vital to our understanding of infection and the immune response. For instance, what is the diversity of the T cell repertoire? These questions are partially addressed by high-throughput sequencing techniques that enable identification of immunological and microbiological “species” in a sample. Estimators of the number of unseen species are needed to estimate population diversity from sample diversity. Here we test five widely used non-parametric estimators, and develop and validate a novel method, DivE, to estimate species richness and distribution. We used three independent datasets: (i) viral populations from subjects infected with human T-lymphotropic virus type 1; (ii) T cell antigen receptor clonotype repertoires; and (iii) microbial data from infant faecal samples. When applied to datasets with rarefaction curves that did not plateau, existing estimators systematically increased with sample size. In contrast, DivE consistently and accurately estimated diversity for all datasets. We identify conditions that limit the application of DivE. We also show that DivE can be used to accurately estimate the underlying population frequency distribution. We have developed a novel method that is significantly more accurate than commonly used biodiversity estimators in microbiological and immunological populations. PMID:24945836

  6. NIK is involved in constitutive activation of the alternative NF-{kappa}B pathway and proliferation of pancreatic cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Nishina, Takashi [Division of Cellular and Molecular Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639 (Japan); Yamaguchi, Noritaka [Division of Cellular and Molecular Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639 (Japan); Consolidated Research Institute for Advanced Science and Medical Care, Waseda University, 513 Wasedatsurumaki-cho, Shinjuku-ku, Tokyo 162-0041 (Japan); Gohda, Jin [Division of Cellular and Molecular Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639 (Japan); Semba, Kentaro [Consolidated Research Institute for Advanced Science and Medical Care, Waseda University, 513 Wasedatsurumaki-cho, Shinjuku-ku, Tokyo 162-0041 (Japan); Department of Life Science and Medical Bio-science, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480 (Japan); Inoue, Jun-ichiro, E-mail: jun-i@ims.u-tokyo.ac.jp [Division of Cellular and Molecular Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639 (Japan)

    2009-10-09

    Pancreatic cancer has one of the poorest prognoses among human neoplasms. Constitutive activation of NF-{kappa}B is frequently observed in pancreatic cancer cells and is involved in their malignancy. However, little is known about the molecular mechanism of this constitutive NF-{kappa}B activation. Here, we show that the alternative pathway is constitutively activated and NF-{kappa}B-inducing kinase (NIK), a mediator of the alternative pathway, is significantly expressed in pancreatic cancer cells. siRNA-mediated silencing of NIK expression followed by subcellular fractionation revealed that NIK is constitutively involved in the processing of p100 and nuclear transport of p52 and RelB in pancreatic cancer cells. In addition, NIK silencing significantly suppressed proliferation of pancreatic cancer cells. These results clearly indicate that NIK is involved in the constitutive activation of the alternative pathway and controls cell proliferation in pancreatic cancer cells. Therefore, NIK might be a novel target for the treatment of pancreatic cancer.

  7. A new assay format for NF-kappaB based on a DNA triple helix and a fluorescence resonance energy transfer.

    Science.gov (United States)

    Altevogt, Dominik; Hrenn, Andrea; Kern, Claudia; Clima, Lilia; Bannwarth, Willi; Merfort, Irmgard

    2009-10-07

    Herein we report a feasibility study for a new concept to detect DNA binding protein NF-kappaB based on a DNA triple helix formation in combination with a fluorescence resonance energy transfer (FRET). The new principle avoids expensive antibodies and radioactivity and might have implications for assays of other DNA binding proteins.

  8. NF-kappaB is involved in SHetA2 circumvention of TNF-alpha resistance, but not induction of intrinsic apoptosis.

    Science.gov (United States)

    Chengedza, Shylet; Benbrook, Doris Mangiaracina

    2010-03-01

    Treatment of cancer with tumor necrosis factor-alpha (TNF-alpha) is hindered by resistance and toxicity. The flexible heteroarotinoid, SHetA2, sensitizes resistant ovarian cancer cells to TNF-alpha-induced extrinsic apoptosis, and also induces intrinsic apoptosis as a single agent. This study tested the hypothesis that nuclear factor-kappaB (NF-kappaB) is involved in SHetA2-regulated intrinsic and extrinsic apoptosis. SHetA2 inhibited basal and TNF-alpha-induced or hydrogen peroxide-induced NF-kappaB activity through counter-regulation of upstream kinase (IkappaB kinase) activity, inhibitor protein (IkappaB-alpha) phosphorylation, and p-65 NF-kappaB subunit nuclear translocation, but independently of reactive oxygen species generation. Ectopic over-expression of p-65, or treatment with TNF-alpha receptor 1 (TNFR1) small interfering RNA or a caspase-8 inhibitor, each attenuated synergistic apoptosis by SHetA2 and TNF-alpha, but did not affect intrinsic apoptosis caused by SHetA2. In conclusion, NF-kappaB repression is involved in SHetA2 circumvention of resistance to TNF-alpha-induced extrinsic apoptosis, but not in SHetA2 induction of intrinsic apoptosis.

  9. Inhibitory effects of curcumin and capsaicin on phorbol ester-induced activation of eukaryotic transcription factors, NF-kappaB and AP-1.

    Science.gov (United States)

    Surh, Y J; Han, S S; Keum, Y S; Seo, H J; Lee, S S

    2000-01-01

    Recently, considerable attention has been focused on identifying dietary and medicinal phytochemicals that can inhibit, retard or reverse the multi-stage carcinogenesis. Spices and herbs contain phenolic substances with potent antioxidative and chemopreventive properties. Curcumin, a yellow colouring agent from turmeric and capsaicin, a pungent principle of red pepper exhibit profound anticarcinogenic and antimutagenic activities. Two well-defined eukaryotic transcription factors, nuclear factor-kappa B (NF-kappaB) and activator protein 1 (AP-1) have been implicated in pathogenesis of many human diseases including cancer. These transcription factors are known to be activated by a wide array of external stimuli, such as tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), tumor necrosis factor, reactive oxygen species, bacterial lipopolysaccharide, and ultraviolet. In the present study, we found that topical application of TPA onto dorsal skin of female ICR mice resulted in marked activation of epidermal NF-kappaB and AP-1. Curcumin and capsaicin, when topically applied prior to TPA, significantly attenuated TPA-induced activation of each transcription factor in mouse skin. Likewise, both compounds inhibited NF-kappaB and AP-1 activation in cultured human promyelocytic leukemia (HL-60) cells stimulated with TPA. Based on these findings, it is likely that curcumin and capsaicin exert anti-tumor promotional effects through suppression of the tumor promoter-induced activation of transcription factors, NF-kappaB and AP-1.

  10. Lactobacillus rhamnosus GR-1 enhances NF-kappaB activation in Escherichia coli-stimulated urinary bladder cells through TLR4

    Directory of Open Access Journals (Sweden)

    Karlsson Mattias

    2012-01-01

    Full Text Available Abstract Background Epithelial cells of the urinary tract recognize pathogenic bacteria through pattern recognition receptors on their surface, such as toll-like receptors (TLRs, and mount an immune response through the activation of the NF-kappaB pathway. Some uropathogenic bacteria can subvert these cellular responses, creating problems with how the host eliminates pathogens. Lactobacillus is a genus of lactic acid bacteria that are part of the microbiota and consist of many probiotic strains, some specifically for urogenital infections. Immunomodulation has emerged as an important mode of action of probiotic and commensal lactobacilli and given the importance of epithelial cells, we evaluated the effect of the urogenital probiotic Lactobacillus rhamnosus GR-1 on epithelial immune activation. Results Immune activation through the NF-kappaB pathway was initiated by stimulation of T24 urothelial cells with heat-killed Escherichia coli and this was further potentiated when cells were co-cultured with live L. rhamnosus GR-1. Heat-killed lactobacilli were poor activators of NF-kappaB. Concomitant stimulation of bladder cells with E. coli and L. rhamnosus GR-1 increased the levels of the pro-inflammatory cytokine TNF, whereas IL-6 and CXCL8 levels were reduced. Another probiotic, L. rhamnosus GG, was also able to potentiate NF-kappaB in these cells although at a significantly reduced level compared to the GR-1 strain. The transcript numbers and protein levels of the lipopolysaccharide receptor TLR4 were significantly increased after co-stimulation with E. coli and lactobacilli compared to controls. Furthermore, inhibition of TLR4 activation by polymixin B completely blocked the lactobacilli potentiation of NF-kappaB. Conclusions The immunological outcome of E. coli challenge of bladder cells was influenced by probiotic L. rhamnosus GR-1, by enhancing the activation of NF-kappaB and TNF release. Thus the urogenital probiotic L. rhamnosus GR-1

  11. Metastatic function of BMP-2 in gastric cancer cells: The role of PI3K/AKT, MAPK, the NF-{kappa}B pathway, and MMP-9 expression

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Myoung Hee [Graduate School of Medicine, Korea University College of Medicine, Korea University, Seoul 136-705 (Korea, Republic of); Oh, Sang Cheul [Division of Oncology/Hematology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 136-705 (Korea, Republic of); Lee, Hyun Joo [Department of Pathology, Korea University College of Medicine, Korea University, Seoul 136-705 (Korea, Republic of); Kang, Han Na; Kim, Jung Lim [Graduate School of Medicine, Korea University College of Medicine, Korea University, Seoul 136-705 (Korea, Republic of); Kim, Jun Suk [Division of Oncology/Hematology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 136-705 (Korea, Republic of); Yoo, Young A., E-mail: ydanbi@korea.ac.kr [Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul 136-705 (Korea, Republic of)

    2011-07-15

    Bone morphogenetic proteins (BMPs) have been implicated in tumorigenesis and metastatic progression in various types of cancer cells, but the role and cellular mechanism in the invasive phenotype of gastric cancer cells is not known. Herein, we determined the roles of phosphoinositide 3-kinase (PI3K)/AKT, extracellular signal-regulated protein kinase (ERK), nuclear factor (NF)-{kappa}B, and matrix metalloproteinase (MMP) expression in BMP-2-mediated metastatic function in gastric cancer. We found that stimulation of BMP-2 in gastric cancer cells enhanced the phosphorylation of AKT and ERK. Accompanying activation of AKT and ERK kinase, BMP-2 also enhanced phosphorylation/degradation of I{kappa}B{alpha} and the nuclear translocation/activation of NF-{kappa}B. Interestingly, blockade of PI3K/AKT and ERK signaling using LY294002 and PD98059, respectively, significantly inhibited BMP-2-induced motility and invasiveness in association with the activation of NF-{kappa}B. Furthermore, BMP-2-induced MMP-9 expression and enzymatic activity was also significantly blocked by treatment with PI3K/AKT, ERK, or NF-{kappa}B inhibitors. Immunohistochemistry staining of 178 gastric tumor biopsies indicated that expression of BMP-2 and MMP-9 had a significant positive correlation with lymph node metastasis and a poor prognosis. These results indicate that the BMP-2 signaling pathway enhances tumor metastasis in gastric cancer by sequential activation of the PI3K/AKT or MAPK pathway followed by the induction of NF-{kappa}B and MMP-9 activity, indicating that BMP-2 has the potential to be a therapeutic molecular target to decrease metastasis.

  12. Protective protein/cathepsin A down-regulates osteoclastogenesis by associating with and degrading NF-kappaB p50/p65.

    Science.gov (United States)

    Masuhara, Masaaki; Sato, Takuya; Hada, Naoto; Hakeda, Yoshiyuki

    2009-01-01

    Disruption of the cooperative function balance between osteoblasts and osteoclasts causes various bone disorders, some of which are attributed to abnormal osteoclast recruitment. Osteoclast differentiation is dependent on the receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) as well as the macrophage colony-stimulating factor. The osteoclast formation induced by cytokines requires activation of NF-kappaB, AP-1 and nuclear factor of activated T cells c1. However, osteoclasts are not the only cell types that express these transcription factors, suggesting that some unknown molecules specific for osteoclasts may associate with the transcription factors. Here, we explored the possibility of molecules binding directly to NF-kappaB and cloned protective protein/cathepsin A (PPCA) by yeast two-hybrid screening using a cDNA library of osteoclast precursors. Forced expression of PPCA with p50/p65 in HEK293 cells decreased both the level of p50/p65 proteins and the transcriptional activity. Abundant PPCA was detected in the lysosomes of the transfected HEK293 cells, but a small amount of this enzyme was also present in the cytosolic fraction. In addition, over-expression of PPCA caused the disappearance of p50/p65 in both the lysosomal and cytosolic fractions. PPCA was expressed throughout osteoclastogenesis, and the expression was slightly up-regulated by RANKL signaling. Knockdown of PPCA in osteoclast precursors with PPCA siRNA stimulated binding of nuclear proteins to oligonucleotides containing an NF-kappaB binding motif and increased osteoclastogenesis. Our present results indicate a novel role for PPCA in osteoclastogenesis via down-regulation of NF-kappaB activity and suggest a new function for PPCA as an NF-kappaB-degrading enzyme in addition to its known multifunctional properties.

  13. Sucralfate prevents the delay of wound repair in intestinal epithelial cells by hydrogen peroxide through NF-kappaB pathway.

    Science.gov (United States)

    Shindo, Kenichi; Iizuka, Masahiro; Sasaki, Kenji; Konno, Shiho; Itou, Hiroaki; Horie, Yasuo; Watanabe, Sumio

    2006-05-01

    Recent studies have shown that sucralfate (SF) has therapeutic effects on colonic inflammation in ulcerative colitis. The aim of this study was to clarify the function of SF for wound repair in intestinal epithelial cells (IEC). (1) Activation of signal proteins [ERK1/2 mitogen-activated protein kinase (MAPK), IkappaB-alpha] in IEC-6 cells after stimulation with 10(-4) M potassium sucrose octasulfate (SOS), which is the functional element of SF, was assessed by Western blot. (2) Induction of transforming growth factor (TGF)-beta1, TGF-alpha, EGF, and cyclooxygenase-2 (COX-2) mRNA after stimulation of IEC-6 cells with SOS was assessed by reverse transcriptase-polymerase chain reaction. (3) IEC-6 cells were wounded and cultured for 24 h with various concentrations of SOS in the absence or presence of 20 microM H(2)O(2). Epithelial migration or proliferation was assessed by counting migrating cells or bromodeoxyuridine (BrdU)-positive cells across the wound border. (1) SOS activated IkappaB-alpha, but it did not activate ERK1/2 MAPK. (2) SOS enhanced the expression of COX-2 mRNA, but it did not change the mRNA expression of other growth factors. (3) SOS did not enhance wound repair in IEC-6 cells, but it decreased the number of dead cells (maximum, 74%) (P < 0.01) in a dose-dependent manner and prevented the diminishment of epithelial migration (maximum, 61%) (P < 0.01) and proliferation (maximum, 37%) (P < 0.05) induced by H(2)O(2). These functions of SOS were suppressed by the NF-kappaB and COX-2 inhibitors. SOS prevented the delay of wound repair in IEC-6 cells induced by H(2)O(2), probably through induction of COX-2 and an anti-apoptotic mechanism. These effects of SOS might be given through the activation of the NF-kappaB pathway.

  14. IAPs contain an evolutionarily conserved ubiquitin-binding domain that regulates NF-kappaB as well as cell survival and oncogenesis

    DEFF Research Database (Denmark)

    Gyrd-Hansen, Mads; Darding, Maurice; Miasari, Maria

    2008-01-01

    found that the UBA domain is essential for the oncogenic potential of cIAP1, to maintain endothelial cell survival and to protect cells from TNF-alpha-induced apoptosis. Moreover, the UBA domain is required for XIAP and cIAP2-MALT1 to activate NF-kappaB. Our data suggest that the UBA domain of cIAP2......-MALT1 stimulates NF-kappaB signalling by binding to polyubiquitylated NEMO. Significantly, 98% of all cIAP2-MALT1 fusion proteins retain the UBA domain, suggesting that ubiquitin-binding contributes to the oncogenic potential of cIAP2-MALT1 in MALT lymphoma. Our data identify IAPs as ubiquitin...

  15. Transcriptional down-regulation of thromboxane A(2) receptor expression via activation of MAPK ERK1/2, p38/NF-kappaB pathways

    DEFF Research Database (Denmark)

    Zhang, Wei; Zhang, Yaping; Edvinsson, Lars

    2009-01-01

    culture of the arteries, VSMC TP receptors were studied by using myography, real-time PCR and immunohistochemistry. We observed that organ culture for 24 and 48 h resulted in depressed TP receptor-mediated contraction in the VSMC, in parallel with decreased TP receptor mRNA and protein expressions....... Phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), p38 and nuclear factor-kappaB (NF-kappaB) was seen by Western blot within 1-3 h after organ culture. Inhibition of ERK1/2, p38 or NF-kappaB reversed depressed contraction as well as decreased receptor mRNA expression. Actinomycin D...

  16. Transcriptional Down-Regulation of Thromboxane A(2) Receptor Expression via Activation of MAPK ERK1/2, p38/NF-kappaB Pathways

    DEFF Research Database (Denmark)

    Zhang, Wei; Zhang, Yaping; Edvinsson, Lars

    2008-01-01

    culture of the arteries, VSMC TP receptors were studied by using myography, real-time PCR and immunohistochemistry. We observed that organ culture for 24 and 48 h resulted in depressed TP receptor-mediated contraction in the VSMC, in parallel with decreased TP receptor mRNA and protein expressions....... Phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), p38 and nuclear factor-kappaB (NF-kappaB) was seen by Western blot within 1-3 h after organ culture. Inhibition of ERK1/2, p38 or NF-kappaB reversed depressed contraction as well as decreased receptor mRNA expression. Actinomycin D...

  17. Felodipine attenuates vascular inflammation in a fructose-induced rat model of metabolic syndrome via the inhibition of NF-kappaB activation.

    Science.gov (United States)

    Tan, Hong-wei; Xing, Shan-shan; Bi, Xiu-ping; Li, Li; Gong, Hui-ping; Zhong, Ming; Zhang, Yun; Zhang, Wei

    2008-09-01

    Metabolic syndrome is associated with an increased incidence of atherosclerosis. Clinical studies have shown that calcium channel blockers (CCB) inhibit the progression of atherosclerosis. However, the underlying mechanism is unclear. We investigated the inhibitory effect of felodipine on adhesion molecular expression and macrophage infiltration in the aorta of high fructose-fed rats (FFR). Male Wistar rats were given 10% fructose in drinking water. After 32 weeks of high fructose feeding, they were treated with felodipine (5 mg x kg(-1) x d(-1)) for 6 weeks. The control rats were given a normal diet and water. The aortic expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and the infiltration of macrophages were measured by real-time RT-PCR and/or immunohistochemistry. NF-kappaB activity was measured by electrophoretic mobility shift assay (EMSA). After 32 weeks of high fructose feeding, FFR displayed increased body weight, systolic blood pressure (SBP), serum insulin, and triglycerides when compared with the control rats. The aortic expressions of ICAM-1 and VCAM-1 were significantly increased in FFR than in the control rats and accompanied by the increased activity of NF-kappaB. FFR also showed significantly increased CD68- positive macrophages in the aortic wall. After treatment with felodipine, SBP, serum insulin, and the homeostasis model assessment decreased significantly. In addition to reducing ICAM-1 and VCAM-1, felodipine decreased macrophages in the aortic wall. EMSA revealed that felodipine inhibited NF-kappaB activation in FFR. Felodipine inhibited vessel wall inflammation. The inhibition of NF-kappaB may be involved in the modulation of vascular inflammatory response by CCB in metabolic syndrome.

  18. Moderate extracellular acidification inhibits capsaicin-induced cell death through regulating calcium mobilization, NF-{kappa}B translocation and ROS production in synoviocytes

    Energy Technology Data Exchange (ETDEWEB)

    Hu, Fen; Yang, Shuang; Zhao, Dan; Zhu, Shuyan; Wang, Yuxiang [Department of Biophysics, School of Physics and Key Laboratory of Bioactive Materials of Education Ministry, Nankai University, Tianjin 300071 (China); Li, Junying, E-mail: jyli04@nankai.edu.cn [Department of Biophysics, School of Physics and Key Laboratory of Bioactive Materials of Education Ministry, Nankai University, Tianjin 300071 (China)

    2012-07-20

    Highlights: Black-Right-Pointing-Pointer Moderate extracellular acidification regulates intracellular Ca{sup 2+} mobilization. Black-Right-Pointing-Pointer Moderate acidification activates NF-{kappa}B nuclear translocation in synoviocytes. Black-Right-Pointing-Pointer Moderate acidification depresses the ROS production induced by capsaicin. Black-Right-Pointing-Pointer Moderate acidification inhibits capsaicin-caused synoviocyte death. -- Abstract: We previously show the expression of transient receptor potential vanilloid 1 (TRPV1) in primary synoviocytes from collagen-induced arthritis (CIA) rats. Capsaicin and lowered extracellular pH from 7.4 to 5.5 induce cell death through TRPV1-mediated Ca{sup 2+} entry and reactive oxygen species (ROS) production. However, under the pathological condition in rheumatoid arthritis, the synovial fluid is acidified to a moderate level (about pH 6.8). In the present study, we examined the effects of pH 6.8 on the TRPV1-mediated cell death. Our finding is different or even opposite from what was observed at pH 5.5. We found that the moderate extracellular acidification (from pH 7.4 to 6.8) inhibited the capsaicin-induced Ca{sup 2+} entry through attenuating the activity of TRPV1. In the mean time, it triggered a phospholipse C (PLC)-related Ca{sup 2+} release from intracellular stores. The nuclear translocation of NF-{kappa}B was found at pH 6.8, and this also depends on PLC activation. Moreover, the capsaicin-evoked massive ROS production and cell death were depressed at pH 6.8, both of which are dependent on the activation of PLC and NF-{kappa}B. Taken together, these results suggested that the moderate extracellular acidification inhibited the capsaicin-induced synoviocyte death through regulating Ca{sup 2+} mobilization, activating NF-{kappa}B nuclear translocation and depressing ROS production.

  19. NF-kappaB and p53 are the dominant apoptosis-inducing transcription factors elicited by the HIV-1 envelope.

    Science.gov (United States)

    Perfettini, Jean-Luc; Roumier, Thomas; Castedo, Maria; Larochette, Nathanael; Boya, Patricia; Raynal, Brigitte; Lazar, Vladimir; Ciccosanti, Fabiola; Nardacci, Roberta; Penninger, Josef; Piacentini, Mauro; Kroemer, Guido

    2004-03-01

    The coculture of cells expressing the HIV-1 envelope glycoprotein complex (Env) with cells expressing CD4 results into cell fusion, deregulated mitosis, and subsequent cell death. Here, we show that NF-kappaB, p53, and AP1 are activated in Env-elicited apoptosis. The nuclear factor kappaB (NF-kappaB) super repressor had an antimitotic and antiapoptotic effect and prevented the Env-elicited phosphorylation of p53 on serine 15 and 46, as well as the activation of AP1. Transfection with dominant-negative p53 abolished apoptosis and AP1 activation. Signs of NF-kappaB and p53 activation were also detected in lymph node biopsies from HIV-1-infected individuals. Microarrays revealed that most (85%) of the transcriptional effects of HIV-1 Env were blocked by the p53 inhibitor pifithrin-alpha. Macroarrays led to the identification of several Env-elicited, p53-dependent proapoptotic transcripts, in particular Puma, a proapoptotic "BH3-only" protein from the Bcl-2 family known to activate Bax/Bak. Down modulation of Puma by antisense oligonucleotides, as well as RNA interference of Bax and Bak, prevented Env-induced apoptosis. HIV-1-infected primary lymphoblasts up-regulated Puma in vitro. Moreover, circulating CD4+ lymphocytes from untreated, HIV-1-infected donors contained enhanced amounts of Puma protein, and these elevated Puma levels dropped upon antiretroviral therapy. Altogether, these data indicate that NF-kappaB and p53 cooperate as the dominant proapoptotic transcription factors participating in HIV-1 infection.

  20. Inhibition of transcription factor NF-kappaB signaling proteins IKKbeta and p65 through specific cysteine residues by epoxyquinone A monomer: correlation with its anti-cancer cell growth activity.

    Science.gov (United States)

    Liang, Mei-Chih; Bardhan, Sujata; Pace, Emily A; Rosman, Diana; Beutler, John A; Porco, John A; Gilmore, Thomas D

    2006-02-28

    Transcription factor NF-kappaB is constitutively active in many human chronic inflammatory diseases and cancers. Epoxyquinone A monomer (EqM), a synthetic derivative of the natural product epoxyquinol A, has previously been shown to be a potent inhibitor of tumor necrosis factor-alpha (TNF-alpha)-induced activation of NF-kappaB, but the mechanism by which EqM inhibits NF-kappaB activation was not known. In this report, we show that EqM blocks activation of NF-kappaB by inhibiting two molecular targets: IkappaB kinase IKKbeta and NF-kappaB subunit p65. EqM inhibits TNF-alpha-induced IkappaBalpha phosphorylation and degradation by targeting IKKbeta, and an alanine substitution for Cys179 in the activation loop of IKKbeta makes it resistant to EqM-mediated inhibition. EqM also directly inhibits DNA binding by p65, but not p50; moreover, replacement of Cys38 in p65 with Ser abolishes EqM-mediated inhibition of DNA binding. Pretreatment of cells with reducing agent dithiothreitol dose-dependently reduces EqM-mediated inhibition of NF-kappaB, further suggesting that EqM directly modifies the thiol group of Cys residues in protein targets. Modifications of the exocyclic alkene of EqM substantially reduce EqM's ability to inhibit NF-kappaB activation. In the human SUDHL-4 lymphoma cell line, EqM inhibits both proliferation and NF-kappaB DNA binding, and activates caspase-3 activity. EqM also effectively inhibits the growth of human leukemia, kidney, and colon cancer cell lines in the NCI's tumor cell panel. Among six colon cancer cell lines, those with low amounts of constitutive NF-kappaB DNA-binding activity are generally more sensitive to growth inhibition by EqM. Taken together, these results suggest that EqM inhibits growth and induces cell death in tumor cells through a mechanism that involves inhibition of NF-kappaB activity at multiple steps in the signaling pathway.

  1. Stevioside ameliorates high-fat diet-induced insulin resistance and adipose tissue inflammation by downregulating the NF-{kappa}B pathway

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Zhiquan; Xue, Liqiong; Guo, Cuicui; Han, Bing; Pan, Chunming; Zhao, Shuangxia; Song, Huaidong [State Key Laboratory of Medical Genomics, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025 (China); Ma, Qinyun, E-mail: qinyunma@126.com [State Key Laboratory of Medical Genomics, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025 (China)

    2012-01-27

    Highlights: Black-Right-Pointing-Pointer Stevioside ameliorates high-fat diet-induced insulin resistance. Black-Right-Pointing-Pointer Stevioside alleviates the adipose tissue inflammation. Black-Right-Pointing-Pointer Stevioside reduces macrophages infiltration into the adipose tissue. Black-Right-Pointing-Pointer Stevioside suppresses the activation of NF-{kappa}B in the adipose tissue. -- Abstract: Accumulating evidence suggests that adipose tissue is the main source of pro-inflammatory molecules that predispose individuals to insulin resistance. Stevioside (SVS) is a widely used sweetener with multiple beneficial effects for diabetic patients. In this study, we investigated the effect of SVS on insulin resistance and the pro-inflammatory state of adipose tissue in mice fed with a high-fat diet (HFD). Oral administration of SVS for 1 month had no effect on body weight, but it significantly improved fasting glucose, basal insulin levels, glucose tolerance and whole body insulin sensitivity. Interestingly, these changes were accompanied with decreased expression levels of several inflammatory cytokines in adipose tissue, including TNF-{alpha}, IL6, IL10, IL1{beta}, KC, MIP-1{alpha}, CD11b and CD14. Moreover, macrophage infiltration in adipose tissue was remarkably reduced by SVS. Finally, SVS significantly suppressed the nuclear factor-kappa b (NF-{kappa}B) signaling pathway in adipose tissue. Collectively, these results suggested that SVS may ameliorate insulin resistance in HFD-fed mice by attenuating adipose tissue inflammation and inhibiting the NF-{kappa}B pathway.

  2. Acrolein inhibits cytokine gene expression by alkylating cysteine and arginine residues in the NF-kappaB1 DNA binding domain.

    Science.gov (United States)

    Lambert, Cherie; Li, Jimei; Jonscher, Karen; Yang, Teng-Chieh; Reigan, Philip; Quintana, Megan; Harvey, Jean; Freed, Brian M

    2007-07-06

    Cigarette smoke is a potent inhibitor of pulmonary T cell responses, resulting in decreased immune surveillance and an increased incidence of respiratory tract infections. The alpha,beta-unsaturated aldehydes in cigarette smoke (acrolein and crotonaldehyde) inhibited production of interleukin-2 (IL-2), IL-10, granulocyte-macrophage colony-stimulating factor, interferon-gamma, and tumor necrosis factor-alpha by human T cells but did not inhibit production of IL-8. The saturated aldehydes (acetaldehyde, propionaldehyde, and butyraldehyde) in cigarette smoke were inactive. Acrolein inhibited induction of NF-kappaB DNA binding activity after mitogenic stimulation of T cells but had no effect on induction of NFAT or AP-1. Acrolein inhibited NF-kappaB1 (p50) binding to the IL-2 promoter in a chromatin immunoprecipitation assay by >99%. Using purified recombinant p50 in an electrophoretic mobility shift assay, we demonstrated that acrolein was 2000-fold more potent than crotonaldehyde in blocking DNA binding to an NF-kappaB consensus sequence. Matrix-assisted laser desorption/ionization time-of-flight and tandem mass spectrometry demonstrated that acrolein alkylated two amino acids (Cys-61 and Arg-307) in the DNA binding domain. Crotonaldehyde reacted with Cys-61, but not Arg-307, whereas the saturated aldehydes in cigarette smoke did not react with p50. These experiments demonstrate that aldehydes in cigarette smoke can regulate gene expression by direct modification of a transcription factor.

  3. Oleamide suppresses lipopolysaccharide-induced expression of iNOS and COX-2 through inhibition of NF-kappaB activation in BV2 murine microglial cells.

    Science.gov (United States)

    Oh, Young Taek; Lee, Jung Yeon; Lee, Jinhwa; Lee, Ju Hie; Kim, Ja-Eun; Ha, Joohun; Kang, Insug

    2010-05-03

    Oleamide (cis-9-octadecenamide) is an endogenous sleep-inducing fatty acid amide that accumulates in the cerebrospinal fluid of the sleep-deprived animals. Microglia are the major immune cells involved in neuroinflammation causing brain damage during infection, ischemia, and neurodegenerative disease. In this study, we examined the effects of oleamide on LPS-induced production of proinflammatory mediators and the mechanisms involved in BV2 microglia. Oleamide inhibited LPS-induced production of NO and prostaglandin E2 as well as expression of iNOS and COX-2. We showed that oleamide blocked LPS-induced NF-kappaB activation and phosphorylation of inhibitor kappaB kinase (IKK). We also showed that oleamide inhibited LPS-induced phosphorylation of Akt, p38 MAPK, and ERK, activation of PI 3-kinase, and accumulation of reactive oxygen species (ROS). Finally, we showed that a specific antagonist of the CB2 receptor, AM630, blocked the inhibitory effects of oleamide on LPS-induced production of proinflammatory mediators and activation of NF-kappaB. Taken together, our results suggest that oleamide shows an anti-inflammatory effect through inhibition of NF-kappaB activation in LPS-stimulated BV2 microglia. 2010 Elsevier Ireland Ltd. All rights reserved.

  4. Human xenospecific T suppressor cells inhibit T helper cell proliferation to porcine aortic endothelial cells, and NF-kappaB activity in porcine APC.

    Science.gov (United States)

    Ciubotariu, R; Li, J; Colovai, A I; Platt, J L; Cortesini, R; Suciu Foca Cortesini, N

    2001-05-01

    Human T suppressor cells (Ts), capable of preventing autologous T helper cells (Th) from reacting against xenogeneic pig endothelial cells and pig APC can be generated in vitro. Ts derive from a population of CD3(+)CD8(+)CD28(-) T lymphocytes and specifically recognize the MHC class I antigens of the APC used for in vitro immunization. To study the mechanism that underlies suppression, we investigated whether Ts inhibit the expression of costimulatory molecules in xenogeneic professional and semiprofessional APC. We found that Ts down-regulate Th-induced expression of CD86 in pig APC, and that this effect occurs at the level of transcription, as indicated by nuclear run-on and Northern blot assays. EMSA results revealed that inhibition of CD86 expression is mediated by inactivation of transcription factor NF-kappaB. Furthermore, transfection of pig APC with a vector expressing NF-kappaB p65 partially rescued Th-induced expression of the CD86 molecule. These results strongly support the concept that xenospecific Ts inhibit the APC function of xenogeneic cells by preventing activation of NF-kappaB.

  5. Delphinidin, a specific inhibitor of histone acetyltransferase, suppresses inflammatory signaling via prevention of NF-{kappa}B acetylation in fibroblast-like synoviocyte MH7A cells

    Energy Technology Data Exchange (ETDEWEB)

    Seong, Ah-Reum; Yoo, Jung-Yoon; Choi, KyungChul [Department of Biochemistry and Molecular Biology, Center for Chronic Metabolic Disease Research, College of Medicine, Yonsei University, Seoul (Korea, Republic of); Lee, Mee-Hee [Department of Biochemistry and Molecular Biology, Center for Chronic Metabolic Disease Research, College of Medicine, Yonsei University, Seoul (Korea, Republic of); Brain Korea 21 Project for Medical Sciences, Yonsei University, College of Medicine, Seoul (Korea, Republic of); Lee, Yoo-Hyun [Department of Food Science and Nutrition, The University of Suwon, Kyunggi-do (Korea, Republic of); Lee, Jeongmin [Department of Medical Nutrition, Kyung Hee University, Kyunggi-do (Korea, Republic of); Jun, Woojin [Department of Food and Nutrition, Chonnam National University, Gwangju (Korea, Republic of); Kim, Sunoh, E-mail: sunoh@korea.ac.kr [Jeollanamdo Institute of Natural Resources Research, Jeonnam (Korea, Republic of); Yoon, Ho-Geun, E-mail: yhgeun@yuhs.ac [Department of Biochemistry and Molecular Biology, Center for Chronic Metabolic Disease Research, College of Medicine, Yonsei University, Seoul (Korea, Republic of); Brain Korea 21 Project for Medical Sciences, Yonsei University, College of Medicine, Seoul (Korea, Republic of)

    2011-07-08

    Highlights: {yields} Delphinidin is a novel inhibitor of p300/CBP histone acetyltransferase. {yields} Delphinidin prevents the hyperacetylation of p65 by inhibiting the HAT activity of p300/CBP. {yields} Delphinidin efficiently suppresses the expression of inflammatory cytokines in MH7A cells via hypoacetylation of NF-{kappa}B. {yields} Delphinidin inhibits cytokine release in the Jurkat T lymphocyte cell line. -- Abstract: Histone acetyltransferase (HAT) inhibitors (HATi) isolated from dietary compounds have been shown to suppress inflammatory signaling, which contributes to rheumatoid arthritis. Here, we identified a novel HATi in Punica granatum L. known as delphinidin (DP). DP did not affect the activity of other epigenetic enzymes (histone deacetylase, histone methyltransferase, or sirtuin1). DP specifically inhibited the HAT activities of p300/CBP. It also inhibited p65 acetylation in MH7A cells, a human rheumatoid arthritis synovial cell line. DP-induced hypoacetylation was accompanied by cytosolic accumulation of p65 and nuclear localization of IKB{alpha}. Accordingly, DP treatment inhibited TNF{alpha}-stimulated increases in NF-{kappa}B function and expression of NF-{kappa}B target genes in these cells. Importantly, DP suppressed lipopolysaccharide-induced pro-inflammatory cytokine expression in Jurkat T lymphocytes, demonstrating that HATi efficiently suppresses cytokine-mediated immune responses. Together, these results show that the HATi activity of DP counters anti-inflammatory signaling by blocking p65 acetylation and that this compound may be useful in preventing inflammatory arthritis.

  6. MAML1 regulates cell viability via the NF-{kappa}B pathway in cervical cancer cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Kuncharin, Yanin [Medical Microbiology Interdisciplinary Program, Graduate School, Chulalongkorn University, Payathai Road, Pathumwan, Bangkok 10330 (Thailand); Sangphech, Naunpun [Biotechnology Program, Faculty of Science, Chulalongkorn University, Payathai Road, Pathumwan, Bangkok 10330 (Thailand); Kueanjinda, Patipark [Medical Microbiology Interdisciplinary Program, Graduate School, Chulalongkorn University, Payathai Road, Pathumwan, Bangkok 10330 (Thailand); Bhattarakosol, Parvapan [Medical Microbiology Interdisciplinary Program, Graduate School, Chulalongkorn University, Payathai Road, Pathumwan, Bangkok 10330 (Thailand); Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Payathai Road, Pathumwan, Bangkok 10330 (Thailand); Palaga, Tanapat, E-mail: tanapat.p@chula.ac.th [Department of Microbiology, Faculty of Science, Chulalongkorn University, Payathai Road, Pathumwan, Bangkok 10330 (Thailand)

    2011-08-01

    The Notch signaling pathway plays important roles in tumorigenesis in a context-dependent manner. In human cervical cancer, alterations in Notch signaling have been reported, and both tumor-suppressing and tumor-promoting roles of Notch signaling have been proposed; however, the precise molecular mechanisms governing these roles in cervical cancer remain controversial. MAML is a transcriptional co-activator originally identified by its role in Notch signaling. Recent evidence suggests that it also plays a role in other signaling pathways, such as the p53 and {beta}-catenin pathways. MAML is required for stable formation of Notch transcriptional complexes at the promoters of Notch target genes. Chromosomal translocations affecting MAML have been shown to promote tumorigenesis. In this study, we used a truncated dominant-negative MAML1 (DN-MAML) to investigate the role of MAML in HPV-positive cervical cancer cell lines. Three human cervical cancer cell lines (HeLa, SiHa and CaSki) expressed all Notch receptors and the Notch target genes Hes1 and MAML1. Among these 3 cell lines, constitutive appearance of cleaved Notch1 was found only in CaSki cells, which suggests that Notch1 is constitutively activated in this cell line. Gamma secretase inhibitor (GSI) treatment, which suppresses Notch receptor activation, completely abrogated this form of Notch1 but had no effect on cell viability. Overexpression of DN-MAML by retroviral transduction in CaSki cells resulted in significant decreases in the mRNA levels of Hes1 and Notch1 but had no effects on the levels of MAML1, p53 or HPV E6/E7. DN-MAML expression induced increased viability of CaSki cells without any effect on cell cycle progression or cell proliferation. In addition, clonogenic assay experiments revealed that overexpression of DN-MAML resulted in increased colony formation compared to the overexpression of the control vector. When the status of the NF-{kappa}B pathway was investigated, CaSki cells overexpressing

  7. Distinct p300-responsive mechanisms promote caspase-dependent apoptosis by human T-cell lymphotropic virus type 1 Tax protein.

    Science.gov (United States)

    Nicot, C; Harrod, R

    2000-11-01

    The dysregulation of cellular apoptosis pathways has emerged as a critical early event associated with the development of many types of human cancers. Numerous viral and cellular oncogenes, aside from their inherent transforming properties, are known to induce programmed cell death, consistent with the hypothesis that genetic defects are required to support tumor survival. Here, we report that nuclear expression of the CREB-binding protein (CBP)/p300-binding domain of the human T-cell lymphotropic virus type 1 (HTLV-1) transactivator, Tax, triggers an apoptotic death-inducing signal during short-term clonal analyses, as well as in transient cell death assays. Coexpression of the antiapoptotic factor Bcl-2 increased serum stimulation; incubation with the chemical caspase inhibitor z-Val-Ala-DL-Asp fluoromethylketone antagonized Tax-induced cell death. The CBP/p300-binding defective Tax mutants K88A and V89A exhibited markedly reduced cytotoxic effects compared to the wild-type Tax protein. Importantly, nuclear expression of the minimal CBP/p300-binding peptide of Tax induced apoptosis in the absence of Tax-dependent transcriptional activities, while its K88A counterpart did not cause cell death. Further, Tax-mediated apoptosis was effectively prevented by ectopic expression of the p300 coactivator. We also report that activation of the NF-kappaB transcription pathway by Tax, under growth arrest conditions, results in apoptosis that occurs independent of direct Tax coactivator effects. Our results allude to a novel pivotal role for the transcriptional coactivator p300 in determining cell fate and raise the possibility that dysregulated coactivator usage may pose an early barrier to transformation that must be selectively overcome as a prerequisite for the initiation of neoplasia.

  8. A Smac-mimetic sensitizes prostate cancer cells to TRAIL-induced apoptosis via modulating both IAPs and NF-kappaB

    International Nuclear Information System (INIS)

    Dai, Yao; Liu, Meilan; Tang, Wenhua; Li, Yongming; Lian, Jiqin; Lawrence, Theodore S; Xu, Liang

    2009-01-01

    Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent for human cancer therapy, prostate cancer still remains resistant to TRAIL. Both X-linked inhibitor of apoptosis (XIAP) and nuclear factor-kappaB function as key negative regulators of TRAIL signaling. In this study, we evaluated the effect of SH122, a small molecule mimetic of the second mitochondria-derived activator of caspases (Smac), on TRAIL-induced apoptosis in prostate cancer cells. The potential of Smac-mimetics to bind XIAP or cIAP-1 was examined by pull-down assay. Cytotoxicity of TRAIL and/or Smac-mimetics was determined by a standard cell growth assay. Silencing of XIAP or cIAP-1 was achieved by transient transfection of short hairpin RNA. Apoptosis was detected by Annexin V-PI staining followed by flow cytometry and by Western Blot analysis of caspases, PARP and Bid. NF-kappaB activation was determined by subcellular fractionation, real time RT-PCR and reporter assay. SH122, but not its inactive analog, binds to XIAP and cIAP-1. SH122 significantly sensitized prostate cancer cells to TRAIL-mediated cell death. Moreover, SH122 enhanced TRAIL-induced apoptosis via both the death receptor and the mitochondrial pathway. Knockdown of both XIAP and cIAP-1 sensitized cellular response to TRAIL. XIAP-knockdown attenuated sensitivity of SH122 to TRAIL-induced cytotoxicity, confirming that XIAP is an important target for IAP-inhibitor-mediated TRAIL sensitization. SH122 also suppressed TRAIL-induced NF-kappaB activation by preventing cytosolic IkappaB-alpha degradation and RelA nuclear translocation, as well as by suppressing NF-kappaB target gene expression. These results demonstrate that SH122 sensitizes human prostate cancer cells to TRAIL-induced apoptosis by mimicking Smac and blocking both IAPs and NF-kappaB. Modulating IAPs may represent a promising approach to overcoming TRAIL-resistance in human prostate cancer with constitutively active NF-kappaB signaling

  9. The plant limonoid 7-oxo-deacetoxygedunin inhibits RANKL-induced osteoclastogenesis by suppressing activation of the NF-{kappa}B and MAPK pathways

    Energy Technology Data Exchange (ETDEWEB)

    Wisutsitthiwong, Chonnaree; Buranaruk, Chayanit [Graduate Program in Industrial Microbiology, Department of Microbiology, Faculty of Science, Chulalongkorn University, Phayathai Road, Bangkok 10330 (Thailand); Pudhom, Khanitha [Department of Chemistry, Faculty of Science and Center for Petroleum, Petrochemicals and Advanced Materials, Chulalongkorn University, Phayathai Road, Bangkok 10330 (Thailand); Palaga, Tanapat, E-mail: tanapat.p@chula.ac.th [Graduate Program in Industrial Microbiology, Department of Microbiology, Faculty of Science, Chulalongkorn University, Phayathai Road, Bangkok 10330 (Thailand)

    2011-11-18

    Highlights: Black-Right-Pointing-Pointer A gedunin type limonoid from seeds of mangroves, 7-oxo-7-deacetoxygedunin, exhibits strong anti-osteoclastogenic activity. Black-Right-Pointing-Pointer Treatment with this limonoid results in significant decrease in expression of NFATc1 and osteoclast-related genes. Black-Right-Pointing-Pointer The mode of action of this limonoid is by inhibiting activation of the NF-{kappa}B and MAPK pathways which are activated by RANKL. -- Abstract: Osteoclasts together with osteoblasts play pivotal roles in bone remodeling. Aberrations in osteoclast differentiation and activity contribute to osteopenic disease. Osteoclasts differentiate from monocyte/macrophage progenitors, a process that is initiated by the interaction between receptor activator of NF-{kappa}B (RANK) and its ligand, RANKL. In this study, we identified 7-oxo-7-deacetoxygedunin (7-OG), a gedunin type limonoid from seeds of the mangrove Xylocarpus moluccensis, as a potent inhibitor of osteoclastogenesis. Additionally, 7-OG showed strong anti-osteoclastogenic activity with low cytotoxicity against the monocyte/macrophage progenitor cell line, RAW264.7. The IC50 for anti-osteoclastogenic activity was 4.14 {mu}M. Treatment with 7-OG completely abolished the appearance of multinucleated giant cells with tartrate-resistant acid phosphatase activity in RAW264.7 cells stimulated with RANKL. When the expression of genes related to osteoclastogenesis was investigated, a complete downregulation of NFATc1 and cathepsin K and a delayed downregulation of irf8 were observed upon 7-OG treatment in the presence of RANKL. Furthermore, treatment with this limonoid suppressed RANKL-induced activation of p38, MAPK and Erk and nuclear localization of NF-{kappa}B p65. Taken together, we present evidence indicating a plant limonoid as a novel osteoclastogenic inhibitor that could be used for osteoporosis and related conditions.

  10. Increased levels of NOTCH1, NF-kappaB, and other interconnected transcription factors characterize primitive sets of hematopoietic stem cells.

    Science.gov (United States)

    Panepucci, Rodrigo Alexandre; Oliveira, Lucila Habib B; Zanette, Dalila Luciola; Viu Carrara, Rita de Cassia; Araujo, Amélia Goes; Orellana, Maristela Delgado; Bonini de Palma, Patrícia Vianna; Menezes, Camila C B O; Covas, Dimas Tadeu; Zago, Marco Antonio

    2010-03-01

    As previously shown, higher levels of NOTCH1 and increased NF-kappaB signaling is a distinctive feature of the more primitive umbilical cord blood (UCB) CD34+ hematopoietic stem cells (HSCs), as compared to bone marrow (BM). Differences between BM and UCB cell composition also account for this finding. The CD133 marker defines a more primitive cell subset among CD34+ HSC with a proposed hemangioblast potential. To further evaluate the molecular basis related to the more primitive characteristics of UCB and CD133+ HSC, immunomagnetically purified human CD34+ and CD133+ cells from BM and UCB were used on gene expression microarrays studies. UCB CD34+ cells contained a significantly higher proportion of CD133+ cells than BM (70% and 40%, respectively). Cluster analysis showed that BM CD133+ cells grouped with the UCB cells (CD133+ and CD34+) rather than to BM CD34+ cells. Compared with CD34+ cells, CD133+ had a higher expression of many transcription factors (TFs). Promoter analysis on all these TF genes revealed a significantly higher frequency (than expected by chance) of NF-kappaB-binding sites (BS), including potentially novel NF-kappaB targets such as RUNX1, GATA3, and USF1. Selected transcripts of TF related to primitive hematopoiesis and self-renewal, such as RUNX1, GATA3, USF1, TAL1, HOXA9, HOXB4, NOTCH1, RELB, and NFKB2 were evaluated by real-time PCR and were all significantly positively correlated. Taken together, our data indicate the existence of an interconnected transcriptional network characterized by higher levels of NOTCH1, NF-kappaB, and other important TFs on more primitive HSC sets.

  11. Dexamethasone protection from TNF-alpha-induced cell death in MCF-7 cells requires NF-kappaB and is independent from AKT

    Directory of Open Access Journals (Sweden)

    Mejía Salvador

    2006-02-01

    Full Text Available Abstract Background The biochemical bases for hormone dependence in breast cancer have been recognized as an important element in tumor resistance, proliferation and metastasis. On this respect, dexamethasone (Dex dependent protection against TNF-alpha-mediated cell death in the MCF-7 cell line has been demonstrated to be a useful model for the study of this type of cancer. Recently, cytoplasmic signaling induced by steroid receptors has been described, such as the activation of the PI3K/Akt and NF-kappaB pathways. We evaluated their possible participation in the Dex-dependent protection against TNF-alpha-mediated cell death. Results Cellular cultures of the MCF-7 cell line were exposed to either, TNF-alpha or TNF-alpha and Dex, and cell viability was evaluated. Next, negative dominants of PI3K and IkappaB-alpha, designed to block the PI3K/Akt and NF-kappaB pathways, respectively, were transfected and selection and evaluation of several clones overexpressing the mutants were examined. Also, correlation with inhibitor of apoptosis proteins (IAPs expression was examined. Independent inhibition of these two pathways allowed us to test their participation in Dex-dependent protection against TNF-alpha-cytotoxicity in MCF-7 cells. Expression of the PI3K dominant negative mutant did not alter the protection conferred by Dex against TNF-alpha mediated cell death. Contrariwise, clones expressing the IkappaB-alpha dominant negative mutant lost the Dex-conferred protection against TNF-alpha. In these clones degradation of c-IAP was accelerated, while that of XIAP was remained unaffected. Conclusion NF-kappaB, but not PI3K/Akt activation, is required for the Dex protective effect against TNF-alpha-mediated cell death, and correlates with lack of degradation of the anti-apoptotic protein c-IAP1.

  12. Dexamethasone protection from TNF-alpha-induced cell death in MCF-7 cells requires NF-kappaB and is independent from AKT.

    Science.gov (United States)

    Machuca, Catalina; Mendoza-Milla, Criselda; Córdova, Emilio; Mejía, Salvador; Covarrubias, Luis; Ventura, José; Zentella, Alejandro

    2006-02-21

    The biochemical bases for hormone dependence in breast cancer have been recognized as an important element in tumor resistance, proliferation and metastasis. On this respect, dexamethasone (Dex) dependent protection against TNF-alpha-mediated cell death in the MCF-7 cell line has been demonstrated to be a useful model for the study of this type of cancer. Recently, cytoplasmic signaling induced by steroid receptors has been described, such as the activation of the PI3K/Akt and NF-kappaB pathways. We evaluated their possible participation in the Dex-dependent protection against TNF-alpha-mediated cell death. Cellular cultures of the MCF-7 cell line were exposed to either, TNF-alpha or TNF-alpha and Dex, and cell viability was evaluated. Next, negative dominants of PI3K and IkappaB-alpha, designed to block the PI3K/Akt and NF-kappaB pathways, respectively, were transfected and selection and evaluation of several clones overexpressing the mutants were examined. Also, correlation with inhibitor of apoptosis proteins (IAPs) expression was examined. Independent inhibition of these two pathways allowed us to test their participation in Dex-dependent protection against TNF-alpha-cytotoxicity in MCF-7 cells. Expression of the PI3K dominant negative mutant did not alter the protection conferred by Dex against TNF-alpha mediated cell death. Contrariwise, clones expressing the IkappaB-alpha dominant negative mutant lost the Dex-conferred protection against TNF-alpha. In these clones degradation of c-IAP was accelerated, while that of XIAP was remained unaffected. NF-kappaB, but not PI3K/Akt activation, is required for the Dex protective effect against TNF-alpha-mediated cell death, and correlates with lack of degradation of the anti-apoptotic protein c-IAP1.

  13. JANEX-1, a JAK3 inhibitor, protects pancreatic islets from cytokine toxicity through downregulation of NF-{kappa}B activation and the JAK/STAT pathway

    Energy Technology Data Exchange (ETDEWEB)

    Lv, Na; Kim, Eun-Kyung; Song, Mi-Young [Department of Biochemistry, Medical School and Diabetes Research Center, Chonbuk National University, Jeonju, Jeonbuk 561-756 (Korea, Republic of); Choi, Ha-Na; Moon, Woo Sung [Department of Pathology, Medical School and Diabetes Research Center, Chonbuk National University, Jeonju, Jeonbuk 561-756 (Korea, Republic of); Park, Sung-Joo [Department of Herbology, School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 570-749 (Korea, Republic of); Park, Jin-Woo [Department of Biochemistry, Medical School and Diabetes Research Center, Chonbuk National University, Jeonju, Jeonbuk 561-756 (Korea, Republic of); Kwon, Kang-Beom, E-mail: desson@wonkwang.ac.kr [Department of Physiology, School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 570-749 (Korea, Republic of); Park, Byung-Hyun, E-mail: bhpark@chonbuk.ac.kr [Department of Biochemistry, Medical School and Diabetes Research Center, Chonbuk National University, Jeonju, Jeonbuk 561-756 (Korea, Republic of)

    2009-07-15

    JANEX-1/WHI-P131, a selective Janus kinase 3 (JAK3) inhibitor, has been shown to delay the onset of diabetes in the NOD mouse model. However, the molecular mechanism by which JANEX-1 protects pancreatic {beta}-cells is unknown. In the current study, we investigated the role of JANEX-1 on interleukin (IL)-1{beta} and interferon (IFN)-{gamma}-induced {beta}-cell damage using isolated islets. JANEX-1-pretreated islets showed resistance to cytokine toxicity, namely suppressed nitric oxide (NO) production, reduced inducible form of NO synthase (iNOS) expression, and decreased islet destruction. The molecular mechanism by which JANEX-1 inhibits iNOS expression was mediated through suppression of the nuclear factor {kappa}B (NF-{kappa}B) and JAK/signal transducer and activator of transcription (STAT) pathways. Islets treated with the cytokines downregulated the protein levels of suppressor of cytokine signaling (SOCS)-1 and SOCS-3, but pretreatment with JANEX-1 attenuated these decreases. Additionally, islets from JAK3{sup -/-} mice were more resistant to cytokine toxicity than islets from control mice. These results demonstrate that JANEX-1 protects {beta}-cells from cytokine toxicity through suppression of the NF-{kappa}B and JAK/STAT pathways and upregulation of SOCS proteins, suggesting that JANEX-1 may be used to preserve functional {beta}-cell mass.

  14. NFkappaB activation is essential for miR-21 induction by TGFβ1 in high glucose conditions

    Energy Technology Data Exchange (ETDEWEB)

    Madhyastha, Radha, E-mail: radharao@med.miyazaki-u.ac.jp; Madhyastha, HarishKumar; Pengjam, Yutthana; Nakajima, Yuichi; Omura, Sayuri; Maruyama, Masugi

    2014-09-05

    Highlights: • Transforming growth factor beta 1 (TGFβ1) induces miR-21 in high glucose conditions. • NFkappaB activation and subsequent ROS generation are necessary for TGFβ1’s effect. • TGFβ1 facilitates binding of NFkB p65 to miR-21 promoter. • SMAD proteins bind to R-SBE sites on primary miR-21, in NFkB dependent manner. - Abstract: Transforming growth factor beta1 (TGFβ1) is a pleiotropic growth factor with a very broad spectrum of effects on wound healing. Chronic non-healing wounds such as diabetic foot ulcers express reduced levels of TGFβ1. On the other hand, our previous studies have shown that the microRNA miR-21 is differentially regulated in diabetic wounds and that it promotes migration of fibroblast cells. Although interplay between TGFβ1 and miR-21 are studied in relation to cancer, their interaction in the context of chronic wounds has not yet been investigated. In this study, we examined if TGFβ1 could stimulate miR-21 in fibroblasts that are subjected to high glucose environment. MiR-21 was, in fact, induced by TGFβ1 in high glucose conditions. The induction by TGFβ1 was dependent on NFκB activation and subsequent ROS generation. TGFβ1 was instrumental in degrading the NFκB inhibitor IκBα and facilitating the nuclear translocation of NFκB p65 subunit. EMSA studies showed enhanced DNA binding activity of NFκB in the presence of TGFβ1. ChIP assay revealed binding of p65 to miR-21 promoter. NFκB activation was also required for the nuclear translocation of Smad 4 protein and subsequent direct interaction of Smad proteins with primary miR-21 as revealed by RNA-IP studies. Our results show that manipulation of TGFβ1–NFκB–miR-21 pathway could serve as an innovative approach towards therapeutics to heal diabetic ulcers.

  15. NFkappaB activation is essential for miR-21 induction by TGFβ1 in high glucose conditions

    International Nuclear Information System (INIS)

    Madhyastha, Radha; Madhyastha, HarishKumar; Pengjam, Yutthana; Nakajima, Yuichi; Omura, Sayuri; Maruyama, Masugi

    2014-01-01

    Highlights: • Transforming growth factor beta 1 (TGFβ1) induces miR-21 in high glucose conditions. • NFkappaB activation and subsequent ROS generation are necessary for TGFβ1’s effect. • TGFβ1 facilitates binding of NFkB p65 to miR-21 promoter. • SMAD proteins bind to R-SBE sites on primary miR-21, in NFkB dependent manner. - Abstract: Transforming growth factor beta1 (TGFβ1) is a pleiotropic growth factor with a very broad spectrum of effects on wound healing. Chronic non-healing wounds such as diabetic foot ulcers express reduced levels of TGFβ1. On the other hand, our previous studies have shown that the microRNA miR-21 is differentially regulated in diabetic wounds and that it promotes migration of fibroblast cells. Although interplay between TGFβ1 and miR-21 are studied in relation to cancer, their interaction in the context of chronic wounds has not yet been investigated. In this study, we examined if TGFβ1 could stimulate miR-21 in fibroblasts that are subjected to high glucose environment. MiR-21 was, in fact, induced by TGFβ1 in high glucose conditions. The induction by TGFβ1 was dependent on NFκB activation and subsequent ROS generation. TGFβ1 was instrumental in degrading the NFκB inhibitor IκBα and facilitating the nuclear translocation of NFκB p65 subunit. EMSA studies showed enhanced DNA binding activity of NFκB in the presence of TGFβ1. ChIP assay revealed binding of p65 to miR-21 promoter. NFκB activation was also required for the nuclear translocation of Smad 4 protein and subsequent direct interaction of Smad proteins with primary miR-21 as revealed by RNA-IP studies. Our results show that manipulation of TGFβ1–NFκB–miR-21 pathway could serve as an innovative approach towards therapeutics to heal diabetic ulcers

  16. Angiotensin II accelerates functional recovery in the rat sciatic nerve in vivo: role of the AT2 receptor and the transcription factor NF-kappaB.

    Science.gov (United States)

    Reinecke, Kirstin; Lucius, Ralph; Reinecke, Alexander; Rickert, Uta; Herdegen, Thomas; Unger, Thomas

    2003-11-01

    The AT2 receptor regulates several functions of nerve cells, e.g., ionic fluxes, cell differentiation, and axonal regeneration, but also modulates programmed cell death. We tested the hypothesis that angiotensin II (ANG II) via its AT2 receptor not only promotes regeneration but also functional recovery after sciatic nerve crush in adult rats. ANG II (10(-7), 10(-9), 10(-11) M) applied locally via osmotic minipumps promoted functional recovery with maximal effects after the lowest concentration. The toe spread distance as a parameter for re-innervation after 20 days was significantly (Pelectrical stimulation (return of sensorimotor function) was reduced to 14.6 days vs. 17.9 days in the control group (PSchwann cells. Histological criteria, morphometric analyses, and electron microscopy confirmed the functional data. These results are the first to present direct evidence for an involvement of the AT2 receptor and NF-kappaB in peripheral nerve regeneration.

  17. An aqueous stem bark extract of Mangifera indica (Vimang) inhibits T cell proliferation and TNF-induced activation of nuclear transcription factor NF-kappaB.

    Science.gov (United States)

    Garrido, Gabino; Blanco-Molina, Magdalena; Sancho, Rocío; Macho, Antonio; Delgado, René; Muñoz, Eduardo

    2005-03-01

    A commercial aqueous stem bark extract of Mangifera indica L. (Vimang) has been reported to have antiinflammatory, immunomodulatory and antioxidant activities. The molecular basis for these diverse properties is still unknown. This study shows that a stem bark extract of M. indica inhibits early and late events in T cell activation, including CD25 cell surface expression, progression to the S-phase of the cell cycle and proliferation in response to T cell receptor (TCR) stimulation. Moreover, the extract prevented TNFalpha-induced IkappaBalpha degradation and the binding of NF-kappaB to the DNA. This study may help to explain at the molecular level some of the biological activities attributed to the aqueous stem bark extract of M. indica (Vimang).

  18. Assessment of hypoxia and TNF-alpha response by a vector with HRE and NF-kappaB response elements.

    Science.gov (United States)

    Chen, Zhilin; Eadie, Ashley L; Hall, Sean R; Ballantyne, Laurel; Ademidun, David; Tse, M Yat; Pang, Stephen C; Melo, Luis G; Ward, Christopher A; Brunt, Keith R

    2017-01-01

    Hypoxia and inflammatory cytokine activation (H&I) are common processes in many acute and chronic diseases. Thus, a single vector that responds to both hypoxia and inflammatory cytokines, such as TNF-alpha, is useful for assesing the severity of such diseases. Adaptation to hypoxia is regulated primarily by hypoxia inducible transcription factor (HIF alpha) nuclear proteins that engage genes containing a hypoxia response element (HRE). Inflammation activates a multitude of cytokines, including TNF-alpha, that invariably modulate activation of the nuclear factor kappa B (NF-kB) transcription factor. We constructed a vector that encompassed both a hypoxia response element (HRE), and a NF-kappaB responsive element. We show that this vector was functionally responsive to both hypoxia and TNF-alpha, in vitro and in vivo . Thus, this vector might be suitable for the detection and assessment of hypoxia or TNF-alpha.

  19. The upregulation of receptor activator NF-kappaB ligand expression by interleukin-1alpha and Porphyromonas endodontalis in human osteoblastic cells.

    Science.gov (United States)

    Chen, S-C; Huang, F-M; Lee, S-S; Li, M-Z; Chang, Y-C

    2009-04-01

    To investigate the receptor activator of nuclear factor-kappa B (NF-kappaB) ligand (RANKL) in osteoblastic cells stimulated with inflammatory mediators. The expression of RANKL in human osteoblastic cell line U2OS stimulated by pro-inflammatory cytokine interleukin (IL)-1alpha and black-pigmented bacteria Porphyromonas endodontalis was investigated by Western blot and enzyme-linked immunosorbent assay (ELISA). The significance of the results obtained from control and treated groups was statistically analysed by the paired Student's t-test. IL-1alpha was found to upregulate RANKL production in U2OS cells (P endodontalis also increased RANKL expression in U2OS cells after 4-h incubation period demonstrated by Western blot and ELISA (P endodontalis may be involved in developing apical periodontitis through the stimulation of RANKL production.

  20. Caractérisation des processus d'ubiquitination régulant le facteur de transcription NF-kappaB au cours de l’activation lymphocytaire Rôle de l’E3 ligase TRIM13 et de la déubiquitinase USP34

    OpenAIRE

    Hatchi , Emeline

    2014-01-01

    The transcription factor NF-KappaB plays a critical role in the development, homeostasis, the survival of the immune system, but also in the propagation of certain lymphomas. The optimal activation of NF-KappaB in response to the engagement of many immunoreceptors rely on the implementation of large signalosomes where specific adaptors are recruited and poly-Ubiquitinylated in a non-Degradative manner. In response to proinflammatory cytokines or activation of antigen receptors, these Ubiquiti...

  1. The inhibition of NF-kappaB activation pathways and the induction of apoptosis by dithiocarbamates in T cells are blocked by the glutathione precursor N-acetyl-L-cysteine

    OpenAIRE

    Fernandez, P C; Machado, J; Heussler, Volker; Botteron, C; Palmer, G H; Dobbelaere, D A

    1999-01-01

    Nuclear factor-kappaB regulates genes that control immune and inflammatory responses and are involved in the pathogenesis of several diseases, including AIDS and cancer. It has been proposed that reactive oxygen intermediates participate in NF-kappaB activation pathways, and compounds with putative antioxidant activity such as N-acetyl-L-cysteine (NAC) and pyrrolidine dithiocarbamate (PDTC) have been used interchangeably to demonstrate this point. We examined their effects, separately and com...

  2. The bio-complex "reaction pattern in vertebrate cells" reduces cytokine-induced cellular adhesion molecule mRNA expression in human endothelial cells by attenuation of NF-kappaB translocation.

    Science.gov (United States)

    Rönnau, Cindy; Liebermann, Herbert E H; Helbig, Franz; Staudt, Alexander; Felix, Stephan B; Ewert, Ralf; Landsberger, Martin

    2009-02-28

    The bio-complex "reaction pattern in vertebrate cells" (RiV) is mainly represented by characteristic exosome-like particles--probably as reaction products of cells to specific stress. The transcription factor NF-kappaB plays a central role in inflammation. We tested the hypothesis that RiV particle preparations (RiV-PP) reduce cellular adhesion molecule (CAM) expression (ICAM-1, VCAM-1, E-selectin) by the attenuation of NF-kappaB translocation in human umbilical vein endothelial cells (HUVEC). After 4 hours, pre-incubation of HUVEC with RiV-PP before stimulation with TNF-alpha significantly reduced ICAM-1 (65.5+/-10.3%) and VCAM-1 (71.1+/-12.3%) mRNA expression compared to TNF-alpha-treated cells (100%, n=7). ICAM-1 surface expression was significantly albeit marginally reduced in RiV/TNF-alpha- treated cells (92.0+/-5.6%, n=4). No significant effect was observed on VCAM-1 surface expression. In RiV/TNF-alpha-treated cells (n=4), NF-kappaB subunits p50 (85.7+/-4.1%) and p65 (85.0+/-1.8%) nuclear translocation was significantly reduced. RiV-PP may exert an anti-inflammatory effect in HUVEC by reducing CAM mRNA expression via attenuation of p50 and p65 translocation.

  3. Effects of overexpression of IL-1 receptor-associated kinase on NFkappaB activation, IL-2 production and stress-activated protein kinases in the murine T cell line EL4.

    Science.gov (United States)

    Knop, J; Wesche, H; Lang, D; Martin, M U

    1998-10-01

    The association and activation of the IL-1 receptor-associated protein kinase (IRAK) to the IL-1 receptor complex is one of the earliest events detectable in IL-1 signal transduction. We generated permanent clones of the murine T cell line EL4 6.1 overexpressing human (h)IRAK to evaluate the role of this kinase in IL-1 signaling. Overexpression of hIRAK enhanced IL-1-stimulated activation of the transcription factor NFkappaB, whereas a truncated form (N-IRAK) specifically inhibited IL-1-dependent NFkappaB activity. In clones stably overexpressing hIRAK a weak constitutive activation of NFkappaB correlated with a low basal IL-2 production which was enhanced in an IL-1-dependent manner. Compared to the parental cell line the dose-response curve of IL-1-induced IL-2 production was shifted in both potency and efficacy. These results demonstrate that IRAK directly triggers NFkappaB-mediated gene expression in EL4 cells. Qualitatively different effects were observed for the IL-1-induced activation of stress-activated protein (SAP) kinases: permanent overexpression of IRAK did not affect the dose dependence but prolonged the kinetics of IL-1-induced activation of SAP kinases, suggesting that this signaling branch may be regulated by distinct mechanisms.

  4. Sphingosine 1-phosphate-induced ICAM-1 expression via NADPH oxidase/ROS-dependent NF-kappaB cascade on human pulmonary alveolar epithelial cells

    Directory of Open Access Journals (Sweden)

    Chin-Chung eLin

    2016-03-01

    Full Text Available The intercellular adhesion molecule-1 (ICAM-1 expression is frequently correlated with the lung inflammation. A bioactive sphingolipid metabolite, sphingosine-1-phosphate (S1P, was involved in inflammation through the adhesion molecules induction, and then caused lung injury. However, the transduction mechanisms of the S1P stimulation to induce ICAM-1 expression in human pulmonary alveolar epithelial cells (HPAEpiCs remain unclear. Here, we demonstrated that exposure of HPAEpiCs to S1P significantly induces ICAM-1 expression leading to increase monocyte adhesion on the surface of HPAEpiCs. These phenomena were effectively attenuated by pretreatments with series of inhibitors such as Rottlerin (PKCdelta, PF431396 (PYK2, diphenyleneiodonium chloride (DPI, apocynin (NADPH oxidase, Edaravone (ROS, and Bay11-7082 (NF-kappaB. Consistently, knockdown with siRNA transfection of PKCdelta, PYK2, p47phox, and p65 exhibited the same results. Pretreatment with both Gq-coupled receptor antagonist (GPA2A and Gi/o-coupled receptor antagonist (GPA2 also blocked S1P-induced ICAM-1 protein and mRNA expression. We observed that S1P induced PYK2 activation via a Gq-coupled receptor/PKCdelta-dependent pathway. In addition, S1P induced NADPH oxidase activation and intracellular ROS generation, which were also reduced by Rottlerin or PF431396. We demonstrated that S1P induced NF-kappaB p65 phosphorylation and translocation from the cytosol to the nucleus in HPAEpiCs, which was inhibited by Rottlerin, PF431396, APO, DPI, or Edaravone. In the in vitro study, we established that S1P induced monocyte adhesion via an ICAM-1-dependent pathway. In the in vivo study, we found that S1P induced ICAM-1 protein and mRNA levels in the lung fractions, pulmonary hematoma, and leukocyte (mainly eosinophils and neutrophils count in bronchoalveolar lavage (BAL fluid in mice via a PKCdelta/PYK2/NADPH oxidase/ROS/NF-kappaB signaling pathway. We concluded that S1P may induce lung

  5. Quince (Cydonia oblonga Miller) peel polyphenols modulate LPS-induced inflammation in human THP-1-derived macrophages through NF-{kappa}B, p38MAPK and Akt inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Essafi-Benkhadir, Khadija [Laboratoire d' epidemiologie Moleculaire et Pathologie Experimentale Appliquee Aux Maladies Infectieuses, Institut Pasteur de Tunis (Tunisia); Refai, Amira [Laboratoire de Recherche sur la Transmission, le Controle et l' immunobiologie des Infections, Institut Pasteur de Tunis (Tunisia); Riahi, Ichrak [Laboratoire d' epidemiologie Moleculaire et Pathologie Experimentale Appliquee Aux Maladies Infectieuses, Institut Pasteur de Tunis (Tunisia); Fattouch, Sami [Laboratory LIP-MB National Institute of Applied Sciences and Technology, Tunis (Tunisia); Karoui, Habib [Laboratoire d' epidemiologie Moleculaire et Pathologie Experimentale Appliquee Aux Maladies Infectieuses, Institut Pasteur de Tunis (Tunisia); Essafi, Makram, E-mail: makram.essafi@pasteur.rns.tn [Laboratoire de Recherche sur la Transmission, le Controle et l' immunobiologie des Infections, Institut Pasteur de Tunis (Tunisia)

    2012-02-03

    Highlights: Black-Right-Pointing-Pointer Quince peel polyphenols inhibit LPS-induced secretion of TNF-{alpha} and IL-8. Black-Right-Pointing-Pointer Quince peel polyphenols augment LPS-induced secretion of IL-10 and IL-6. Black-Right-Pointing-Pointer Quince peel polyphenols-mediated inhibition of LPS-induced secretion of TNF-{alpha} is partially mediated by IL-6. Black-Right-Pointing-Pointer The anti-inflammatory effects of quince polyphenols pass through NF-{kappa}B, p38MAPK and Akt inhibition. -- Abstract: Chronic inflammation is a hallmark of several pathologies, such as rheumatoid arthritis, gastritis, inflammatory bowel disease, atherosclerosis and cancer. A wide range of anti-inflammatory chemicals have been used to treat such diseases while presenting high toxicity and numerous side effects. Here, we report the anti-inflammatory effect of a non-toxic, cost-effective natural agent, polyphenolic extract from the Tunisian quince Cydonia oblonga Miller. Lipopolysaccharide (LPS) treatment of human THP-1-derived macrophages induced the secretion of high levels of the pro-inflammatory cytokine TNF-{alpha} and the chemokine IL-8, which was inhibited by quince peel polyphenolic extract in a dose-dependent manner. Concomitantly, quince polyphenols enhanced the level of the anti-inflammatory cytokine IL-10 secreted by LPS-treated macrophages. We further demonstrated that the unexpected increase in IL-6 secretion that occurred when quince polyphenols were associated with LPS treatment was partially responsible for the polyphenols-mediated inhibition of TNF-{alpha} secretion. Biochemical analysis showed that quince polyphenols extract inhibited the LPS-mediated activation of three major cellular pro-inflammatory effectors, nuclear factor-kappa B (NF-{kappa}B), p38MAPK and Akt. Overall, our data indicate that quince peel polyphenolic extract induces a potent anti-inflammatory effect that may prove useful for the treatment of inflammatory diseases and that a quince

  6. NF-{kappa}B p50 promotes tumor cell invasion through negative regulation of invasion suppressor gene CRMP-1 in human lung adenocarcinoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Ming, Gao [Cancer Research Center, College of Medicine, National Taiwan University, Taipei, Taiwan (China); National Center of Excellence for Clinical Trial and Research, National Taiwan University, Hospital, Taipei, Taiwan (China); Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan (China); Yeh, P Y [Cancer Research Center, College of Medicine, National Taiwan University, Taipei, Taiwan (China); Department of Oncology, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 10016, Taiwan (China); Lu, Y -S [Cancer Research Center, College of Medicine, National Taiwan University, Taipei, Taiwan (China); National Center of Excellence for Clinical Trial and Research, National Taiwan University, Hospital, Taipei, Taiwan (China); Department of Oncology, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 10016, Taiwan, ROC (China); Chang, W C [Cancer Research Center, College of Medicine, National Taiwan University, Taipei, Taiwan (China); Kuo, M -L [Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan (China); Cheng, A -L [Cancer Research Center, College of Medicine, National Taiwan University, Taipei, Taiwan (China); National Center of Excellence for Clinical Trial and Research, National Taiwan University, Hospital, Taipei, Taiwan (China); Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan (China); Department of Oncology, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 10016, Taiwan (China); Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 10016, Taiwan (China)], E-mail: alcheng@ntu.edu.tw

    2008-11-14

    Lung adenocarcinoma Cl1-5 cells were selected from parental Cl1-0 cells based on their high metastatic potential. In a previous study, CRMP-1, an invasion suppressor gene, was shown to be suppressed in Cl1-5 cells. However, the regulation of CRMP-1 expression has not been explored. In this study, we showed nuclear factor-{kappa}B controls CRMP-1 expression. The electromobility shift assay showed that while Cl1-0 cells exhibited low NF-{kappa}B activity in response to TNF-{alpha}, an abundance of basal and TNF-{alpha}-induced NF-{kappa}B-DNA complex was detected in Cl1-5 cells. Supershift-coupled EMSA and Western blotting of nuclear proteins, however, revealed p50 protein, but not classic p65/p50 heterodimer in the complex. ChIP and EMSA demonstrated that p50 binds to a {kappa}B site residing between -1753 and -1743 of the CRMP-1 promoter region. Transfection of antisense p50 gene into Cl1-5 cells increased the CRMP-1 protein level and decreased the invasive activity of Cl1-5 cells.

  7. Downregulation of proapoptotic Bim augments IL-2-independent T-cell transformation by human T-cell leukemia virus type-1 Tax

    International Nuclear Information System (INIS)

    Higuchi, Masaya; Takahashi, Masahiko; Tanaka, Yuetsu; Fujii, Masahiro

    2014-01-01

    Human T-cell leukemia virus type 1 (HTLV-1), an etiological agent of adult T-cell leukemia, immortalizes and transforms primary human T cells in vitro in both an interleukin (IL)-2-dependent and IL-2-independent manner. Expression of the HTLV-1 oncoprotein Tax transforms the growth of the mouse T-cell line CTLL-2 from being IL-2-dependent to IL-2-independent. Withdrawal of IL-2 from normal activated T cells induces apoptosis, which is mediated through the inducible expression of several proapoptotic proteins, including Bim. In this study, we found that Tax protects IL-2-depleted T cells against Bim-induced apoptosis. Withdrawal of IL-2 from CTLL-2 cells induced a prominent increase in the level of Bim protein in CTLL-2 cells, but not in Tax-transformed CTLL-2 cells. This inhibition of Bim in Tax-transformed CTLL-2 cells was mediated by two mechanisms: downregulation of Bim mRNA and posttranscriptional reduction of Bim protein. Transient expression of Tax in CTLL-2 cells also inhibited IL-2 depletion–induced expression of Bim, however, this decrease in Bim protein expression was not due to downregulation of Bim mRNA, thus indicating that Bim mRNA downregulation in Tax-transformed CTLL-2 occurs only after long-term expression of Tax. Transient expression of Tax in CTLL-2 cells also induced Erk activation, however, this was not involved in the reduction of Bim protein. Knockdown of Bim expression in CTLL-2 cells augmented Tax-induced IL-2-independent transformation. HTLV-1 infection of human T cells also reduced their levels of Bim protein, and restoring Bim expression in HTLV-1-infected cells reduced their proliferation by inducing apoptosis. Taken together, these results indicate that Tax-induced downregulation of Bim in HTLV-1-infected T cells promotes their IL-2-independent growth, thereby supporting the persistence of HTLV-1 infection in vivo

  8. Transforming growth factor-beta 1 (TGF-beta1) promotes IL-2 mRNA expression through the up-regulation of NF-kappaB, AP-1 and NF-AT in EL4 cells.

    Science.gov (United States)

    Han, S H; Yea, S S; Jeon, Y J; Yang, K H; Kaminski, N E

    1998-12-01

    Transforming growth factor beta1 (TGF-beta1) has been previously shown to modulate interleukin 2 (IL-2) secretion by activated T-cells. In the present studies, we determined that TGF-beta1 induced IL-2 mRNA expression in the murine T-cell line EL4, in the absence of other stimuli. IL-2 mRNA expression was significantly induced by TGF-beta1 (0.1-1 ng/ml) over a relatively narrow concentration range, which led to the induction of IL-2 secretion. Under identical condition, we examined the effect of TGF-beta1 on the activity of nuclear factor AT (NF-AT), nuclear factor kappaB (NF-kappaB), activator protein-1 (AP-1) and octamer, all of which contribute to the regulation of IL-2 gene expression. Electrophoretic mobility shift assays showed that TGF-beta1 markedly increased NF-AT, NF-kappaB and AP-1 binding to their respective cognate DNA binding sites, whereas octamer binding remained constant, as compared with untreated cells. Employing a reporter gene expression system with p(NF-kappaB)3-CAT, p(NF-AT)3-CAT and p(AP-1)3-CAT, TGF-beta1 treatment of transfected EL4 cells induced a dose-related increase in chloramphenicol acetyltransferase activity that correlated well with the DNA binding profile found in the electrophoretic mobility shift assay studies. These results show that TGF-beta1, in the absence of any additional stimuli, up-regulates the activity of key transcription factors involved in IL-2 gene expression, including NF-AT, NF-kappaB and AP-1, to help promote IL-2 mRNA expression by EL4 cells.

  9. Syndrome Cerebelleux Et Infection A Htlv-1 A L\\'hôpital Central De ...

    African Journals Online (AJOL)

    Aucun de nos 2 patients n\\'a bénéficié d\\'une IRM cérébrale ou médullaire, ce qui ne nous permets pas d\\'exclure formellement une sclérose en plaques (SEP). Cependant, le mode évolutif, l\\'absence de signes pyramidaux et le peu de réponse à la corticothérapie ne nous ont pas permis de retenir le diagnostic de SEP.

  10. HTLV-1 and HIV-1 co-infection: A case report and review of the literature

    Directory of Open Access Journals (Sweden)

    Carmen Isache

    2016-01-01

    HTLV and HIV share the same routes of transmission and the same tropism for T-lymphocytes. Co-infection occurs probably more frequently than we are aware, since testing for HTLV is not routinely performed in outpatient HIV clinics.

  11. The HTLV-1 oncoprotein Tax is modified by the ubiquitin related modifier 1 (Urm1).

    Science.gov (United States)

    Hleihel, Rita; Khoshnood, Behzad; Dacklin, Ingrid; Omran, Hayssam; Mouawad, Carine; Dassouki, Zeina; El-Sabban, Marwan; Shirinian, Margret; Grabbe, Caroline; Bazarbachi, Ali

    2018-04-17

    Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy secondary to chronic human T-cell lymphotropic virus 1 infection, triggered by the virally encoded oncoprotein Tax. The transforming activity and subcellular localization of Tax is strongly influenced by posttranslational modifications, among which ubiquitylation and SUMOylation have been identified as key regulators of the nuclear/cytoplasmic shuttling of Tax, as well as its ability to activate NF-κB signaling. Adding to the complex posttranslational modification landscape of Tax, we here demonstrate that Tax also interacts with the ubiquitin-related modifier 1 (Urm1). Conjugation of Urm1 to Tax results in a redistribution of Tax to the cytoplasm and major increase in the transcription of the NF-ĸB targets Rantes and interleukin-6. Utilizing a tax-transgenic Drosophila model, we show that the Urm1-dependent subcellular targeting of Tax is evolutionary conserved, and that the presence of Urm1 is strongly correlated with the transcriptional output of Diptericin, an antimicrobial peptide and established downstream target of NF-κB in flies. These data put forward Urm1 as a novel Tax modifier that modulates its oncogenic activity and hence represents a potential novel target for developing new strategies for treating ATL.

  12. How Does HTLV-1 Undergo Oncogene-Dependent Replication Despite a Strong Immune Response?

    Directory of Open Access Journals (Sweden)

    Hélène Gazon

    2018-01-01

    Full Text Available In 1987, Mitsuaki Yoshida proposed the following model (Yoshida and Seiki, 1987: “... T-cells activated through the endogenous p40x would express viral antigens including the envelope glycoproteins which are exposed on the cell surface. These glycoproteins are targets of host immune surveillance, as is evidenced by the cytotoxic effects of anti-envelope antibodies or patient sera. Eventually all cells expressing the viral antigens, that is, all cells driven by the p40x would be rejected by the host. Only those cells that did not express the viral antigens would survive. Later, these antigen-negative infected cells would begin again to express viral antigens, including p40x, thus entering into the second cycle of cell propagation. These cycles would be repeated in so-called healthy virus carriers for 20 or 30 years or longer....” Three decades later, accumulated experimental facts particularly on intermittent viral transcription and regulation by the host immune response appear to prove that Yoshida was right. This Hypothesis and Theory summarizes the evidences that support this paradigm.

  13. HTLV-1 antibodies in serum and cerebrospinal fluid in tropical spastic paraparesis in Brazil

    Directory of Open Access Journals (Sweden)

    A. Spina-França

    1990-12-01

    Full Text Available HTLV-l antibodies were investigated in serum and in CSF of 150 patients with neurologic disorders mainly myelopathies. The patients were considered into three groups according to the possible relationship of their disease to the presence of HTLV-l antibodies: no relationship risk (control group, occasional risk group, and possible risk group. In this latter are 56 patients with crural spastic paraparesis or paraplegia of unknown etiology (SP. HTLV-l antibodies were tested by the passive particle-agglutination method for anti-ATLA antibody detection. The search was negative in all patients of the control group, and positive (serum and/or CSF in 16.5% of the patients from the second group and in 55.4% of the SP patients group. Clinical patterns in SP cases with HTLV-l antibodies were those of tropical spastic paraparesis (TSP. CSF patterns considered (cytology, protein content and gamma-globulins rate were different between TSP group with HTLV-l antibodies in CSF and SP group with no HTLV-l antibodies detection either in serum or in CSF. The difference was significant. Results of this investigation confirm the high incidence of TSP in Brazil, and bring additional indication for searching HTLV-l antibodies in the CSF.

  14. Molecular Studies of HTLV-1 Infection in Newly Recognized High Risk Population

    Science.gov (United States)

    1993-07-10

    members. Members of this community continued to marry close relatives for over the next 150 years. Markers of consanguinity are high among Mashadi...Caribbean region, and relationship to adult T cell leukemia/lymphoma. Int J Cancer 1982;30:257-264. 51. Hattori T, Uchiyama T, Topibana K, Takatsuki K

  15. Silencing of FKBP51 alleviates the mechanical pain threshold, inhibits DRG inflammatory factors and pain mediators through the NF-kappaB signaling pathway.

    Science.gov (United States)

    Yu, Hong-Mei; Wang, Qi; Sun, Wen-Bo

    2017-09-05

    Neuropathic pain is chronic pain caused by lesions or diseases of the somatosensory system, currently available analgesics provide only temporal relief. The precise role of FK506 binding protein 51 (FKBP51) in neuropathic pain induced by chronic constriction injury (CCI) is not clear. The purpose of the present study was to investigate the effects and possible mechanisms of FKBP51 in neuropathic pain in the rat model of CCI. Our results showed that FKBP51 was obviously upregulated in a time-dependent manner in the dorsal root ganglion (DRG) of CCI rats. Additionally, silencing of FKBP51 remarkably attenuated mechanical allodynia and thermal hyperalgesia as reflected by paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) in CCI rats. Moreover, knockdown of FKBP51 reduced the production of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6), nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) expression in the DRG of CCI rats. Furthermore, we revealed that inhibition of FKBP51 greatly suppressed the activation of the NF-kappaB (NF-κB) signaling in the DRG of CCI rats. Interestingly, similar to the FKBP51 siRNA (si-FKBP51), ammonium pyrrolidinedithiocarbamate (PDTC, an inhibitor of NF-κB) also alleviated neuropathic pain and neuro-inflammation, indicating that knockdown of FKBP51 alleviated neuropathic pain development of CCI rats by inhibiting the activation of NF-κB signaling pathway. Taken together, our findings indicate that FKBP51 may serve as a novel therapeutic target for neuropathic pain. Copyright © 2017. Published by Elsevier B.V.

  16. Sphingosine 1-phosphate (S1P)/S1P receptor 1 signaling regulates receptor activator of NF-{kappa}B ligand (RANKL) expression in rheumatoid arthritis

    Energy Technology Data Exchange (ETDEWEB)

    Takeshita, Harunori [Division of Rheumatology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501 (Japan); Kitano, Masayasu, E-mail: mkitano6@hyo-med.ac.jp [Division of Rheumatology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501 (Japan); Iwasaki, Tsuyoshi [Department of Pharmacy, Hyogo University of Health Sciences, 1-3-6 Minatojima Kobe, Hyogo 650-8530 (Japan); Kitano, Sachie; Tsunemi, Sachi; Sato, Chieri; Sekiguchi, Masahiro; Azuma, Naoto [Division of Rheumatology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501 (Japan); Miyazawa, Keiji [Discovery Research III, Research and Development, Kissei Pharmaceutical Company, 4365-1 Hodakakashiwara, Azumino, Nagano 399-8304 (Japan); Hla, Timothy [Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, 1300 York Avenue, Box 69, NY 10065 (United States); Sano, Hajime [Division of Rheumatology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501 (Japan)

    2012-03-09

    Highlights: Black-Right-Pointing-Pointer MH7A cells and CD4{sup +} T cells expressed S1P1 and RANKL. Black-Right-Pointing-Pointer S1P increased RANKL expression in MH7A cells and CD4{sup +} T cells. Black-Right-Pointing-Pointer The effect of S1P in MH7A cells was inhibited by specific Gi/Go inhibitors. -- Abstract: Sphingosine 1-phosphate (S1P)/S1P receptor 1 (S1P1) signaling plays an important role in synovial cell proliferation and inflammatory gene expression by rheumatoid arthritis (RA) synoviocytes. The purpose of this study is to clarify the role of S1P/S1P1 signaling in the expression of receptor activator of NF-{kappa}B ligand (RANKL) in RA synoviocytes and CD4{sup +} T cells. We demonstrated MH7A cells, a human RA synovial cell line, and CD4{sup +} T cells expressed S1P1 and RANKL. Surprisingly, S1P increased RANKL expression in MH7A cells and CD4{sup +} T cells in a dose-dependent manner. Moreover, S1P enhanced RANKL expression induced by stimulation with TNF-{alpha} in MH7A cells and CD4{sup +} T cells. These effects of S1P in MH7A cells were inhibited by pretreatment with PTX, a specific Gi/Go inhibitor. These findings suggest that S1P/S1P1 signaling may play an important role in RANKL expression by MH7A cells and CD4{sup +} T cells. S1P/S1P1 signaling of RA synoviocytes is closely connected with synovial hyperplasia, inflammation, and RANKL-induced osteoclastogenesis in RA. Thus, regulation of S1P/S1P1 signaling may become a novel therapeutic target for RA.

  17. Regulation of human T-lymphotropic virus type I latency and reactivation by HBZ and Rex.

    Directory of Open Access Journals (Sweden)

    Subha Philip

    2014-04-01

    Full Text Available Human T lymphotropic virus type I (HTLV-I infection is largely latent in infected persons. How HTLV-1 establishes latency and reactivates is unclear. Here we show that most HTLV-1-infected HeLa cells become senescent. By contrast, when NF-κB activity is blocked, senescence is averted, and infected cells continue to divide and chronically produce viral proteins. A small population of infected NF-κB-normal HeLa cells expresses low but detectable levels of Tax and Rex, albeit not Gag or Env. In these "latently" infected cells, HTLV-1 LTR trans-activation by Tax persists, but NF-κB trans-activation is attenuated due to inhibition by HBZ, the HTLV-1 antisense protein. Furthermore, Gag-Pol mRNA localizes primarily in the nuclei of these cells. Importantly, HBZ was found to inhibit Rex-mediated export of intron-containing mRNAs. Over-expression of Rex or shRNA-mediated silencing of HBZ led to viral reactivation. Importantly, strong NF-κB inhibition also reactivates HTLV-1. Hence, during HTLV-1 infection, when Tax/Rex expression is robust and dominant over HBZ, productive infection ensues with expression of structural proteins and NF-κB hyper-activation, which induces senescence. When Tax/Rex expression is muted and HBZ is dominant, latent infection is established with expression of regulatory (Tax/Rex/HBZ but not structural proteins. HBZ maintains viral latency by down-regulating Tax-induced NF-κB activation and senescence, and by inhibiting Rex-mediated expression of viral structural proteins.

  18. Human T-Cell Leukemia Virus Type 1 Tax-Deregulated Autophagy Pathway and c-FLIP Expression Contribute to Resistance against Death Receptor-Mediated Apoptosis

    Science.gov (United States)

    Wang, Weimin; Zhou, Jiansuo; Shi, Juan; Zhang, Yaxi; Liu, Shilian

    2014-01-01

    ABSTRACT The human T-cell leukemia virus type 1 (HTLV-1) Tax protein is considered to play a central role in the process that leads to adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 Tax-expressing cells show resistance to apoptosis induced by Fas ligand (FasL) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). The regulation of Tax on the autophagy pathway in HeLa cells and peripheral T cells was recently reported, but the function and underlying molecular mechanism of the Tax-regulated autophagy are not yet well defined. Here, we report that HTLV-1 Tax deregulates the autophagy pathway, which plays a protective role during the death receptor (DR)-mediated apoptosis of human U251 astroglioma cells. The cellular FLICE-inhibitory protein (c-FLIP), which is upregulated by Tax, also contributes to the resistance against DR-mediated apoptosis. Both Tax-induced autophagy and Tax-induced c-FLIP expression require Tax-induced activation of IκB kinases (IKK). Furthermore, Tax-induced c-FLIP expression is regulated through the Tax-IKK-NF-κB signaling pathway, whereas Tax-triggered autophagy depends on the activation of IKK but not the activation of NF-κB. In addition, DR-mediated apoptosis is correlated with the degradation of Tax, which can be facilitated by the inhibitors of autophagy. IMPORTANCE Our study reveals that Tax-deregulated autophagy is a protective mechanism for DR-mediated apoptosis. The molecular mechanism of Tax-induced autophagy is also illuminated, which is different from Tax-increased c-FLIP. Tax can be degraded via manipulation of autophagy and TRAIL-induced apoptosis. These results outline a complex regulatory network between and among apoptosis, autophagy, and Tax and also present evidence that autophagy represents a new possible target for therapeutic intervention for the HTVL-1 related diseases. PMID:24352466

  19. The Fps/Fes kinase regulates the inflammatory response to endotoxin through down-regulation of TLR4, NF-kappaB activation, and TNF-alpha secretion in macrophages.

    Science.gov (United States)

    Parsons, Sean A; Greer, Peter A

    2006-12-01

    Fps/Fes and Fer are members of a distinct subfamily of cytoplasmic protein tyrosine kinases that have recently been implicated in the regulation of innate immunity. Previous studies showed that mice lacking Fps/Fes are hypersensitive to systemic LPS challenge, and Fer-deficient mice displayed enhanced recruitment of leukocytes in response to local LPS challenge. This study identifies physiological, cellular, and molecular defects that contribute to the hyperinflammatory phenotype in Fps/Fes null mice. Plasma TNF-alpha levels were elevated in LPS challenged Fps/Fes null mice as compared with wild-type mice and cultured Fps/Fes null peritoneal macrophages treated with LPS showed increased TNF-alpha production. Cultured Fps/Fes null macrophages also displayed prolonged LPS-induced degradation of IkappaB-alpha, increased phosphorylation of the p65 subunit of NF-kappaB, and defective TLR4 internalization, compared with wild-type macrophages. Together, these observations provide a likely mechanistic basis for elevated proinflammatory cytokine secretion by Fps/Fes null macrophages and the increased sensitivity of Fps/Fes null mice to endotoxin. We posit that Fps/Fes modulates the innate immune response of macrophages to LPS, in part, by regulating internalization and down-regulation of the TLR4 receptor complex.

  20. Effect of repetitive transcranial magnetic stimulation on reducing spasticity in patients suffering from HTLV-1-associated myelopathy.

    Science.gov (United States)

    Amiri, Mostafa; Nafissi, Shahriar; Jamal-Omidi, Shirin; Amiri, Motahareh; Fatehi, Farzad

    2014-12-01

    Human T-lymphotropic virus type 1 has been implicated in human T-lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Regarding its endemicity in Iran and the role of repetitive transcranial magnetic stimulation in reducing spasticity, we decided to evaluate the efficacy of repetitive transcranial magnetic stimulation in reducing spasticity (as primary outcome) and pain, muscle power, and quality of life (as secondary outcomes) in patients suffering from HAM/TSP. In this pretest-posttest study, nine definite patients with HAM/TSP (according to WHO guidelines) were recruited. All patients underwent five consecutive daily sessions of active repetitive transcranial magnetic stimulation (each session consisting of 20 trains of 10 pulses at 5 Hz and an intensity of 90% of resting motor threshold for the biceps brachii muscle). Main outcome measures including spasticity (by modified Ashworth scale), pain (by visual analog scale), muscle power, and quality of life (by SF 36) were measured before the study and days 5, 7, 30 after the termination of the sessions. Seven (77.8%) females and 2 (22.2%) males were recruited with the mean age of 52 ± 12.67 years, and the mean duration of the disease was 5 ± 3.94. Comparison of the repeated measures showed a statistically significant decrease in pain and spasticity in lower limbs. The decrement in spasticity was persistent even 30 days after the intervention; however, the pain reduction was seen only 5 days after the procedure. No change in quality of life, and muscle power was detected. It seems that repetitive transcranial magnetic stimulation could decrease spasticity and pain in patients with HAM/TSP, and this effect could persistently continue by 1 month, but it did not influence patients' muscle power and quality of life, and it could be used as an adjuvant therapy in patients suffering from human T-lymphotropic virus type 1-associated HAM/TSP.

  1. Downregulation of proapoptotic Bim augments IL-2-independent T-cell transformation by human T-cell leukemia virus type-1 Tax.

    Science.gov (United States)

    Higuchi, Masaya; Takahashi, Masahiko; Tanaka, Yuetsu; Fujii, Masahiro

    2014-12-01

    Human T-cell leukemia virus type 1 (HTLV-1), an etiological agent of adult T-cell leukemia, immortalizes and transforms primary human T cells in vitro in both an interleukin (IL)-2-dependent and IL-2-independent manner. Expression of the HTLV-1 oncoprotein Tax transforms the growth of the mouse T-cell line CTLL-2 from being IL-2-dependent to IL-2-independent. Withdrawal of IL-2 from normal activated T cells induces apoptosis, which is mediated through the inducible expression of several proapoptotic proteins, including Bim. In this study, we found that Tax protects IL-2-depleted T cells against Bim-induced apoptosis. Withdrawal of IL-2 from CTLL-2 cells induced a prominent increase in the level of Bim protein in CTLL-2 cells, but not in Tax-transformed CTLL-2 cells. This inhibition of Bim in Tax-transformed CTLL-2 cells was mediated by two mechanisms: downregulation of Bim mRNA and posttranscriptional reduction of Bim protein. Transient expression of Tax in CTLL-2 cells also inhibited IL-2 depletion-induced expression of Bim, however, this decrease in Bim protein expression was not due to downregulation of Bim mRNA, thus indicating that Bim mRNA downregulation in Tax-transformed CTLL-2 occurs only after long-term expression of Tax. Transient expression of Tax in CTLL-2 cells also induced Erk activation, however, this was not involved in the reduction of Bim protein. Knockdown of Bim expression in CTLL-2 cells augmented Tax-induced IL-2-independent transformation. HTLV-1 infection of human T cells also reduced their levels of Bim protein, and restoring Bim expression in HTLV-1-infected cells reduced their proliferation by inducing apoptosis. Taken together, these results indicate that Tax-induced downregulation of Bim in HTLV-1-infected T cells promotes their IL-2-independent growth, thereby supporting the persistence of HTLV-1 infection in vivo. © 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  2. Acidic pH stimulates the production of the angiogenic CXC chemokine, CXCL8 (interleukin-8), in human adult mesenchymal stem cells via the extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, and NF-kappaB pathways.

    Science.gov (United States)

    Bischoff, David S; Zhu, Jian-Hua; Makhijani, Nalini S; Yamaguchi, Dean T

    2008-07-01

    Blood vessel injury results in limited oxygen tension and diffusion leading to hypoxia, increased anaerobic metabolism, and elevated production of acidic metabolites that cannot be easily removed due to the reduced blood flow. Therefore, an acidic extracellular pH occurs in the local microenvironment of disrupted bone. The potential role of acidic pH and glu-leu-arg (ELR(+)) CXC chemokines in early events in bone repair was studied in human mesenchymal stem cells (hMSCs) treated with medium of decreasing pH (7.4, 7.0, 6.7, and 6.4). The cells showed a reciprocal increase in CXCL8 (interleukin-8, IL-8) mRNA levels as extracellular pH decreased. At pH 6.4, CXCL8 mRNA was induced >60x in comparison to levels at pH 7.4. hMSCs treated with osteogenic medium (OGM) also showed an increase in CXCL8 mRNA with decreasing pH; although, at a lower level than that seen in cells grown in non-OGM. CXCL8 protein was secreted into the medium at all pHs with maximal induction at pH 6.7. Inhibition of the G-protein-coupled receptor alpha, G(alphai), suppressed CXCL8 levels in response to acidic pH; whereas phospholipase C inhibition had no effect on CXCL8. The use of specific mitogen-activated protein kinase (MAPK) signal transduction inhibitors indicated that the pH-dependent increase in CXCL8 mRNA is due to activation of ERK and p38 pathways. The JNK pathway was not involved. NF-kappaB inhibition resulted in a decrease in CXCL8 levels in hMSCs grown in non-OGM. However, OGM-differentiated hMSCs showed an increase in CXCL8 levels when treated with the NF-kappaB inhibitor PDTC, a pyrrolidine derivative of dithiocarbamate. 2008 Wiley-Liss, Inc.

  3. HTLV 1 associated adult T cell lymphoma/leukemia a clinicopathologic, immunophenotypic tale of three cases from non-endemic region of south India

    Directory of Open Access Journals (Sweden)

    Faiq Ahmed

    2012-01-01

    Full Text Available Adult T cell lymphoma/leukemia is a peripheral T-cell neoplasm caused by human T-cell lymphotrophic virus-1, affects mostly adults with systemic involvement and poor prognosis. Diagnosis of adult T-Cell leukemia/Lymphoma is challenging. The clinico-pathologic and immuno-phenotypic features of the three cases will be presented.

  4. Outcome of patients with HTLV-1-associated adult T-cell leukemia/lymphoma after SCT: a retrospective study by the EBMT LWP.

    Science.gov (United States)

    Bazarbachi, A; Cwynarski, K; Boumendil, A; Finel, H; Fields, P; Raj, K; Nagler, A; Mohty, M; Sureda, A; Dreger, P; Hermine, O

    2014-10-01

    Adult T-cell leukemia/lymphoma (ATL) carries a dismal prognosis. Experience with allo-SCT for ATL appears encouraging but is limited to Japanese series. This retrospective analysis of the EBMT registry revealed 21 HTLV-I seropositive ATL including 7 acute and 12 lymphoma subtypes. Four patients received auto-SCT and rapidly died from ATL. Out of 17 allo-SCT (4 myeloablative, 13 reduced intensity), 6 are still alive (4 were in CR1 at SCT). Eleven patients died within 2 years, eight from relapse/progression and three from transplant toxicity. Six of seven informative patients who lived >12 months had chronic GVHD. Overall these results indicate that allo-SCT but not auto-SCT may salvage a subset of ATL patients, supporting the existence of graft vs ATL effect also in non-Japanese patients.

  5. NF-kappaB: Two Sides of the Same Coin.

    Science.gov (United States)

    Pires, Bruno R B; Silva, Rafael C M C; Ferreira, Gerson M; Abdelhay, Eliana

    2018-01-09

    Nuclear Factor-kappa B (NF-κB) is a transcription factor family that regulates a large number of genes that are involved in important physiological processes, including survival, inflammation, and immune responses. More recently, constitutive expression of NF-κB has been associated with several types of cancer. In addition, microorganisms, such as viruses and bacteria, cooperate in the activation of NF-κB in tumors, confirming the multifactorial role of this transcription factor as a cancer driver. Recent reports have shown that the NF-κB signaling pathway should receive attention for the development of therapies. In addition to the direct effects of NF-κB in cancer cells, it might also impact immune cells that can both promote or prevent tumor development. Currently, with the rise of cancer immunotherapy, the link among immune cells, inflammation, and cancer is a major focus, and NF-κB could be an important regulator for the success of these therapies. This review discusses the contrasting roles of NF-κB as a regulator of pro- and antitumor processes and its potential as a therapeutic target.

  6. Evaluation of NF-kappaB Signaling in T Cells

    Science.gov (United States)

    2009-01-01

    General Signaling Pathways Science STKE 2000. 12. Bubeck Wardenburg, J., C. Fu, J. K. Jackman , H. Flotow, S. E. Wilkinson, D. H. Williams, R. Johnson...Data were an- alyzed using the MKASSAY program developed by J. Kappler (Howard Hughes Medical Institute, Denver, CO). Results CD4 T cells from PKC

  7. The Tax oncogene enhances ELL incorporation into p300 and P-TEFb containing protein complexes to activate transcription.

    Science.gov (United States)

    Fufa, Temesgen D; Byun, Jung S; Wakano, Clay; Fernandez, Alfonso G; Pise-Masison, Cynthia A; Gardner, Kevin

    2015-09-11

    The eleven-nineteen lysine-rich leukemia protein (ELL) is a key regulator of RNA polymerase II mediated transcription. ELL facilitates RNA polymerase II transcription pause site entry and release by dynamically interacting with p300 and the positive transcription elongation factor b (P-TEFb). In this study, we investigated the role of ELL during the HTLV-1 Tax oncogene induced transactivation. We show that ectopic expression of Tax enhances ELL incorporation into p300 and P-TEFb containing transcriptional complexes and the subsequent recruitment of these complexes to target genes in vivo. Depletion of ELL abrogates Tax induced transactivation of the immediate early genes Fos, Egr2 and NF-kB, suggesting that ELL is an essential cellular cofactor of the Tax oncogene. Thus, our study identifies a novel mechanism of ELL-dependent transactivation of immediate early genes by Tax and provides the rational for further defining the genome-wide targets of Tax and ELL. Published by Elsevier Inc.

  8. Human T-lymphotropic Virus-1/2 detected in drug abused men who have sex with men infected with HIV in Surakarta, Indonesia

    Science.gov (United States)

    Agung Prasetyo, Afiono; Sari, Yulia

    2018-05-01

    Human T-lymphotropic virus types 1 and 2 (HTLV-1/2) share similar routes of transmission with human immunodeficiency virus (HIV), and the HTLV-1/2 co-infection may affect the clinical course of HIV infection. The HIV/HTLV-1/2 co-infection risk higher if the patient performing the high-risk activities. This study evaluated the presentation of HTLV-1 and 2 in HIV-infected men who have sex with men with drug abused history in Surakarta Indonesia. Blood samples collected from HIV-infected men who have sex with men with drug abused history in Surakarta were tested using HTLV-1/2 enzyme-linked immunosorbent assays and confirmed by RT-PCR nested addressed the part of HTLV-1 LTR and HTLV-2 LTR region, respectively. The specificity of the molecular assays was confirmed by sequencing the amplicons. The anti HTLV-1/2 positive rate was 17.4% (8/46). All positive serological samples were confirmed by nested RT-PCR. Of these, three was HTLV-1 positive and five was HTLV-2 positive. Molecular analysis of positive PCR products revealed that all HTLV-1 isolates had a close relationship with HTLV-1 isolated in Japan while all HTLV-2 isolates with that of isolated in the USA. HTLV-1 and HTLV-2 were detected in drug abused men who have sex with men infected with HIV in Surakarta.

  9. DMPD: Shared principles in NF-kappaB signaling. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available ML File (.csml) Open .csml file with CIOPlayer Open .csml file with CIOPlayer - ※CIO Playerのご利用上の注意 Open .csml file with CIO Open .csml file with CIO - ※CIOのご利用上の注意 ...

  10. NF-kappaB Activity in Macrophages Determines Metastatic Potential of Breast Tumor Cells

    Science.gov (United States)

    2011-08-01

    about the relatively low number of mice in the control group so we decided to generate additional mice to increase the numbers in each group (Second...mammary epithelium increases tumor latency and decreases tumor burden. Oncogene 2010, In press. 10. Connelly L, Barham W, Pigg R, Saint-Jean L, Sherrill T...littermate controls (Fig. 5E, 5G ). These differences were consistent with defects in saccular airway branching morphogenesis. The lack of effect in mice

  11. NFkappaB in the mechanism of ammonia-induced astrocyte swelling in culture.

    NARCIS (Netherlands)

    Sinke, A.P.; Jayakumar, A.R.; Panickar, K.S.; Moriyama, M.; Reddy, P.V.; Norenberg, M.D.

    2008-01-01

    Astrocyte swelling and brain edema are major neuropathological findings in the acute form of hepatic encephalopathy (fulminant hepatic failure), and substantial evidence supports the view that elevated brain ammonia level is an important etiological factor in this condition. Although the mechanism

  12. IAPs: from caspase inhibitors to modulators of NF-kappaB, inflammation and cancer

    DEFF Research Database (Denmark)

    Gyrd-Hansen, Mads; Meier, Pascal

    2010-01-01

    . The development of such inhibitors has radically changed our knowledge of the signalling processes that are regulated by IAPs. Recent studies indicate that IAPs not only regulate caspases and apoptosis, but also modulate inflammatory signalling and immunity, mitogenic kinase signalling, proliferation and mitosis...

  13. Bifidobacterium animalis AHC7 protects against pathogen-induced NF-kappaB activation in vivo

    LENUS (Irish Health Repository)

    O'Mahony, David

    2010-12-22

    Abstract Background Bifidobacteria and lactobacilli are among the early and important colonizers of the gastrointestinal tract and are generally considered to be part of a normal, healthy microbiota. It is believed that specific strains within the microbiota can influence host immune-reactivity and may play a role in protection from infection and aberrant inflammatory activity. One such strain, Bifidobacterium animalis AHC7, has been previously shown to protect against Salmonella typhimurium infection in mice and helps resolve acute idiopathic diarrhea in dogs. The aim of this study was to investigate the potential molecular and cellular mechanisms underpinning the Bifidobacterium animalis AHC7 protective effect. Results Following 4 hours of infection with Salmonella typhimurium, NF-κB activation was significantly elevated in vivo in placebo and Enterococcus faecium-fed animals while Bifidobacterium animalis AHC7 consumption significantly attenuated the NF-κB response. In vitro anti-CD3\\/CD28 stimulated Peyer\\'s patch cells secreted significantly less TNF-α and IFN-γ following Bifidobacterium animalis AHC7 consumption. Stimulated cells released more IL-12p70 but this difference did not reach statistical significance. No alteration in mucosal IL-6, IL-10 or MCP-1 levels were observed. No statistically significant change in the cytokine profile of mesenteric lymph node cells was noted. In vitro, Bifidobacterium animalis AHC7 was bound by dendritic cells and induced secretion of both IL-10 and IL-12p70. In addition, co-culture of CD4+ T cells with Bifidobacterium animalis AHC7-stimulated dendritic cells resulted in a significant increase in CD25+Foxp3+ T cell numbers. Conclusion Bifidobacterium animalis AHC7 exerts an anti-inflammatory effect via the attenuation of pro-inflammatory transcription factor activation in response to an infectious insult associated with modulation of pro-inflammatory cytokine production within the mucosa. The cellular mechanism underpinning Bifidobacterium animalis AHC7 mediated attenuation of NF-κB activation may include recognition of the bacterium by dendritic cells and induction of CD25+Foxp3+ T cells.

  14. Novel Functions of NF-kappaB2/p52 in Androgen Receptor Signaling in CRPC

    Science.gov (United States)

    2015-09-01

    Lin SX, Labrie C, Simard J, Breton R, et al. The key role of 17 beta-hydroxysteroid dehydrogenases in sex steroid biology. Steroids 1997;62:148–58...Togawa AMJ, Ishizaki H, et al. Progressive impairment of kid neys and reproductive organs in mice lacking Rho GDIalpha. Oncogene 1999;18(39):5373 5380. 17...motility. Mol Cell Biol 1999;13(1):545 554. 16. Togawa AMJ, Ishizaki H, et al. Progressive impairment of kid neys and reproductive organs in mice

  15. Short communication: molecular characterization of dog and cat p65 subunits of NF-kappaB.

    Science.gov (United States)

    Ishikawa, Shingo; Takemitsu, Hiroshi; Li, Gebin; Mori, Nobuko; Yamamoto, Ichiro; Arai, Toshiro

    2015-04-01

    Nuclear factor kappa B (NF-κB) plays an important role in the immune system. The p65 subunit is an important part of NF-κB unit, and studies of dog and cat p65 subunits of NF-κB (dp65 and cp65) are important in understanding their immune function. In this study, we described the molecular characterization of dp65 and cp65. The dp65 and cp65 complementary DNA encoded 542 and 555 amino acids, respectively, showing a high sequence homology with the mammalian p65 subunit (>87.5%). Quantitative polymerase chain reaction revealed that the p65 messenger RNA is highly expressed in the dog stomach and cat heart and adipose tissue. Functional NF-κB promoter-luciferase reporter vectors revealed that our isolated dp65 and cp65 cDNA encodes a functionally active protein. Transiently expressed dp65 and cp65 up-regulated pro-inflammatory cytokine expression levels in dog and cat, respectively. These findings suggest that dp65 and cp65 play important roles in regulating immune function. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Prevalence of bortezomib-resistant constitutive NF-kappaB activity in mantle cell lymphoma

    Directory of Open Access Journals (Sweden)

    Kahl Brad S

    2008-05-01

    Full Text Available Abstract Background The proteasome inhibitor bortezomib can inhibit activation of the transcription factor NF-κB, a mechanism implicated in its anti-neoplastic effects observed in mantle cell lymphoma (MCL. However, NF-κB can be activated through many distinct mechanisms, including proteasome independent pathways. While MCL cells have been shown to harbor constitutive NF-κB activity, what fraction of this activity in primary MCL samples is sensitive or resistant to inhibition by bortezomib remains unclear. Results Proteasome activity in the EBV-negative MCL cell lines Jeko-1 and Rec-1 is inhibited by greater than 80% after exposure to 20 nM bortezomib for 4 hours. This treatment decreased NF-κB activity in Jeko-1 cells, but failed to do so in Rec-1 cells when assessed by electrophoretic mobility shift assay (EMSA. Concurrently, Rec-1 cells were more resistant to the cytotoxic effects of bortezomib than Jeko-1 cells. Consistent with a proteasome inhibitor resistant pathway of activation described in mouse B-lymphoma cells (WEHI231 and a breast carcinoma cell line (MDA-MB-468, the bortezomib-resistant NF-κB activity in Rec-1 cells is inhibited by calcium chelators, calmodulin inhibitors, and perillyl alcohol, a monoterpene capable of blocking L-type calcium channels. Importantly, the combination of perillyl alcohol and bortezomib is synergistic in eliciting Rec-1 cell cytotoxicity. The relevance of these results is illuminated by the additional finding that a considerable fraction of primary MCL samples (8 out of 10 displayed bortezomib-resistant constitutive NF-κB activity. Conclusion Our findings show that bortezomib-resistant NF-κB activity is frequently observed in MCL samples and suggest that this activity may be relevant to MCL biology as well as serve as a potential therapeutic target.

  17. Human T-cell lymphotropic virus type 1 and its oncogenesis

    Institute of Scientific and Technical Information of China (English)

    Lan-lan ZHANG; Jing-yun WEI; Long WANG; Shi-le HUANG; Ji-long CHEN

    2017-01-01

    Human T-cell lymphotropic virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia/lymphoma (ATL),a rapidly progressing clonal malignancy of CD4+ T lymphocytes.Exploring the host-HTLV-1 interactions and the molecular mechanisms underlying HTLV-1-mediated tumorigenesis is critical for developing efficient therapies against the viral infection and associated leukemia/lymphoma.It has been demonstrated to date that several HTLV-1 proteins play key roles in the cellular transformation and immortalization of infected T lymphocytes.Of note,the HTLV-1 oncoprotein Tax inhibits the innate IFN response through interaction with MAVS,STING and RIP1,causing the suppression of TBK1-mediated phosphorylation of IRF3/IRF7.The HTLV-1 protein HBZ disrupts genomic integrity and inhibits apoptosis and autophagy of the target cells.Furthermore,it is revealed that HBZ enhances the proliferation of ATL cells and facilitates evasion of the infected cells from immunosurveillance.These studies provide insights into the molecular mechanisms by which HTLV-1 mediates the formation of cancer as well as useful strategies for the development of new therapeutic interventions against ATL.In this article,we review the recent advances in the understanding of the pathogenesis,the underlying mechanisms,clinical diagnosis and treatment of the disease caused by HTLV-1 infection.In addition,we discuss the future direction for targeting HTLV-1-associated cancers and strategies against HTLV-1.

  18. Human T-lymphotropic virus-1/2 detected in drug abused men who have sex with men in Surakarta Indonesia

    Science.gov (United States)

    Prasetyo, Afiono Agung; Sari, Yulia

    2017-02-01

    Human T-cell lymphotropic virus types 1 and 2 (HTLV-1/2) are retroviruses that probably among the most neglected blood-borne pathogens. The molecular epidemiology data of HTLV-1/2 in Indonesia is very rare. This study evaluated the prevalence of HTLV-1 and 2 in men who have sex with men with drug abused history in Surakarta Indonesia, to track the presentation of HTLV-1/2 in Indonesia. All blood samples collected from men who have sex with men with drug abused history in Surakarta in 2009-2013 were tested using enzyme linked immunosorbent assays and confirmed by RT-PCR nested addressed the part of HTLV-1 LTR and HTLV-2 LTR region, respectively. The specificity of the molecular assays was confirmed by sequencing the amplicons. The anti HTLV-1/2 positive rate was 4.8% (6/126). All positive serological samples were confirmed by nested RT-PCR. Of these, two was HTLV-1 positive and four was HTLV-2 positive. Molecular analysis of positive PCR products revealed that all HTLV-1 isolate had close relationship with HTLV-1 isolated in Japan while all HTLV-2 isolate with that of isolated in USA. HTLV-1 and HTLV-2 were detected in men who have sex with men with drug abused history in Surakarta indicated that these viruses were circulated in Indonesia, especially in the high risk communities

  19. Double control systems for human T-cell leukemia virus type 1 by innate and acquired immunity.

    Science.gov (United States)

    Kannagi, Mari; Hasegawa, Atsuhiko; Kinpara, Shuichi; Shimizu, Yukiko; Takamori, Ayako; Utsunomiya, Atae

    2011-04-01

    Human T-cell leukemia virus type 1 (HTLV-1) is the causative retrovirus of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1-specific T-cell responses elicit antitumor and antiviral effects in experimental models, and are considered to be one of the most important determinants of the disease manifestation, since they are activated in HAM/TSP but not in ATL patients. The combination of low T-cell responses and elevated HTLV-1 proviral loads are features of ATL, and are also observed in a subpopulation of HTLV-1 carriers at the asymptomatic stage, suggesting that these features may be underlying risk factors. These risks may potentially be reduced by vaccination to activate HTLV-1-specific T-cell responses. HAM/TSP and ATL patients also differ in their levels of HTLV-1 mRNA expression, which are generally low in vivo but slightly higher in HAM/TSP patients. Our recent study indicated that viral expression in HTLV-1-infected T-cells is suppressed by stromal cells in culture through type-I IFNs. The suppression was reversible after isolation from the stromal cells, mimicking a long-standing puzzling phenomenon in HTLV-1 infection where the viral expression is very low in vivo and rapidly induced in vitro. Collectively, HTLV-1 is controlled by both acquired and innate immunity in vivo: HTLV-1-specific T-cells survey infected cells, and IFNs suppress viral expression. Both effects would contribute to a reduction in viral pathogenesis, although they may potentially influence or conflict with one another. The presence of double control systems for HTLV-1 infection provides a new concept for understanding the pathogenesis of HTLV-1-mediated malignant and inflammatory diseases. © 2011 Japanese Cancer Association.

  20. Human T-lymphotropic virus type 1 infection and disease in Spain.

    Science.gov (United States)

    de Mendoza, Carmen; Caballero, Estrella; Aguilera, Antonio; Requena, Silvia; de Lejarazu, Raúl Ortiz; Pirón, María; González, Rocío; Jiménez, Ana; Roc, Lourdes; Treviño, Ana; Benito, Rafael; Fernández-Alonso, Miriam; Aguinaga, Aitziber; Rodríguez, Carmen; García-Costa, Juan; Blanco, Lidia; Ramos, José M; Calderón, Enrique; Eirós, José M; Sauleda, Silvia; Barreiro, Pablo; Soriano, Vicente

    2017-07-31

    : Human T-lymphotropic virus type 1 (HTLV-1) infection is a neglected disease despite roughly 15 million people are chronically infected worldwide. Lifelong less than 10% of carriers develop life-threatening diseases, mostly a subacute myelopathy known as tropical spastic paraparesis (TSP) and a lymphoproliferative disorder named adult T-cell leukemia (ATL). HTLV-1 is efficiently transmitted perinatally (breastfeeding), sexually (more from men to women) and parenterally (transfusions, injection drug user (IDU), and transplants). To date there is neither prophylactic vaccine nor effective antiviral therapy. A total of 327 cases of HTLV-1 infection had been reported at the HTLV-1 Spanish registry until December 2016, of whom 34 had been diagnosed with TSP and 25 with ATL. Overall 62% were Latin American immigrants and 13% were persons of African origin. The incidence of HTLV-1 in Spain has remained stable for nearly a decade with 20-25 new cases yearly. Of the 21 newly diagnosed HTLV-1 cases during year 2016, one was a native Spaniard pregnant woman, and four presented with symptomatic disease, including three with ATL and one with TSP. Underdiagnosis of HTLV-1 in Spain must be high (iceberg model), which may account for the disproportionate high rate of symptomatic cases (almost 20%) and the late recognition of preventable HTLV-1 transmissions in special populations, such as newborns and transplant recipients. Our current estimate is of 10 000 persons living with HTLV-1 infection in Spain. Given the large flux of immigrants and visitors from HTLV-1 endemic regions to Spain, the expansion of HTLV-1 screening policies is warranted. At this time, it seems worth recommending HTLV testing to all donor/recipient organ transplants and pregnant women regardless place of birth. Although current leukoreduction procedures largely prevent HTLV-1 transmission by blood transfusions, HTLV testing of all first-time donors should be cost-effective contributing to unveil

  1. MAIT cells are reduced in frequency and functionally impaired in human T lymphotropic virus type 1 infection: Potential clinical implications.

    Science.gov (United States)

    Paquin-Proulx, Dominic; Greenspun, Benjamin C; Costa, Emanuela A S; Segurado, Aluisio C; Kallas, Esper G; Nixon, Douglas F; Leal, Fabio E

    2017-01-01

    HTLV-1 infection is associated with several inflammatory disorders, including the neurodegenerative condition HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). It is unclear why a minority of infected subjects develop HAM/TSP. The cellular immune response has been implicated in the development of inflammatory alterations in these patients; however the pathogenic mechanisms for disease progression remain unclear. Furthermore, HTLV-1-infected individuals have an increase incidence of Mycobacterium tuberculosis (Mtb) infection, suggesting that immunological defect are associated with HTLV-1 infection. Evidence suggests an important role for Mucosal-associated invariant T (MAIT) cells in the early control of Mtb infection. Chronic viral infections like HIV and HCV have been associated with decreased frequency and functionality of MAIT cells. We hypothesized that HTLV-1 infection is associated with similar perturbations in MAIT cells. We investigated MAIT cell frequency, phenotype, and function by flow cytometry in a cohort of 10 asymptomatic and 10 HAM/TSP HTLV-1 infected patients. We found that MAIT cells from HTLV-1-infected subjects were reduced and showed high co-expression of the activation markers CD38 and HLA-DR but normal levels of CCR6 and CD127. MAIT cells had a lower expression of the transcription factor PLZF in HAM/TSP patients. Unlike Tax-specific CD8+T cells, which are hyperfunctional, MAIT cells from HTLV-1-infected subjects had a poor IFNγ response following antigen stimulation. MAIT cell perturbations in HTLV-1 infection were not associated with HTLV-1 proviral load and MAIT cells were not infected by HTLV-1 in vivo. Rather, MAIT cells loss was associated with immune activation. Overall, our results do not support a role for MAIT cells in HAM/TSP pathogenesis but reduced numbers of MAIT cells, together with their poor functionality, could contribute to the increased susceptibility of HTLV-1-infected individuals to other infectious

  2. MAIT cells are reduced in frequency and functionally impaired in human T lymphotropic virus type 1 infection: Potential clinical implications.

    Directory of Open Access Journals (Sweden)

    Dominic Paquin-Proulx

    Full Text Available HTLV-1 infection is associated with several inflammatory disorders, including the neurodegenerative condition HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP. It is unclear why a minority of infected subjects develop HAM/TSP. The cellular immune response has been implicated in the development of inflammatory alterations in these patients; however the pathogenic mechanisms for disease progression remain unclear. Furthermore, HTLV-1-infected individuals have an increase incidence of Mycobacterium tuberculosis (Mtb infection, suggesting that immunological defect are associated with HTLV-1 infection. Evidence suggests an important role for Mucosal-associated invariant T (MAIT cells in the early control of Mtb infection. Chronic viral infections like HIV and HCV have been associated with decreased frequency and functionality of MAIT cells. We hypothesized that HTLV-1 infection is associated with similar perturbations in MAIT cells. We investigated MAIT cell frequency, phenotype, and function by flow cytometry in a cohort of 10 asymptomatic and 10 HAM/TSP HTLV-1 infected patients. We found that MAIT cells from HTLV-1-infected subjects were reduced and showed high co-expression of the activation markers CD38 and HLA-DR but normal levels of CCR6 and CD127. MAIT cells had a lower expression of the transcription factor PLZF in HAM/TSP patients. Unlike Tax-specific CD8+T cells, which are hyperfunctional, MAIT cells from HTLV-1-infected subjects had a poor IFNγ response following antigen stimulation. MAIT cell perturbations in HTLV-1 infection were not associated with HTLV-1 proviral load and MAIT cells were not infected by HTLV-1 in vivo. Rather, MAIT cells loss was associated with immune activation. Overall, our results do not support a role for MAIT cells in HAM/TSP pathogenesis but reduced numbers of MAIT cells, together with their poor functionality, could contribute to the increased susceptibility of HTLV-1-infected individuals to

  3. Long Terminal Repeat Circular DNA as Markers of Active Viral Replication of Human T Lymphotropic Virus-1 in Vivo

    Directory of Open Access Journals (Sweden)

    James M Fox

    2016-03-01

    Full Text Available Clonal expansion of human T-lymphotropic virus type-1 (HTLV-1 infected cells in vivo is well documented. Unlike human immunodeficiency virus type 1 (HIV-1, HTLV-1 plasma RNA is sparse. The contribution of the “mitotic” spread of HTLV-1 compared with infectious spread of the virus to HTLV-1 viral burden in established infection is uncertain. Since extrachromosomal long terminal repeat (LTR DNA circles are indicators of viral replication in HIV-1 carriers with undetectable plasma HIV RNA, we hypothesised that HTLV-1 LTR circles could indicate reverse transcriptase (RT usage and infectious activity. 1LTR and 2LTR DNA circles were measured in HTLV-1 cell lines and peripheral blood mononuclear cells (PBMC of asymptomatic carriers (ACs and patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP or adult T cell leukaemia/lymphoma (ATLL. 1LTR DNA circles were detected in 14/20 patients at a mean of 1.38/100 PBMC but did not differentiate disease status nor correlate with HTLV-1 DNA copies. 2LTR DNA circles were detected in 30/31 patients and at higher concentrations in patients with HTLV-1-associated diseases, independent of HTLV-1 DNA load. In an incident case the 2LTR DNA circle concentration increased 2.1 fold at the onset of HAM/TSP compared to baseline. Detectable and fluctuating levels of HTLV-1 DNA circles in patients indicate viral RT usage and virus replication. Our results indicate HTLV-1 viral replication capacity is maintained in chronic infection and may be associated with disease onset.

  4. Use of anti-tumor necrosis factor biologics in the treatment of rheumatoid arthritis does not change human T-lymphotropic virus type 1 markers: a case series.

    Science.gov (United States)

    Umekita, Kunihiko; Umeki, Kazumi; Miyauchi, Shunichi; Ueno, Shiro; Kubo, Kazuyoshi; Kusumoto, Norio; Takajo, Ichiro; Nagatomo, Yasuhiro; Okayama, Akihiko

    2015-09-01

    Anti-tumor necrosis factor (anti-TNF) biologics are effective in the treatment of rheumatoid arthritis (RA); however, it is still not clear whether this treatment promotes the development of malignancies such as lymphoma. Human T-lymphotropic virus type 1 (HTLV-1), which is a causative agent of adult T-cell lymphoma (ATL), is prevalent in Japan. Many HTLV-1-positive patients with RA are assumed to exist; however, there have thus far been no reports on the effect of anti-TNF biologics on HTLV-1-positive patients. We analyzed the response to treatment with anti-TNF biologics and change of HTLV-1 markers in two cases of RA. The two cases showed no response based on the European League Against of Rheumatism response criteria 60-96 weeks after administration of anti-TNF biologics (infliximab and etanercept). No signs of ATL were observed and HTLV-1 markers, such as proviral load and clonality of HTLV-1-infected cells, showed no significant change in either of two cases. Therefore, treatment with anti-TNF biologics did not induce activation of HTLV-1, although the effect on RA was not as effective as in HTLV-1-negative patients in this limited study. Further long-term study with a greater number of patients is necessary to clarify the safety and efficacy of anti-TNF biologics in HTLV-1-positive patients with RA.

  5. Family Aggregation of Human T-Lymphotropic Virus 1-Associated Diseases: a Systematic Review

    Directory of Open Access Journals (Sweden)

    Carolina Alvarez

    2016-10-01

    Full Text Available Human T-lymphotropic virus 1 (HTLV-1 is a retrovirus that produces a persistent infection. Two transmission routes (from mother to child and via sexual intercourse favor familial clustering of HTLV-1. It is yet unknown why most HTLV-1 carriers remain asymptomatic while about 10% of them develop complications. HTLV-1 associated diseases were originally described as sporadic entities, but familial presentations have been reported. To explore what is known about family aggregation of HTLV-1-associated diseases we undertook a systematic review. We aimed at answering whether, when and where family aggregation of HTLV-1-associated diseases was reported, which relatives were affected and which hypotheses were proposed to explain aggregation. We searched MEDLINE, abstract books of HTLV conferences and reference lists of selected papers. Search terms used referred to HTLV-1 infection, and HTLV-1-associated diseases, and family studies. HTLV-1-associated diseases considered are adult T-cell leukemia/lymphoma (ATLL, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP, HTLV-1-associated uveitis, and infective dermatitis. Seventy-four records reported HTLV-1-associated diseases in more than one member of the same family and were included. Most reports came from HTLV-1-endemic countries, mainly Japan (n=30 and Brazil (n=10. These reports described a total of 270 families in which more than one relative had HTLV-1-associated diseases. In most families, different family members suffered from the same disease (n=221. The diseases most frequently reported were ATLL (114 families and HAM/TSP (101 families. Most families (n=142 included two to four affected individuals. The proportion of ATLL patients with family history of ATLL ranged from 2% to 26%. The proportion of HAM/TSP patients with family history of HAM/TSP ranged from 1% to 48%. The predominant cluster types for ATLL were clusters of siblings and parent-child pairs and for HAM/TSP, an

  6. Direct evidence for a chronic CD8+-T-cell-mediated immune reaction to tax within the muscle of a human T-cell leukemia/lymphoma virus type 1-infected patient with sporadic inclusion body myositis.

    Science.gov (United States)

    Ozden, Simona; Cochet, Madeleine; Mikol, Jacqueline; Teixeira, Antonio; Gessain, Antoine; Pique, Claudine

    2004-10-01

    Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) infection can lead to the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), concomitantly with or without other inflammatory disorders such as myositis. These pathologies are considered immune-mediated diseases, and it is assumed that migration within tissues of both HTLV-1-infected CD4(+) T cells and anti-HTLV-1 cytotoxic T cells represents a pivotal event. However, although HTLV-1-infected T cells were found in inflamed lesions, the antigenic specificity of coinfiltrated CD8(+) T cells remains to be determined. In this study, we performed both ex vivo and in situ analyses using muscle biopsies obtained from an HTLV-1-infected patient with HAM/TSP and sporadic inclusion body myositis. We found that both HTLV-1-infected CD4(+) T cells and CD8(+) T cells directed to the dominant Tax antigen can be amplified from muscle cell cultures. Moreover, we were able to detect in two successive muscle biopsies both tax mRNA-positive mononuclear cells and T cells recognized by the Tax11-19/HLA-A*02 tetramer and positive for perforin. These findings provide the first direct demonstration that anti-Tax cytotoxic T cells are chronically recruited within inflamed tissues of an HTLV-1 infected patient, which validates the cytotoxic immune reaction model for the pathogenesis of HTLV-1-associated inflammatory disease.

  7. Molecular epidemiology of endemic human T-lymphotropic virus type 1 in a rural community in Guinea-Bissau.

    Directory of Open Access Journals (Sweden)

    Carla van Tienen

    Full Text Available Human T-Lymphotropic Virus Type 1 (HTLV-1 infection causes lethal adult T-cell leukemia (ATL and severely debilitating HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP in up to 5% of infected adults. HTLV-1 is endemic in parts of Africa and the highest prevalence in West Africa (5% has been reported in Caio, a rural area in the North-West of Guinea-Bissau. It is not known which HTLV-1 variants are present in this community. Sequence data can provide insights in the molecular epidemiology and help to understand the origin and spread of HTLV-1.To gain insight into the molecular diversity of HTLV-1 in West Africa.HTLV-1 infected individuals were identified in community surveys between 1990-2007. The complete Long Terminal Repeat (LTR and p24 coding region of HTLV-1 was sequenced from infected subjects. Socio-demographic data were obtained from community census and from interviews performed by fieldworkers. Phylogenetic analyses were performed to characterize the relationship between the Caio HTLV-1 and HTLV-1 from other parts of the world.LTR and p24 sequences were obtained from 72 individuals (36 LTR, 24 p24 only and 12 both. Consistent with the low evolutionary change of HTLV-1, many of the sequences from unrelated individuals showed 100% nucleotide identity. Most (45 of 46 of the LTR sequences clustered with the Cosmopolitan HTLV-1 subtype 1a, subgroup D (1aD. LTR and p24 sequences from two subjects were divergent and formed a significant cluster with HTLV-1 subtype 1g, and with the most divergent African Simian T-cell Lymphotropic Virus, Tan90.The Cosmopolitan HTLV-1 1aD predominates in this rural West African community. However, HTLV-1 subtype 1g is also present. This subtype has not been described before in West Africa and may be more widespread than previously thought. These data are in line with the hypothesis that multiple monkey-to-man zoonotic events are contributing to HTLV-1 diversity.

  8. Regulation of IFN regulatory factor 4 expression in human T cell leukemia virus-I-transformed T cells.

    Science.gov (United States)

    Sharma, Sonia; Grandvaux, Nathalie; Mamane, Yael; Genin, Pierre; Azimi, Nazli; Waldmann, Thomas; Hiscott, John

    2002-09-15

    IFN regulatory factor (IRF)-4 is a lymphoid/myeloid-restricted member of the IRF transcription factor family that plays an essential role in the homeostasis and function of mature lymphocytes. IRF-4 expression is tightly regulated in resting primary T cells and is transiently induced at the mRNA and protein levels after activation by Ag-mimetic stimuli such as TCR cross-linking or treatment with phorbol ester and calcium ionophore (PMA/ionomycin). However, IRF-4 is constitutively upregulated in human T cell leukemia virus type I (HTLV-I) infected T cells as a direct gene target for the HTLV-I Tax oncoprotein. In this study we demonstrate that chronic IRF-4 expression in HTLV-I-infected T lymphocytes is associated with a leukemic phenotype, and we examine the mechanisms by which continuous production of IRF-4 is achieved in HTLV-I-transformed T cells. IRF-4 expression in HTLV-1-infected cells is driven through activation of the NF-kappaB and NF-AT pathways, resulting in the binding of p50, p65, and c-Rel to the kappaB1 element and p50, c-Rel, and NF-ATp to the CD28RE element within the -617 to -209 region of the IRF-4 promoter. Furthermore, mutation of either the kappaB1 or CD28RE sites blocks Tax-mediated transactivation of the human IRF-4 promoter in T cells. These experiments constitute the first detailed analysis of human IRF-4 transcriptional regulation within the context of HTLV-I infection and transformation of CD4(+) T lymphocytes.

  9. DMPD: Dual role of oxidized LDL on the NF-kappaB signaling pathway. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available (.html) CSML File (.csml) Open .csml file with CIOPlayer Open .csml file with CIOPlayer - ※CIO Playerのご利用上の注意 Open .csml file with CIO Open .csml file with CIO - ※CIOのご利用上の注意 ...

  10. Class A scavenger receptor promotes osteoclast differentiation via the enhanced expression of receptor activator of NF-{kappa}B (RANK)

    Energy Technology Data Exchange (ETDEWEB)

    Takemura, Kenichi [Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556 (Japan); Department of Orthopaedic and Neuro-Musculoskeletal Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto (Japan); Sakashita, Naomi; Fujiwara, Yukio; Komohara, Yoshihiro; Lei, XiaoFeng; Ohnishi, Koji [Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556 (Japan); Suzuki, Hiroshi [National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido (Japan); Kodama, Tatsuhiko [Department of Molecular Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo (Japan); Mizuta, Hiroshi [Department of Orthopaedic and Neuro-Musculoskeletal Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto (Japan); Takeya, Motohiro, E-mail: takeya@kumamoto-u.ac.jp [Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556 (Japan)

    2010-01-22

    Osteoclasts originate from bone marrow monocyte/macrophage lineage cells, and their differentiation depends on macrophage colony-stimulating factor (M-CSF) and receptor activator nuclear factor kappa B (RANK) ligand. Class A scavenger receptor (SR-A) is one of the principal functional molecules of macrophages, and its level of expression declines during osteoclast differentiation. To investigate the role of SR-A in osteoclastogenesis, we examined pathological changes in femoral bone and the expression levels of osteoclastogenesis-related molecules in SR-A{sup -/-} mice. The femoral osseous density of SR-A{sup -/-} mice was higher than that of SR-A{sup +/+} mice, and the number of multinucleated osteoclasts was significantly decreased. An in vitro differentiation assay revealed that the differentiation of multinucleated osteoclasts from bone marrow-derived progenitor cells is impaired in SR-A{sup -/-} mice. Elimination of SR-A did not alter the expression level of the M-CSF receptor, c-fms; however, the expression levels of RANK and RANK-related osteoclast-differentiation molecules such as nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1) and microphthalmia-associated transcription factor (MITF) significantly decreased. Furthermore, acetylated low-density lipoprotein (AcLDL), an SR-A ligand, significantly increased the expression level of RANK and MITF during osteoclast differentiation. These data indicate that SR-A promotes osteoclastogenesis via augmentation of the expression level of RANK and its related molecules.

  11. Human adipocytes are highly sensitive to intermittent hypoxia induced NF-kappaB activity and subsequent inflammatory gene expression

    International Nuclear Information System (INIS)

    Taylor, Cormac T.; Kent, Brian D.; Crinion, Sophie J.; McNicholas, Walter T.; Ryan, Silke

    2014-01-01

    Highlights: • Intermittent hypoxia (IH) leads to NF-κB activation in human primary adipocytes. • Adipocytes bear higher pro-inflammatory potential than other human primary cells. • IH leads to upregulation of multiple pro-inflammatory genes in human adipocytes. - Abstract: Introduction: Intermittent hypoxia (IH)-induced activation of pro-inflammatory pathways is a major contributing factor to the cardiovascular pathophysiology associated with obstructive sleep apnea (OSA). Obesity is commonly associated with OSA although it remains unknown whether adipose tissue is a major source of inflammatory mediators in response to IH. The aim of this study was to test the hypothesis that IH leads to augmented inflammatory responses in human adipocytes when compared to cells of non-adipocyte lineages. Methods and results: Human primary subcutaneous and visceral adipocytes, human primary microvascular pulmonary endothelial cells (HUMEC-L) and human primary small airway epithelial cells (SAEC) were exposed to 0, 6 or 12 cycles of IH or stimulated with tumor necrosis factor (TNF)-α. IH led to a robust increase in NF-κB DNA-binding activity in adipocytes compared with normoxic controls regardless of whether the source of adipocytes was visceral or subcutaneous. Notably, the NF-κB response of adipocytes to both IH and TNF-α was significantly greater than that in HUMEC-L and SAEC. Western blotting confirmed enhanced nuclear translocation of p65 in adipocytes in response to IH, accompanied by phosphorylation of I-κB. Parallel to p65 activation, we observed a significant increase in secretion of the adipokines interleukin (IL)-8, IL-6 and TNF-α with IH in adipocytes accompanied by significant upregulation of mRNA expression. PCR-array suggested profound influence of IH on pro-inflammatory gene expression in adipocytes. Conclusion: Human adipocytes demonstrate strong sensitivity to inflammatory gene expression in response to acute IH and hence, adipose tissue may be a key source of inflammatory mediators in OSA

  12. Human adipocytes are highly sensitive to intermittent hypoxia induced NF-kappaB activity and subsequent inflammatory gene expression

    Energy Technology Data Exchange (ETDEWEB)

    Taylor, Cormac T. [School of Medicine and Medical Science, The Conway Institute, University College Dublin (Ireland); Kent, Brian D.; Crinion, Sophie J.; McNicholas, Walter T. [School of Medicine and Medical Science, The Conway Institute, University College Dublin (Ireland); Pulmonary and Sleep Disorders Unit, St. Vincent’s University Hospital, Dublin (Ireland); Ryan, Silke, E-mail: silke.ryan@ucd.ie [School of Medicine and Medical Science, The Conway Institute, University College Dublin (Ireland); Pulmonary and Sleep Disorders Unit, St. Vincent’s University Hospital, Dublin (Ireland)

    2014-05-16

    Highlights: • Intermittent hypoxia (IH) leads to NF-κB activation in human primary adipocytes. • Adipocytes bear higher pro-inflammatory potential than other human primary cells. • IH leads to upregulation of multiple pro-inflammatory genes in human adipocytes. - Abstract: Introduction: Intermittent hypoxia (IH)-induced activation of pro-inflammatory pathways is a major contributing factor to the cardiovascular pathophysiology associated with obstructive sleep apnea (OSA). Obesity is commonly associated with OSA although it remains unknown whether adipose tissue is a major source of inflammatory mediators in response to IH. The aim of this study was to test the hypothesis that IH leads to augmented inflammatory responses in human adipocytes when compared to cells of non-adipocyte lineages. Methods and results: Human primary subcutaneous and visceral adipocytes, human primary microvascular pulmonary endothelial cells (HUMEC-L) and human primary small airway epithelial cells (SAEC) were exposed to 0, 6 or 12 cycles of IH or stimulated with tumor necrosis factor (TNF)-α. IH led to a robust increase in NF-κB DNA-binding activity in adipocytes compared with normoxic controls regardless of whether the source of adipocytes was visceral or subcutaneous. Notably, the NF-κB response of adipocytes to both IH and TNF-α was significantly greater than that in HUMEC-L and SAEC. Western blotting confirmed enhanced nuclear translocation of p65 in adipocytes in response to IH, accompanied by phosphorylation of I-κB. Parallel to p65 activation, we observed a significant increase in secretion of the adipokines interleukin (IL)-8, IL-6 and TNF-α with IH in adipocytes accompanied by significant upregulation of mRNA expression. PCR-array suggested profound influence of IH on pro-inflammatory gene expression in adipocytes. Conclusion: Human adipocytes demonstrate strong sensitivity to inflammatory gene expression in response to acute IH and hence, adipose tissue may be a key source of inflammatory mediators in OSA.

  13. Haloperidol Suppresses NF-kappaB to Inhibit Lipopolysaccharide-Induced Pro-Inflammatory Response in RAW 264 Cells.

    Science.gov (United States)

    Yamamoto, Shunsuke; Ohta, Noriyuki; Matsumoto, Atsuhiro; Horiguchi, Yu; Koide, Moe; Fujino, Yuji

    2016-02-04

    BACKGROUND Haloperidol, a tranquilizing agent, is administered both to treat symptoms of psychotic disorders and to sedate agitated and delirious patients. Notably, haloperidol has been suggested to inhibit the immune response through unknown mechanisms. We hypothesized that the sedative modulates the immune response via NF-κB. MATERIAL AND METHODS Using flow cytometry, we analyzed the effects of haloperidol on expression CD80 and CD86 in RAW 264 cells and in primary macrophages derived from bone marrow. Secretion of interleukin (IL)-1β, IL-6, and IL-12 p40 was measured by enzyme-linked immunosorbent assay. In addition, NF-κB activation was evaluated using a reporter assay based on secretory embryonic alkaline phosphatase. Finally, synthetic antagonists were used to identify the dopamine receptor that mediates the effects of haloperidol. RESULTS Haloperidol inhibited NF-κB activation, and thereby suppressed expression of CD80, as well as secretion of IL-1β, IL-6, and IL-12 p40. CD80 and IL-6 levels were similarly attenuated by a D2-like receptor antagonist, but not by a D1-like receptor antagonist. CONCLUSIONS The data strongly suggest that haloperidol inhibits the immune response by suppressing NF-kB signaling via the dopamine D2 receptor.

  14. Genetic variation in TLR or NFkappaB pathways and the risk of breast cancer: a case-control study

    International Nuclear Information System (INIS)

    Resler, Alexa J; Malone, Kathleen E; Johnson, Lisa G; Malkki, Mari; Petersdorf, Effie W; McKnight, Barbara; Madeleine, Margaret M

    2013-01-01

    Toll-like receptors (TLRs) and the transcription factor nuclear factor-κB (NFκB) are important in inflammation and cancer. We examined the association between breast cancer risk and 233 tagging single nucleotide polymorphisms within 31 candidate genes involved in TLR or NFκB pathways. This population-based study in the Seattle area included 845 invasive breast cancer cases, diagnosed between 1997 and 1999, and 807 controls aged 65–79. Variant alleles in four genes were associated with breast cancer risk based on gene-level tests: MAP3K1, MMP9, TANK, and TLR9. These results were similar when the risk of breast cancer was examined within ductal and luminal subtypes. Subsequent exploratory pathway analyses using the GRASS algorithm found no associations for genes in TLR or NFκB pathways. Using publicly available CGEMS GWAS data to validate significant findings (N = 1,145 cases, N = 1,142 controls), rs889312 near MAP3K1 was confirmed to be associated with breast cancer risk (P = 0.04, OR 1.15, 95% CI 1.01–1.30). Further, two SNPs in TANK that were significant in our data, rs17705608 (P = 0.05) and rs7309 (P = 0.04), had similar risk estimates in the CGEMS data (rs17705608 OR 0.83, 95% CI 0.72–0.96; CGEMS OR 0.90, 95% CI 0.80–1.01 and rs7309 OR 0.83, 95% CI 0.73–0.95; CGEMS OR 0.91, 95% CI 0.81–1.02). Our findings suggest plausible associations between breast cancer risk and genes in TLR or NFκB pathways. Given the few suggestive associations in our data and the compelling biologic rationale for an association between genetic variation in these pathways and breast cancer risk, further studies are warranted that examine these effects

  15. Generation of Soluble Receptor Activator of NF-KappaB Ligand Is Critical for Osteolytic Bone Metastasis

    Science.gov (United States)

    2010-10-01

    maintains the latency of the pro-MMPs (Van Wart and Birkedal-Hansen, 1990). Currently, at least 26 known MMP genes in humans are identified (Kondratiev...transforming growth factor-beta on the expression of collagenase-1 and collagenase-3 in human fibroblasts. J Biol Chem 273 (16): 9769-9777 Van Wart HE...analysis. Gelatin zymography. Total protein (50 μg) isolated from either the TB interface or tumor alone area from animals im- planted with Cl66 tumors

  16. The cachectic mediator proteolysis inducing factor activates NF-kappaB and STAT3 in human Kupffer cells and monocytes

    NARCIS (Netherlands)

    Watchorn, T.M.; Dowidar, N.; Dejong, C.H.; Waddell, I.D.; Garden, O.J.; Ross, J.A.

    2005-01-01

    A novel proteoglycan, proteolysis inducing factor (PIF), is capable of inducing muscle proteolysis during the process of cancer cachexia, and of inducing an acute phase response in human hepatocytes. We investigated whether PIF is able to activate pro-inflammatory pathways in human Kupffer cells,

  17. Rare and Common Variants in CARD14, Encoding an Epidermal Regulator of NF-kappaB, in Psoriasis

    Science.gov (United States)

    Jordan, Catherine T.; Cao, Li; Roberson, Elisha D.O.; Duan, Shenghui; Helms, Cynthia A.; Nair, Rajan P.; Duffin, Kristina Callis; Stuart, Philip E.; Goldgar, David; Hayashi, Genki; Olfson, Emily H.; Feng, Bing-Jian; Pullinger, Clive R.; Kane, John P.; Wise, Carol A.; Goldbach-Mansky, Raphaela; Lowes, Michelle A.; Peddle, Lynette; Chandran, Vinod; Liao, Wilson; Rahman, Proton; Krueger, Gerald G.; Gladman, Dafna; Elder, James T.; Menter, Alan; Bowcock, Anne M.

    2012-01-01

    Psoriasis is a common inflammatory disorder of the skin and other organs. We have determined that mutations in CARD14, encoding a nuclear factor of kappa light chain enhancer in B cells (NF-kB) activator within skin epidermis, account for PSORS2. Here, we describe fifteen additional rare missense variants in CARD14, their distribution in seven psoriasis cohorts (>6,000 cases and >4,000 controls), and their effects on NF-kB activation and the transcriptome of keratinocytes. There were more CARD14 rare variants in cases than in controls (burden test p value = 0.0015). Some variants were only seen in a single case, and these included putative pathogenic mutations (c.424G>A [p.Glu142Lys] and c.425A>G [p.Glu142Gly]) and the generalized-pustular-psoriasis mutation, c.413A>C (p.Glu138Ala); these three mutations lie within the coiled-coil domain of CARD14. The c.349G>A (p.Gly117Ser) familial-psoriasis mutation was present at a frequency of 0.0005 in cases of European ancestry. CARD14 variants led to a range of NF-kB activities; in particular, putative pathogenic variants led to levels >2.5× higher than did wild-type CARD14. Two variants (c.511C>A [p.His171Asn] and c.536G>A [p.Arg179His]) required stimulation with tumor necrosis factor alpha (TNF-α) to achieve significant increases in NF-kB levels. Transcriptome profiling of wild-type and variant CARD14 transfectants in keratinocytes differentiated probably pathogenic mutations from neutral variants such as polymorphisms. Over 20 CARD14 polymorphisms were also genotyped, and meta-analysis revealed an association between psoriasis and rs11652075 (c.2458C>T [p.Arg820Trp]; p value = 2.1 × 10−6). In the two largest psoriasis cohorts, evidence for association increased when rs11652075 was conditioned on HLA-Cw∗0602 (PSORS1). These studies contribute to our understanding of the genetic basis of psoriasis and illustrate the challenges faced in identifying pathogenic variants in common disease. PMID:22521419

  18. The preservative polyquaternium-1 increases cytoxicity and NF-kappaB linked inflammation in human corneal epithelial cells

    Science.gov (United States)

    Paimela, Tuomas; Ryhänen, Tuomas; Kauppinen, Anu; Marttila, Liisa; Salminen, Antero

    2012-01-01

    Purpose In numerous clinical and experimental studies, preservatives present in eye drops have had detrimental effects on ocular epithelial cells. The aim of this study was to compare the cytotoxic and inflammatory effects of the preservative polyquaternium-1 (PQ-1) containing Travatan (travoprost 0.004%) and Systane Ultra eye drops with benzalkonium chloride (BAK) alone or BAK-preserved Xalatan (0.005% latanoprost) eye drops in HCE-2 human corneal epithelial cell culture. Methods HCE-2 cells were exposed to the commercial eye drops Travatan, Systane Ultra, Xalatan, and the preservative BAK. Cell viability was determined using colorimetric MTT (3-(4,5-dimethyldiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and by release of lactate dehydrogenase (LDH). Induction of apoptosis was measured with a using a colorimetric caspase-3 assay kit. DNA binding of the nuclear factor kappa B (NF-κB) transcription factor, and productions of the proinflammatory cytokines, interleukins IL-6 and IL-8, were determined using an enzyme-linked immunosorbent assay (ELISA) method. Results Cell viability, as measured by the MTT assay, declined by up to 50% after exposure to Travatan or Systane Ultra solutions which contain 0.001% PQ-1. BAK at 0.02% rather than at 0.001% concentration evoked total cell death signs on HCE-2 cells. In addition, cell membrane permeability, as measured by LDH release, was elevated by sixfold with Travatan and by a maximum threefold with Systane Ultra. Interestingly, Travatan and Systane Ultra activated NF-κB and elevated the secretion of inflammation markers IL-6 by 3 to eightfold and IL-8 by 1.5 to 3.5 fold, respectively, as analyzed with ELISA. Conclusions Eye drops containing PQ-1 evoke cytotoxicity and enhance the NF-κB driven inflammation reaction in cultured HCE-2 cells. Our results indicate that these harmful effects of ocular solutions preserved with PQ-1 should be further evaluated in vitro and in vivo. PMID:22605930

  19. Natural proteasome inhibitor celastrol suppresses androgen-independent prostate cancer progression by modulating apoptotic proteins and NF-kappaB.

    Directory of Open Access Journals (Sweden)

    Yao Dai

    Full Text Available Celastrol is a natural proteasome inhibitor that exhibits promising anti-tumor effects in human malignancies, especially the androgen-independent prostate cancer (AIPC with constitutive NF-κB activation. Celastrol induces apoptosis by means of proteasome inhibition and suppresses prostate tumor growth. However, the detailed mechanism of action remains elusive. In the current study, we aim to test the hypothesis that celastrol suppresses AIPC progression via inhibiting the constitutive NF-κB activity as well as modulating the Bcl-2 family proteins.We examined the efficacy of celastrol both in vitro and in vivo, and evaluated the role of NF-κB in celastrol-mediated AIPC regression. We found that celastrol inhibited cell proliferation in all three AIPC cell lines (PC-3, DU145 and CL1, with IC₅₀ in the range of 1-2 µM. Celastrol also suppressed cell migration and invasion. Celastrol significantly induced apoptosis as evidenced by increased sub-G1 population, caspase activation and PARP cleavage. Moreover, celastrol promoted cleavage of the anti-apoptotic protein Mcl-1 and activated the pro-apoptotic protein Noxa. In addition, celastrol rapidly blocked cytosolic IκBα degradation and nuclear translocation of RelA. Likewise, celastrol inhibited the expression of multiple NF-κB target genes that are involved in proliferation, invasion and anti-apoptosis. Celastrol suppressed AIPC tumor progression by inhibiting proliferation, increasing apoptosis and decreasing angiogenesis, in PC-3 xenograft model in nude mouse. Furthermore, increased cellular IκBα and inhibited expression of various NF-κB target genes were observed in tumor tissues.Our data suggest that, via targeting the proteasome, celastrol suppresses proliferation, invasion and angiogenesis by inducing the apoptotic machinery and attenuating constitutive NF-κB activity in AIPC both in vitro and in vivo. Celastrol as an active ingredient of traditional herbal medicine could thus be developed as a new therapeutic agent for hormone-refractory prostate cancer.

  20. Regulation of Neph3 gene in podocytes - key roles of transcription factors NF-kappaB and Sp1

    LENUS (Irish Health Repository)

    Ristola, Mervi

    2009-08-24

    Abstract Background Neph3 (filtrin) is expressed in the glomerular podocytes where it localizes at the specialized cell adhesion structures of the foot processes called slit diaphragms which form the outermost layer of the glomerular filtration barrier. Neph3 protein shows homology and structural similarity to Neph1, Neph2 and nephrin, which all are crucial for maintaining the normal glomerular ultrafiltration function. The exact function of Neph3 in the kidney is not known but we have previously shown that the level of Neph3 mRNA is decreased in proteinuric diseases. This suggests that Neph3 may play a role in the pathogenesis of kidney damage, and emphasizes the need to analyze the regulatory mechanisms of Neph3 gene. In this study we investigated the transcriptional regulation of Neph3 gene by identifying transcription factors that control Neph3 expression. Results We cloned and characterized approximately 5 kb fragment upstream of the Neph3 gene. Neph3 proximal promoter near the transcription start site was found to be devoid of TATA and CAAT boxes, but to contain a highly GC-rich area. Using promoter reporter gene constructs, we localized the main activating regulatory region of Neph3 gene in its proximal promoter region from -105 to -57. Within this region, putative transcription factor binding sites for NF-κB and Sp1 were found by computational analysis. Mutational screening indicated that NF-κB and Sp1 response elements are essential for the basal transcriptional activity of the Neph3 promoter. Co-transfection studies further showed that NF-κB and Sp1 regulate Neph3 promoter activity. In addition, overexpression of NF-κB increased endogenous Neph3 gene expression. Chromatin immunoprecipitation assay using cultured human podocytes demonstrated that both NF-κB and Sp1 interact with the Neph3 promoter. Conclusion Our results show that NF-κB and Sp1 are key regulators of Neph3 expression at the basal level in podocytes, therefore providing new insight into the molecular mechanisms that contribute to the expression of Neph3 gene.

  1. Prevalence of Human T-lymphotropic virus type 1 and 2 among blood donors in Manaus, Amazonas State, Brazil

    Directory of Open Access Journals (Sweden)

    Márcia Poinho EncarnaçÃo de Morais

    2017-12-01

    Full Text Available ABSTRACT Introduction: Human T-lymphotropic virus type 1 and 2 (HTLV-1/2 is endemic in Brazil, but few studies have investigated the seroprevalence of HTLV and its subtypes among blood donors in the capital city Manaus, Amazonas State, Brazil. Aim: To estimate the seroprevalence of HTLV-1/2 and to identify circulating subtypes among blood donors in Manaus. Materials and Methods: Blood donors (2001-2003 were screened for HTLV-1/2 antibodies by ELISA. Positive results were confirmed and subtyped by Western blot assays. Prevalence rates were calculated and compared with demographic data. Results: Among the 87,402 individuals screened, 116 (0.13% were seropositive for HTLV-1/2. A second sample (76/116 was collected and retested by HTLV-1/2 ELISA, of which only 41/76 were positive. Western blot confirmed HTLV infection in 24/41 retested blood donors [HTLV-1 (n=16, HTLV-2 (n=5 and HTLV-untypable (n=3]. Discussion: HTLV-1 and HTLV-2 are prevalent among blood donors in Manaus. However, additional studies are needed to comprehend the epidemiology of HTLV-1/2 in Amazonas not only to understand the pathophysiology of the disease providing adequate medical assistance, but also to reduce or block virus transmission.

  2. Fatalt forløbende Strongyloides stercoralis-infektion hos patient uden forudgående kendt immunsuppression

    DEFF Research Database (Denmark)

    Sørensen, M; Andersen, O; Friis-Møller, A

    2000-01-01

    -cell lymphoma were found in a jejunal specimen, and the patient was found to be infected with HTLV-1. Gastrointestinal bleeding in relation to infection with Strongyloides stercoralis is discussed as well as possible relations between the severity of infection, lymphoma and HTLV-1....

  3. Molecular epidemiology of endemic human t-lymphotropic virus type 1 in a rural community in guinea-bissau

    NARCIS (Netherlands)

    C. van Tienen (Carla); T.I. de Silva (Thushan); L.C.J. Alcantara (Luiz); C. Onyango (Clayton); S. Jarju (Sheikh); N. Gonçalves (Nato); T. Vincent (Tim); P. Aaby; H. Whittle (Hilton); M. Schim van der Loeff (Maarten); M. Cotten (Matthew)

    2012-01-01

    textabstractBackground: Human T-Lymphotropic Virus Type 1 (HTLV-1) infection causes lethal adult T-cell leukemia (ATL) and severely debilitating HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in up to 5% of infected adults. HTLV-1 is endemic in parts of Africa and the highest

  4. Molecular Epidemiology of Endemic Human T-Lymphotropic Virus Type 1 in a Rural Community in Guinea-Bissau

    NARCIS (Netherlands)

    van Tienen, Carla; de Silva, Thushan I.; Alcantara, Luiz Carlos Junior; Onyango, Clayton O.; Jarju, Sheikh; Gonçalves, Nato; Vincent, Tim; Aaby, Peter; Whittle, Hilton; Schim van der Loeff, Maarten; Cotten, Matthew

    2012-01-01

    Background: Human T-Lymphotropic Virus Type 1 (HTLV-1) infection causes lethal adult T-cell leukemia (ATL) and severely debilitating HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in up to 5% of infected adults. HTLV-1 is endemic in parts of Africa and the highest prevalence in

  5. Tax relieves transcriptional repression by promoting histone deacetylase 1 release from the human T-cell leukemia virus type 1 long terminal repeat.

    Science.gov (United States)

    Lu, Hanxin; Pise-Masison, Cynthia A; Linton, Rebecca; Park, Hyeon Ung; Schiltz, R Louis; Sartorelli, Vittorio; Brady, John N

    2004-07-01

    Expression of human T-cell leukemia virus type 1 (HTLV-1) is regulated by the viral transcriptional activator Tax. Tax activates viral transcription through interaction with the cellular transcription factor CREB and the coactivators CBP/p300. In this study, we have analyzed the role of histone deacetylase 1 (HDAC1) on HTLV-1 gene expression from an integrated template. First we show that trichostatin A, an HDAC inhibitor, enhances Tax expression in HTLV-1-transformed cells. Second, using a cell line containing a single-copy HTLV-1 long terminal repeat, we demonstrate that overexpression of HDAC1 represses Tax transactivation. Furthermore, a chromatin immunoprecipitation assay allowed us to analyze the interaction of transcription factors, coactivators, and HDACs with the basal and activated HTLV-1 promoter. We demonstrate that HDAC1 is associated with the inactive, but not the Tax-transactivated, HTLV-1 promoter. In vitro and in vivo glutathione S-transferase-Tax pull-down and coimmunoprecipitation experiments demonstrated that there is a direct physical association between Tax and HDAC1. Importantly, biotinylated chromatin pull-down assays demonstrated that Tax inhibits and/or dissociates the binding of HDAC1 to the HTLV-1 promoter. Our results provide evidence that Tax interacts directly with HDAC1 and regulates binding of the repressor to the HTLV-1 promoter.

  6. Are lipid disorders involved in the predominance of human T-lymphotropic virus-1 infections in women?

    Directory of Open Access Journals (Sweden)

    Luciana Debortoli de Carvalho

    2015-12-01

    Full Text Available Abstract INTRODUCTION : The human T-lymphotropic virus-1 (HTLV-1 is associated with chronic inflammatory diseases such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP, a chronic inflammatory disease. Disturbances in lipid metabolism are involved in inflammatory and demyelinating diseases. METHODS : Plasma levels of triglycerides, total cholesterol, and fractions of HTLV-1-infected individuals of both sexes with different clinical progressions were determined. RESULTS : Elevated levels of triglyceride and very low-density lipoproteins (VLDL were exclusively detected in HTLV-1-infected women from asymptomatic and HAM/TSP groups compared with uninfected individuals (p = 0.02. CONCLUSIONS : Elevated triglyceride and VLDL levels in HTLV-1-infected women may be related to the predominance of HAM/TSP in women.

  7. NLRP3 polymorphism is associated with protection against human T-lymphotropic virus 1 infection

    Directory of Open Access Journals (Sweden)

    Anselmo Jiro Kamada

    2014-11-01

    Full Text Available Inter-individual heterogeneity in the response to human T-lymphotropic virus 1 (HTLV-1 infection has been partially attributed to host genetic background. The antiviral activity of the inflammasome cytoplasmic complex recognises viral molecular patterns and regulates immune responses via the activation of interleukin (IL-1 family (IL-1, IL-18 and IL-33 members. The association between polymorphisms in the inflammasome receptors NLRP1 and NLRP3 and HTLV-1 infection was evaluated in a northeastern Brazilian population (84 HTLV-1 carriers and 155 healthy controls. NLRP3 rs10754558 G/G was associated with protection against HTLV-1 infection (p = 0.012; odds ratio = 0.37. rs10754558 affects NLRP3 mRNA stability; therefore, our results suggest that higher NLRP3 expression may augment first-line defences, leading to the effective protection against HTLV-1 infection.

  8. Incidence of adult T-cell leukemia/lymphoma in nonendemic areas.

    Science.gov (United States)

    Yoshida, Noriaki; Chihara, Dai

    2015-02-01

    Adult T-cell leukemia/lymphoma (ATLL) is a mature T-cell neoplasm with extremely poor prognosis caused by human T-cell leukemia virus type 1 (HTLV-1). The distribution of HTLV-1 and the incidence of ATLL in endemic areas have been well described, however, little is known about the incidences and the trends of the disease in nonendemic areas. Recently, studies have shown that the HTLV-1 carriers are increasing in nonendemic areas. Also, the incidence of ATLL seems to be significantly increasing in nonendemic areas suggesting that HTLV-1 carriers have emigrated from endemic areas. These epidemiologic studies indicate the necessity of edification of the disease caused by HTLV-1 and establishing appropriate preventive methods against infection in nonendemic areas.

  9. Molecular Determinants of Human T-lymphotropic Virus Type 1 Transmission and Spread

    Directory of Open Access Journals (Sweden)

    Patrick L. Green

    2011-07-01

    Full Text Available Human T-lymphotrophic virus type-1 (HTLV-1 infects approximately 15 to 20 million people worldwide, with endemic areas in Japan, the Caribbean, and Africa. The virus is spread through contact with bodily fluids containing infected cells, most often from mother to child through breast milk or via blood transfusion. After prolonged latency periods, approximately 3 to 5% of HTLV-1 infected individuals will develop either adult T-cell leukemia/lymphoma (ATL, or other lymphocyte-mediated disorders such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP. The genome of this complex retrovirus contains typical gag, pol, and env genes, but also unique nonstructural proteins encoded from the pX region. These nonstructural genes encode the Tax and Rex regulatory proteins, as well as novel proteins essential for viral spread in vivo such as, p30, p12, p13 and the antisense encoded HBZ. While progress has been made in the understanding of viral determinants of cell transformation and host immune responses, host and viral determinants of HTLV-1 transmission and spread during the early phases of infection are unclear. Improvements in the molecular tools to test these viral determinants in cellular and animal models have provided new insights into the early events of HTLV-1 infection. This review will focus on studies that test HTLV-1 determinants in context to full length infectious clones of the virus providing insights into the mechanisms of transmission and spread of HTLV-1.

  10. Seroprevalence of human T-cell lymphotropic virus-1/2 in blood donors in northern pakistan: implication for blood donor screening

    International Nuclear Information System (INIS)

    Niazi, S.K.

    2015-01-01

    To determine the seroprevalence of Human T-cell Lymphotropic Virus-1/2 (HTLV-1/2) in blood donors in Northern Pakistan. Study Design: Descriptive study. Place and Duration of Study: Armed Forces Institute of Transfusion, Rawalpindi, from July to August 2013. Methodology:A total of 2100 blood donors were screened for anti-HTLV-1/2 antibodies during the study period, in a pool of six, on a highly sensitive, Chemiluminiscent Microparticle Immunoassay (CMIA) based system. The screening test reactive donors were recalled, counseled and interviewed, and a fresh sample was obtained for confirmatory testing. Confirmation was performed using additional immunoassays including Line Immunoassay (LIA); with additional testing for HTLV-1 pvDNAPCR. Frequency and percentages were determined. Results: Four donors (0.19%) were repeatedly screening test-reactive and were subsequently confirmed to be HTLV-1 infected by line immunoassay and HTLV-1 pvDNAPCR. All four donors were male with mean age of 27 ± 6.27 years. Two (50%) of the positive donors gave history of Multiple Sexual Partners (MSP). Conclusion: HTLV-1 seroprevalence in Northern Pakistan blood donors was determined to be 0.19%. Large scale studies, including the cost effectiveness of screening blood donations for anti-HTLV-1/2 in Pakistan, are recommended. (author)

  11. Alteration of blood-brain barrier integrity by retroviral infection.

    Directory of Open Access Journals (Sweden)

    Philippe V Afonso

    2008-11-01

    Full Text Available The blood-brain barrier (BBB, which forms the interface between the blood and the cerebral parenchyma, has been shown to be disrupted during retroviral-associated neuromyelopathies. Human T Lymphotropic Virus (HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP is a slowly progressive neurodegenerative disease associated with BBB breakdown. The BBB is composed of three cell types: endothelial cells, pericytes and astrocytes. Although astrocytes have been shown to be infected by HTLV-1, until now, little was known about the susceptibility of BBB endothelial cells to HTLV-1 infection and the impact of such an infection on BBB function. We first demonstrated that human cerebral endothelial cells express the receptors for HTLV-1 (GLUT-1, Neuropilin-1 and heparan sulfate proteoglycans, both in vitro, in a human cerebral endothelial cell line, and ex vivo, on spinal cord autopsy sections from HAM/TSP and non-infected control cases. In situ hybridization revealed HTLV-1 transcripts associated with the vasculature in HAM/TSP. We were able to confirm that the endothelial cells could be productively infected in vitro by HTLV-1 and that blocking of either HSPGs, Neuropilin 1 or Glut1 inhibits this process. The expression of the tight-junction proteins within the HTLV-1 infected endothelial cells was altered. These cells were no longer able to form a functional barrier, since BBB permeability and lymphocyte passage through the monolayer of endothelial cells were increased. This work constitutes the first report of susceptibility of human cerebral endothelial cells to HTLV-1 infection, with implications for HTLV-1 passage through the BBB and subsequent deregulation of the central nervous system homeostasis. We propose that the susceptibility of cerebral endothelial cells to retroviral infection and subsequent BBB dysfunction is an important aspect of HAM/TSP pathogenesis and should be considered in the design of future therapeutics strategies.

  12. Strongyloidiasis and infective dermatitis alter human T lymphotropic virus-1 clonality in vivo.

    Directory of Open Access Journals (Sweden)

    Nicolas A Gillet

    Full Text Available Human T-lymphotropic Virus-1 (HTLV-1 is a retrovirus that persists lifelong by driving clonal proliferation of infected T-cells. HTLV-1 causes a neuroinflammatory disease and adult T-cell leukemia/lymphoma. Strongyloidiasis, a gastrointestinal infection by the helminth Strongyloides stercoralis, and Infective Dermatitis associated with HTLV-1 (IDH, appear to be risk factors for the development of HTLV-1 related diseases. We used high-throughput sequencing to map and quantify the insertion sites of the provirus in order to monitor the clonality of the HTLV-1-infected T-cell population (i.e. the number of distinct clones and abundance of each clone. A newly developed biodiversity estimator called "DivE" was used to estimate the total number of clones in the blood. We found that the major determinant of proviral load in all subjects without leukemia/lymphoma was the total number of HTLV-1-infected clones. Nevertheless, the significantly higher proviral load in patients with strongyloidiasis or IDH was due to an increase in the mean clone abundance, not to an increase in the number of infected clones. These patients appear to be less capable of restricting clone abundance than those with HTLV-1 alone. In patients co-infected with Strongyloides there was an increased degree of oligoclonal expansion and a higher rate of turnover (i.e. appearance and disappearance of HTLV-1-infected clones. In Strongyloides co-infected patients and those with IDH, proliferation of the most abundant HTLV-1⁺ T-cell clones is independent of the genomic environment of the provirus, in sharp contrast to patients with HTLV-1 infection alone. This implies that new selection forces are driving oligoclonal proliferation in Strongyloides co-infection and IDH. We conclude that strongyloidiasis and IDH increase the risk of development of HTLV-1-associated diseases by increasing the rate of infection of new clones and the abundance of existing HTLV-1⁺ clones.

  13. A Novel Human T-lymphotropic Virus Type 1c Molecular Variant in an Indigenous Individual from New Caledonia, Melanesia.

    Directory of Open Access Journals (Sweden)

    Olivier Cassar

    2017-01-01

    Full Text Available Human T-Lymphotropic Virus type 1 (HTLV-1 is endemic among people of Melanesian descent in Papua New Guinea, Solomon Islands and Vanuatu, and in Indigenous populations from Central Australia. Molecular studies revealed that these Australo-Melanesian strains constitute the highly divergent HTLV-1c subtype. New Caledonia is a French overseas territory located in the Southwest Pacific Ocean. HTLV-1 situation is poorly documented in New Caledonia and the molecular epidemiology of HTLV-1 infection remains unknown.Studying 500 older adults Melanesian natives from New Caledonia, we aim to evaluate the HTLV-1 seroprevalence and to molecularly characterize HTLV-1 proviral strains.Plasma from 262 men and 238 females (age range: 60-96 years old, mean age: 70.5 were screened for anti-HTLV-1 antibodies by particle agglutination (PA and indirect immunofluorescence assay (IFA. Serological confirmation was obtained using Western blot assay. DNAs were extracted from peripheral blood buffy coat of HTLV-1 seropositive individuals, and subjected to four series of PCR (LTR-gag; pro-pol; pol-env and tax-LTR. Primers were designed from highly common conserved regions of the major HTLV-1 subtypes to characterize the entire HTLV-1 proviral genome.Among 500 samples, 3 were PA and IFA positive. The overall seroprevalence was 0.6%. The DNA sample from 1 New Caledonian woman (NCP201 was found positive by PCR and the complete HTLV-1 proviral genome (9,033-bp was obtained. The full-length HTLV-1 genomic sequence from a native woman from Vanuatu (EM5, obtained in the frame of our previous studies, was also characterized. Both sequences belonged to the HTLV-1c Australo-Melanesian subtype. The NCP201 strain exhibited 0.3% nucleotide divergence with the EM5 strain from Vanuatu. Furthermore, divergence reached 1.1% to 2.9% with the Solomon and Australian sequences respectively. Phylogenetic analyses on a 522-bp-long fragment of the gp21-env gene showed the existence of two major

  14. Biopsia por aspiración con aguja fina (BAAF) para el diagnóstico de linfoma no hodking cutáneo asociado a HTLV I-II. Presentación de caso.

    OpenAIRE

    Núñez Carrión., Ericka Cecilia

    2010-01-01

    INTRODUCCIÓN: El HTLV-1 es el primer retrovirus oncógeno humano que fue aislado por vez primera. Más tarde se demostró que el virus del linfoma leucemia de células T humanas (HTLV-1) era el agente causal de la Leucemia/linfoma de células T del adulto (ATL). EL HTLV-1 es más común en Japón y en el Caribe que en los Estados Unidos. También se ha descrito posteriormente en varios países latinoamericanos incluyendo Perú. El HTLV-1 pertenece a la familia de los retrovirus humanos, con tropismo pos...

  15. Human T-cell lymphotropic virus type 1 provirus and phylogenetic analysis in patients with mycosis fungoides and their family relatives.

    Science.gov (United States)

    Shohat, M; Shohat, B; Mimouni, D; Pauli, G; Ellerbrok, H; David, M; Hodak, E

    2006-08-01

    Mycosis fungoides (MF) is a cutaneous T-cell lymphoma of unknown aetiology. A pathogenic role of human T-cell lymphotropic virus type 1 (HTLV-1) has been suggested but remains controversial. To determine whether MF is linked to HTLV-1. Blood samples were collected from 60 patients, 15 family relatives of patients with MF (MFRs), 20 healthy controls and 10 patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The presence of HTLV-1 antibodies in serum was tested by the Western blot rp21e-enhanced test. DNA was extracted from the blood with the Qiagen blood kit. We used 500 ng of DNA either in conventional HTLV-1-specific polymerase chain reaction (PCR) or in real-time PCR using primers sk43 and sk44 together with a tax-specific fluorescent probe. In Western blot, antibodies against three to four HTLV-1 antigens were detected in 52% of patients with MF. All of the patients with HAM/TSP were positive, while only 7% of the MFRs and none of the 20 healthy controls reacted with HTLV-1 antigens in Western blot. One of 60 patients with MF and one of 15 MFRs were positive in HTLV-1 PCR. These two PCR-positive samples which were quantified in real-time PCR showed that fewer than five in 10(6) cells were HTLV-1 infected. We succeeded in amplifying and sequencing the 5' end of the provirus from the blood of the PCR-positive MFR by seminested PCR. A positive result was also obtained in this test. Phylogenetic tree analyses revealed a high homology of this sequence with other HTLV-1 sequences from the Middle East. The above PCR-positive MFR was the brother of a PCR-negative patient with MF. These findings demonstrate that HTLV-1 is probably not the aetiological agent of MF. However, it may play a role in immunosuppression and in the spreading of the disease.

  16. Selective histonedeacetylase inhibitor M344 intervenes in HIV-1 latency through increasing histone acetylation and activation of NF-kappaB.

    Directory of Open Access Journals (Sweden)

    Hao Ying

    Full Text Available Histone deacetylase (HDAC inhibitors present an exciting new approach to activate HIV production from latently infected cells to potentially enhance elimination of these cells and achieve a cure. M344, a novel HDAC inhibitor, shows robust activity in a variety of cancer cells and relatively low toxicity compared to trichostatin A (TSA. However, little is known about the effects and action mechanism of M344 in inducing HIV expression in latently infected cells.Using the Jurkat T cell model of HIV latency, we demonstrate that M344 effectively reactivates HIV-1 gene expression in latently infected cells. Moreover, M344-mediated activation of the latent HIV LTR can be strongly inhibited by a NF-κB inhibitor aspirin. We further show that M344 acts by increasing the acetylation of histone H3 and histone H4 at the nucleosome 1 (nuc-1 site of the HIV-1 long terminal repeat (LTR and by inducing NF-κB p65 nuclear translocation and direct RelA DNA binding at the nuc-1 region of the HIV-1 LTR. We also found that M344 synergized with prostratin to activate the HIV-1 LTR promoter in latently infected cells.These results suggest the potential of M344 in anti-latency therapies and an important role for histone modifications and NF-κB transcription factors in regulating HIV-1 LTR gene expression.

  17. Gene expression profiling of anti-GBM glomerulonephritis model: the role of NF-kappaB in immune complex kidney disease.

    Science.gov (United States)

    Kim, Ju Han; Ha, Il Soo; Hwang, Chang-Il; Lee, Young-Ju; Kim, Jihoon; Yang, Seung-Hee; Kim, Yon Su; Cao, Yun Anna; Choi, Sangdun; Park, Woong-Yang

    2004-11-01

    Immune complexes may cause an irreversible onset of chronic renal disease. Most patients with chronic renal disease undergo a final common pathway, marked by glomerulosclerosis and interstitial fibrosis. We attempted to draw a molecular map of anti-glomerular basement membrane (GBM) glomerulonephritis in mice using oligonucleotide microarray technology. Kidneys were harvested at days 1, 3, 7, 11, and 16 after inducing glomerulonephritis by using anti-GBM antibody. In parallel with examining the biochemical and histologic changes, gene expression profiles were acquired against five pooled control kidneys. Gene expression levels were cross-validated by either reverse transcription-polymerase chain reaction (RT-PCR), real-time PCR, or immunohistochemistry. Pathologic changes in anti-GBM glomerulonephritis were confirmed in both BALB/c and C57BL/6 strains. Among the 13,680 spotted 65mer oligonucleotides, 1112 genes showing significant temporal patterns by permutation analysis of variance (ANOVA) with multiple testing correction [false discovery ratio (FDR) mouse anti-GBM glomerulonephritis model, providing a comprehensive overview on the mechanism governing the initiation and the progression of inflammatory renal disease.

  18. Celastrol ameliorates HIV-1 Tat-induced inflammatory responses via NF-kappaB and AP-1 inhibition and heme oxygenase-1 induction in astrocytes

    International Nuclear Information System (INIS)

    Youn, Gi Soo; Kwon, Dong-Joo; Ju, Sung Mi; Rhim, Hyangshuk; Bae, Yong Soo; Choi, Soo Young; Park, Jinseu

    2014-01-01

    HIV-1 Tat causes extensive neuroinflammation that may progress to AIDS-related encephalitis and dementia. Celastrol possesses various biological activities such as anti-oxidant, anti-tumor, and anti-inflammatory activities. In this study, we investigated the modulatory effects of celastrol on HIV-1 Tat-induced inflammatory responses and the molecular mechanisms underlying its action in astrocytes. Pre-treatment of CRT-MG human astroglioma cells with celastrol significantly inhibited HIV-1 Tat-induced expression of ICAM-1/VCAM-1 and subsequent monocyte adhesiveness in CRT-MG cells. In addition, celastrol suppressed HIV-1 Tat-induced expression of pro-inflammatory chemokines, such as CXCL10, IL-8, and MCP-1. Celastrol decreased HIV-1 Tat-induced activation of JNK MAPK, AP-1, and NF-κB. Furthermore, celastrol induced mRNA and protein expression of HO-1 as well as Nrf2 activation. Blockage of HO-1 expression using siRNA reversed the inhibitory effect of celastrol on HIV-1 Tat-induced inflammatory responses. These results suggest that celastrol has regulatory effects on HIV-1 Tat-induced inflammatory responses by blocking the JNK MAPK-AP-1/NF-κB signaling pathways and inducing HO-1 expression in astrocytes. - Highlights: • Celastrol suppressed HIV-1 Tat-induced expression of pro-inflammatory genes. • Celastrol inhibited HIV-1 Tat -induced activation of JNK MAPK. • Celastrol inhibited HIV-1 Tat-induced activation of both NF-κB and AP-1. • Celastrol inhibited HIV-1 Tat-induced inflammatory responses via HO-1 induction

  19. Constitutive Activation of NF-kappaB in Prostate Carcinoma Cells Through a Positive Feedback Loop: Implication of Inducible IKK-Related Kinase (IKKi)

    National Research Council Canada - National Science Library

    Budunova, Irina V

    2004-01-01

    The overall goal of this project is to understand the role of inducible IKK-related kinase IKKi in constitutive activation of anti-apoptotic transcription factor NF-kB prostate carcinoma (PC) cells...

  20. Suppressor of cytokine signaling 1 (SOCS1) limits NFkappaB signaling by decreasing p65 stability within the cell nucleus.

    Science.gov (United States)

    Strebovsky, Julia; Walker, Patrick; Lang, Roland; Dalpke, Alexander H

    2011-03-01

    Suppressor of cytokine signaling (SOCS) proteins are inhibitors of cytoplasmic Janus kinases (Jak) and signal transducer and activator of transcription (STAT) signaling pathways. Previously the authors surprisingly observed that SOCS1 translocated into the nucleus, which was because of the presence of a nuclear localization sequence. This report now hypothesizes that SOCS1 mediates specific functions within the nuclear compartment because it is instantly transported into the nucleus, as shown by photoactivation and live cell imaging in human HEK293 cells. The NFκB component p65 is identified as an interaction partner for SOCS1 but not for other members of the SOCS family. SOCS1 bound to p65 only within the nucleus. By means of its SOCS box domain, SOCS1 operated as a ubiquitin ligase, leading to polyubiquitination and proteasomal degradation of nuclear p65. Thus, SOCS1 limited prolonged p65 signaling and terminated expression of NFκB inducible genes. Using mutants that lack either nuclear translocation or a functional SOCS box, this report identifies genes that are regulated in a manner dependent on the nuclear availability of SOCS1. Data show that beyond its receptor-proximal function in Jak/STAT signaling, SOCS1 also regulates the duration of NFκB signaling within the cell nucleus, thus exerting a heretofore unrecognized function.

  1. Effects of Low-Dose Aspirin and Fish Oil on Platelet Function and NF-kappaB in Adults with Diabetes Mellitus

    Science.gov (United States)

    Block, Robert C; Abdolahi, Amir; Smith, Brian; Meednu, N; Thevenet-Morrison, Kelly; Cai, Xueya; Cui, Huadong; Mousa, Shaker; Brenna, J. Thomas; Georas, S

    2013-01-01

    SUMMARY Introduction Many diabetics are insensitive to aspirin’s platelet anti-aggregation effects. The possible modulating effects of coadministration of aspirin and fish oil in subjects with diabetes are poorly characterized. Participants and Methods Thirty adults with type 2 diabetes mellitus were treated with aspirin 81 mg/d for 7 days, then with fish oil 4g/day for 28 days, then the combination of fish oil and aspirin for another 7 days. Results Aspirin alone and in combination with fish oil reduced platelet aggregation in most participants. Five of 7 participants classified as aspirin insensitive 1 week after daily aspirin ingestion were sensitive after the combination. Although some platelet aggregation measures correlated positively after aspirin and fish oil ingestion alone and (in combination) in all individuals, correlation was only observed in those who were aspirin insensitive after ingestion of the combination. Conclusions Co-adminstration of aspirin and fish oil may reduce platelet aggregation more than aspirin alone in adults with diabetes mellitus. PMID:23664596

  2. Assessment of Nanobiotechnology-Targeted siRNA Designed to Inhibit NF-kappaB Classical And Alternative Signaling in Breast Tumor Macrophages

    Science.gov (United States)

    2012-07-01

    S2. In a round-bottom flask, 11 g of D-mannose (60 mmol) were dissolved into 30 mL dimethylsulfoxide ( DMSO ). To activate the sugar into a...insoluble phase was dissolved into nanopure water and further extracted 5X with dichloromethane to remove other byproducts and DMSO . The product was... solvent (90 wt% in feed), an initial monomer-to-CTA molar ratio of 100, and a CTA to initiator molar ratio of 10. After rapidly cooling the reaction in

  3. Respiratory syncytial virus and TNFalpha induction of chemokine gene expression involves differential activation of Rel A and NF-kappaB1

    Directory of Open Access Journals (Sweden)

    Roebuck Kenneth A

    2002-03-01

    Full Text Available Abstract Background Respiratory syncytial virus (RSV infection of airway epithelial cells stimulates the expression and secretion of a variety of cytokines including the chemotactic cytokines interleukin-8 (IL-8, monocyte chemoattractant protein-1 (MCP-1, and RANTES (regulated upon activation, normal T cell expressed and secreted. Chemokines are important chemoattractants for the recruitment of distinct sets of leukocytes to airway sites of inflammation. Results We have shown previously that chemokine expression is regulated in airway epithelial cells (A549 in a stimulus-specific manner in part through the redox-responsive transcription factors AP-1 and NF-κB. In this study, we examined the NF-κB-mediated effects of RSV and the proinflammatory cytokine TNFα on the induction of IL-8, MCP-1 and RANTES chemokine gene expression in A549 epithelial cells. The results demonstrate that RSV induces chemokine expression with distinct kinetics that is associated with a specific pattern of NF-κB binding activity. This distinction was further demonstrated by the differential effects of the NF-κB inhibitors dexamethasone (DEX and N-acetyl-L-cysteine (NAC. NAC preferentially inhibited RSV induced chemokine expression, whereas DEX preferentially inhibited TNFα induced chemokine expression. DNA binding studies using NF-κB subunit specific binding ELISA demonstrated that RSV and TNFα induced different NF-κB binding complexes containing Rel A (p65 and NF-κB1 (p50. Both TNFα and RSV strongly induced Rel A the activation subunit of NF-κB, whereas only TNFα was able to substantially induce the p50 subunit. Consistent with the expression studies, RSV but not TNFα induction of Rel A and p50 were markedly inhibited by NAC, providing a mechanism by which TNFα and RSV can differentially activate chemokine gene expression via NF-κB. Conclusions These data suggest that RSV induction of chemokine gene expression, in contrast to TNFα, involves redox-sensitive NF-κB complexes containing predominantly Rel A.

  4. Assessment of Nanobiotechnology-Targeted siRNA Designed to inhibit NF-kappaB Classical and Alternative Signaling in Breast Tumor Macrophages

    Science.gov (United States)

    2013-07-01

    LOCATION DEGREE (if applicable) YEAR(s) FIELD OF STUDY Capital Normal University, Beijing, China B.S 1992- 1996 Biology West Virginia University...of Food Science & Nutritional Engineering, China Agricultural University, Beijing. China . 2009-Pres Research Assistant, Dept. Cancer Biology...play an important function in educating immune cells and controlling angiogenesis. Gabriel Rabinovich (Insti- tuto de Biologica y Medicina Experimental

  5. In Vivo Multimodal Imaging of NF-kappaB (pB) Spatial and Temporal Activation Following Light Injury in the Mouse Retina

    Science.gov (United States)

    2014-01-15

    breathing artifacts in retinal images. The cSLO fea- tures one argon wavelength (488 nm) and two infrared diode lasers (790/820 nm) which were used to...Engineering Heuy-Ching H Wang United States Army of Institutes of Surgical Research January 15, 2014 Interim Report for January 2010 to January...transgenic mouse model were used to perform in vivo experiments of laser - induced thermal damage to the retina. A Heidelberg Spectralis HRA confocal

  6. Adrenergic regulation during acute hepatic infection with Entamoeba histolytica in the hamster: involvement of oxidative stress, Nrf2 and NF-KappaB

    Directory of Open Access Journals (Sweden)

    Aldaba-Muruato Liseth Rubi

    2017-01-01

    Full Text Available Oxidative stress and transcriptional pathways of nuclear factor erythroid 2-related factor 2 (Nrf2 and nuclear factor kappa-B (NF-κB are critically involved in the etiopathology of amebic liver abscess (ALA. In this work, we studied the relationship between the adrenergic nervous system and ALA in the hamster. ALA was visible at 12 h of infection. While 6-hydroxidopamine (6-OHDA decreased infection, propranolol (β-adrenergic blocker treatment was associated with less extensive liver damage, and phentolamine treatment (α-adrenergic blocker significantly reduced ALA compared to 6-OHDA and propranolol. Serum enzymatic activities of alanine aminotransferase (ALT and γ-glutamyl transpeptidase (γ-GTP were increased at 12 h post-infection. Chemical denervation and α and β-adrenergic blockers decreased ALT to normal levels, while 6-OHDA and propranolol showed a trend to decrease γ-GTP but phentolamine significantly reduced γ-GTP. Amebic infection increased oxidized glutathione (GSSG and decreased both reduced glutathione (GSH and the GSH/GSSG ratio. Propranolol and 6-OHDA showed a tendency to decrease GSSG. However, GSH, GSSG and GSH/GSSG returned to normal levels with phentolamine. Furthermore, amebic infection increased pNF-κB and interleukin-1β (IL-1β, and showed a tendency to decrease hemoxigenase-1 (HO-1, but not Nrf2. Chemical denervation showed a trend to decrease pNF-κB and IL-1β, and neither Nrf2 nor HO-1 increased significantly. In addition, NF-κB and IL-1β were attenuated by propranolol and phentolamine treatments, although phentolamine showed significant overexpression of Nrf2 and HO-1. This suggests that the adrenergic system may be involved in oxidative stress and in modulation of the Nrf2 and NF-κB pathways during ALA development.

  7. Lipid-soluble smoke particles upregulate vascular smooth muscle ETB receptors via activation of mitogen-activating protein kinases and NF-kappaB pathways

    DEFF Research Database (Denmark)

    Xu, C.B.; Zheng, J.P.; Zhang, W.

    2008-01-01

    Cigarette smoke is a strong risk factor for cardiovascular disease. However, the underlying molecular mechanisms that lead to cigarette smoke-associated cardiovascular disease remain elusive. With functional and molecular methods, we demonstrate for the first time that lipid-soluble cigarette smoke...... particles (dimethylsulfoxide-soluble cigarette smoke particles; DSP) increased the expression of endothelin type B (ET(B)) receptors in arterial smooth muscle cells. The increased ET(B) receptors in arterial smooth muscle cells was documented as enhanced contractility (sensitive myograph technique...

  8. Diabetes mellitus tipo 2: qual o papel da insulina na expressão de NF-kappaB, PPARγ e CD36?

    Directory of Open Access Journals (Sweden)

    Cristina de Oliveira SILVA

    2014-12-01

    Full Text Available No diabetes mellitus tipo 2 (DM2 e na síndrome de resistência à insulina, as complicações cardiovasculares resultam de um conjunto de processos aterogênicos envolvendo hiperglicemia crônica, excessiva glicação de proteínas (AGEs, ativação do fator nuclear kappa B (NKκB associada com o aumento da expressão de citocinas inflamatórias e estresse oxidativo, observando-se ainda alteração de LDL e expressão do receptor de scavenger CD36. A contribuição da hiperinsulinemia nesta sequência não é completamente elucidada. Nesta revisão, relata-se como a insulina pode modular a expressão proteica de NFκB, PPAR gama (PPARγ e CD36 em células da musculatura lisa vascular (CMLV da aorta de ratos estimuladas pelos AGE.

  9. Logical network of genotoxic stress-induced NF-kappaB signal transduction predicts putative target structures for therapeutic intervention strategies

    Directory of Open Access Journals (Sweden)

    Rainer Poltz

    2009-12-01

    Full Text Available Rainer Poltz1, Raimo Franke1,#, Katrin Schweitzer1, Steffen Klamt2, Ernst-Dieter Gilles2, Michael Naumann11Institute of Experimental Internal Medicine, Otto von Guericke University, Magdeburg, Germany; 2Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany; #Present address: Department of Chemical Biology, Helmholtz Centre for Infection Research, Braunschweig, GermanyAbstract: Genotoxic stress is induced by a broad range of DNA-damaging agents and could lead to a variety of human diseases including cancer. DNA damage is also therapeutically induced for cancer treatment with the aim to eliminate tumor cells. However, the effectiveness of radio- and chemotherapy is strongly hampered by tumor cell resistance. A major reason for radio- and chemotherapeutic resistances is the simultaneous activation of cell survival pathways resulting in the activation of the transcription factor nuclear factor-kappa B (NF-κB. Here, we present a Boolean network model of the NF-κB signal transduction induced by genotoxic stress in epithelial cells. For the representation and analysis of the model, we used the formalism of logical interaction hypergraphs. Model reconstruction was based on a careful meta-analysis of published data. By calculating minimal intervention sets, we identified p53-induced protein with a death domain (PIDD, receptor-interacting protein 1 (RIP1, and protein inhibitor of activated STAT y (PIASy as putative therapeutic targets to abrogate NF-κB activation resulting in apoptosis. Targeting these structures therapeutically may potentiate the effectiveness of radio- and chemotherapy. Thus, the presented model allows a better understanding of the signal transduction in tumor cells and provides candidates as new therapeutic target structures.Keywords: apoptosis, Boolean network, cancer therapy, DNA-damage response, NF-κB

  10. Asymmetric dimethylarginine regulates the lipopolysaccharide-induced nitric oxide production in macrophages by suppressing the activation of NF-kappaB and iNOS expression

    Czech Academy of Sciences Publication Activity Database

    Pekarová, Michaela; Kubala, Lukáš; Martíšková, Hana; Binó, Lucia; Twarogová, M.; Klinke, A.; Rudolph, T.K.; Kuchtová, Z.; Kolářová, Hana; Ambrožová, Gabriela; Kuchta, R.; Kadlec, J.; Lojek, Antonín

    2013-01-01

    Roč. 713, 1-3 (2013), s. 68-77 ISSN 0014-2999 R&D Projects: GA ČR(CZ) GP13-40882P Institutional research plan: CEZ:AV0Z50040702 Institutional support: RVO:68081707 Keywords : Macrophage * Methylarginine * Asymmetric dimethylarginine Subject RIV: BO - Biophysics Impact factor: 2.684, year: 2013

  11. Regulation of NF-kappaB activity and inducible nitric oxide synthase by regulatory particle non-ATPase subunit 13 (Rpn13)

    DEFF Research Database (Denmark)

    Mazumdar, Tuhina; Gorgun, F Murat; Sha, Youbao

    2010-01-01

    Human Rpn13, also known as adhesion regulating molecule 1 (ADRM1), was recently identified as a novel 19S proteasome cap-associated protein, which recruits the deubiquitinating enzyme UCH37 to the 26S proteasome. Knockdown of Rpn13 by siRNA does not lead to global accumulation of ubiquitinated ce......, this study defines two substrates, with important roles in inflammation and host defense for the Rpn13/UCH37 pathway....

  12. Vav-1 expression correlates with NFkappaB activation and CD40-mediated cell death in diffuse large B-cell lymphoma cell lines

    DEFF Research Database (Denmark)

    Hollmann, Annette; Aloyz, Raquel; Baker, Kristi

    2010-01-01

    Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy with a variable response to therapy. We have previously shown that DLBCL cell lines differ in their susceptibility to CD40-mediated cell death, and that resistance to CD40-targeted antibodies correlated with increased expression...... as a potential marker to identify tumours likely to respond to CD40-targeted therapies. Copyright (c) 2010 John Wiley & Sons, Ltd....

  13. Assessment of Nanobiotechnology-Targeted siRNA Designed to Inhibit NF-KappaB Classical and Alternative Signaling in Breast Tumor Macrophages

    Science.gov (United States)

    2014-07-01

    Intraductal Injection of LPS as a Mouse Model of Mastitis : Signaling Visualized via an NF-κB Reporter Transgenic. J Vis Exp. (67). pii: 4030. 2012. PMID...injection of LPS as a mouse model of mastitis : signaling visualized via an NF-κB reporter transgenic. Journal of Visualized Experiments 2012. 4(67...supplies, including media, fetal bovine serum, antibiotics, and nonessential amino acids, were obtained from Life Technologies (Carlsbad, CA). The

  14. Cadmium induces cytotoxicity in human bronchial epithelial cells through upregulation of eIF5A1 and NF-kappaB

    Energy Technology Data Exchange (ETDEWEB)

    Chen, De-Ju; Xu, Yan-Ming; Du, Ji-Ying [Laboratory of Cancer Biology and Epigenetics, Shantou University Medical College, Shantou, Guangdong 515041 (China); Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong 515041 (China); Huang, Dong-Yang [Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong 515041 (China); Lau, Andy T.Y., E-mail: andytylau@stu.edu.cn [Laboratory of Cancer Biology and Epigenetics, Shantou University Medical College, Shantou, Guangdong 515041 (China); Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong 515041 (China)

    2014-02-28

    Highlights: • Normal human bronchial epithelial cells (BEAS-2B) were dosed with cadmium (Cd). • A low level (2 μM) of Cd treatment for 36 h elicited negligible cytotoxicity. • High levels (20 or 30 μM) of Cd treatment for 36 h induced cell death. • High levels of Cd can upregulate the protein levels of eIF5A1 and NF-κB p65. • We suggest that eIF5A1 level is possibly modulated by NF-κB. - Abstract: Cadmium (Cd) and Cd compounds are widely-distributed in the environment and well-known carcinogens. Here, we report that in CdCl{sub 2}-exposed human bronchial epithelial cells (BEAS-2B), the level of p53 is dramatically decreased in a time- and dose-dependent manner, suggesting that the observed Cd-induced cytotoxicity is not likely due to the pro-apoptotic function of p53. Therefore, this prompted us to further study the responsive pro-apoptotic factors by proteomic approaches. Interestingly, we identified that high levels (20 or 30 μM) of Cd can significantly upregulate the protein levels of eukaryotic translation initiation factor 5A1 (eIF5A1) and redox-sensitive transcription factor NF-κB p65. Moreover, there is an enhanced NF-κB nuclear translocation as well as chromatin-binding in Cd-treated BEAS-2B cells. We also show that small interfering RNA-specific knockdown of eIF5A1 in Cd-exposed cells attenuated the Cd cytotoxicity, indicating the potential role of eIF5A1 in Cd cytotoxicity. As eIF5A1 is reported to be related with cell apoptosis but little is known about its transcriptional control, we hypothesize that NF-κB might likely modulate eIF5A1 gene expression. Notably, by bioinformatic analysis, several potential NF-κB binding sites on the upstream promoter region of eIF5A1 gene can be found. Subsequent chromatin immunoprecipitation assay revealed that indeed there is enhanced NF-κB binding on eIF5A1 promoter region of Cd-treated BEAS-2B cells. Taken together, our findings suggest for the first time a regulatory mechanism for the pro-apoptotic protein eIF5A1 in which its level is possibly modulated by NF-κB in human lung cells.

  15. Celastrol ameliorates HIV-1 Tat-induced inflammatory responses via NF-kappaB and AP-1 inhibition and heme oxygenase-1 induction in astrocytes

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    Youn, Gi Soo; Kwon, Dong-Joo; Ju, Sung Mi [Department of Biomedical Science and Research Institute for Bioscience and Biotechnology, Hallym University, Chunchon 200-702 (Korea, Republic of); Rhim, Hyangshuk [Department of Biomedical Sciences, Department of Medical Life Sciences, College of Medicine, the Catholic University of Korea, Seoul 137-701 (Korea, Republic of); Bae, Yong Soo [Department of Biological Science, College of Natural Sciences, Sungkyunkwan University, Suwon 440-746 (Korea, Republic of); Choi, Soo Young [Department of Biomedical Science and Research Institute for Bioscience and Biotechnology, Hallym University, Chunchon 200-702 (Korea, Republic of); Park, Jinseu, E-mail: jinpark@hallym.ac.kr [Department of Biomedical Science and Research Institute for Bioscience and Biotechnology, Hallym University, Chunchon 200-702 (Korea, Republic of)

    2014-10-01

    HIV-1 Tat causes extensive neuroinflammation that may progress to AIDS-related encephalitis and dementia. Celastrol possesses various biological activities such as anti-oxidant, anti-tumor, and anti-inflammatory activities. In this study, we investigated the modulatory effects of celastrol on HIV-1 Tat-induced inflammatory responses and the molecular mechanisms underlying its action in astrocytes. Pre-treatment of CRT-MG human astroglioma cells with celastrol significantly inhibited HIV-1 Tat-induced expression of ICAM-1/VCAM-1 and subsequent monocyte adhesiveness in CRT-MG cells. In addition, celastrol suppressed HIV-1 Tat-induced expression of pro-inflammatory chemokines, such as CXCL10, IL-8, and MCP-1. Celastrol decreased HIV-1 Tat-induced activation of JNK MAPK, AP-1, and NF-κB. Furthermore, celastrol induced mRNA and protein expression of HO-1 as well as Nrf2 activation. Blockage of HO-1 expression using siRNA reversed the inhibitory effect of celastrol on HIV-1 Tat-induced inflammatory responses. These results suggest that celastrol has regulatory effects on HIV-1 Tat-induced inflammatory responses by blocking the JNK MAPK-AP-1/NF-κB signaling pathways and inducing HO-1 expression in astrocytes. - Highlights: • Celastrol suppressed HIV-1 Tat-induced expression of pro-inflammatory genes. • Celastrol inhibited HIV-1 Tat -induced activation of JNK MAPK. • Celastrol inhibited HIV-1 Tat-induced activation of both NF-κB and AP-1. • Celastrol inhibited HIV-1 Tat-induced inflammatory responses via HO-1 induction.

  16. Ethyl pyruvate ameliorates hepatic injury following blunt chest trauma and hemorrhagic shock by reducing local inflammation, NF-kappaB activation and HMGB1 release.

    Science.gov (United States)

    Wagner, Nils; Dieteren, Scott; Franz, Niklas; Köhler, Kernt; Mörs, Katharina; Nicin, Luka; Schmidt, Julia; Perl, Mario; Marzi, Ingo; Relja, Borna

    2018-01-01

    The treatment of patients with multiple trauma including blunt chest/thoracic trauma (TxT) and hemorrhagic shock (H) is still challenging. Numerous studies show detrimental consequences of TxT and HS resulting in strong inflammatory changes, organ injury and mortality. Additionally, the reperfusion (R) phase plays a key role in triggering inflammation and worsening outcome. Ethyl pyruvate (EP), a stable lipophilic ester, has anti-inflammatory properties. Here, the influence of EP on the inflammatory reaction and liver injury in a double hit model of TxT and H/R in rats was explored. Female Lewis rats were subjected to TxT followed by hemorrhage/H (60 min, 35±3 mm Hg) and resuscitation/R (TxT+H/R). Reperfusion was performed by either Ringer`s lactated solution (RL) alone or RL supplemented with EP (50 mg/kg). Sham animals underwent all surgical procedures without TxT+H/R. After 2h, blood and liver tissue were collected for analyses, and survival was assessed after 24h. Resuscitation with EP significantly improved haemoglobin levels and base excess recovery compared with controls after TxT+H/R, respectively (ptrauma and hemorrhagic shock is associated with NF-κB. In particular, the beneficial anti-inflammatory effects of ethyl pyruvate seem to be regulated by the HMGB1/NF-κB axis in the liver, thereby, restraining inflammatory responses and liver injury after double hit trauma in the rat.

  17. Temporal regulation of HTLV-2 expression in infected cell lines and patients: evidence for distinct expression kinetics with nuclear accumulation of APH-2 mRNA

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    Bender Cecilia

    2012-09-01

    Full Text Available Abstract Background Human T-cell leukemia virus types 1 and 2 (HTLV-1 and HTLV-2 are delta retroviruses with similar genetic organization. Although both viruses immortalize T-cells in vitro, they exhibit distinct pathogenic potential in vivo. To search for possible differences in its expression strategy with respect to HTLV-1, we investigated the pattern of HTLV-2 expression in infected cell lines and peripheral blood mononuclear cells (PBMCs from infected patients using splice site-specific quantitative RT-PCR. Findings A novel alternative splice acceptor site for exon 2 was identified; its usage in env transcripts was found to be subtype-specific. Time-course analysis revealed a two-phase expression kinetics in an infected cell line and in PBMCs of two of the three patients examined; this pattern was reminiscent of HTLV-1. In addition, the minus-strand APH2 transcript was mainly detected in the nucleus, a feature that was similar to its HTLV-1 orthologue HBZ. In contrast to HTLV-1, expression of the mRNA encoding the main regulatory proteins Tax and Rex and that of the mRNAs encoding the p28 and truncated Rex inhibitors is skewed towards p28/truncated Rex inhibitors in HTLV-2. Conclusion Our data suggest a general converging pattern of expression of HTLV-2 and HTLV-1 and highlight peculiar differences in the expression of regulatory proteins that might influence the pathobiology of these viruses.

  18. New insights into prevalence, genetic diversity, and proviral load of human T-cell leukemia virus types 1 and 2 in pregnant women in Gabon in equatorial central Africa.

    Science.gov (United States)

    Etenna, Sonia Lekana-Douki; Caron, Mélanie; Besson, Guillaume; Makuwa, Maria; Gessain, Antoine; Mahé, Antoine; Kazanji, Mirdad

    2008-11-01

    Human T-cell leukemia virus type 1 (HTLV-1) is highly endemic in areas of central Africa; mother-to-child transmission and sexual transmission are considered to be the predominant routes. To determine the prevalence and subtypes of HTLV-1/2 in pregnant women in Gabon, we conducted an epidemiological survey in the five main cities of the country. In 907 samples, the HTLV-1 seroprevalence was 2.1%, which is lower than that previously reported. Only one case of HTLV-2 infection was found. The HTLV-1 seroprevalence increased with age and differed between regions (P cosmopolitan subtype A. The new strains of subtype B exhibited wide genetic diversity, but there was no evidence of clustering of specific genomes within geographical regions of the country. Some strains were closely related to simian T-cell leukemia virus type 1 strains of great apes, suggesting that in these areas some HTLV-1 strains could arise from relatively recent interspecies transmission. The sole HTLV-2 strain belonged to subtype B. In this study we showed that the prevalence of HTLV-1 in the southeast is one of the highest in the world for pregnant women.

  19. C7a, a Biphosphinic Cyclopalladated Compound, Efficiently Controls the Development of a Patient-Derived Xenograft Model of Adult T Cell Leukemia/Lymphoma

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    Carlos R. Figueiredo

    2011-07-01

    Full Text Available Adult T-cell leukemia/lymphoma (ATLL is a highly aggressive disease that occurs in individuals infected with the human T lymphotropic virus type 1 (HTLV-1. Patients with aggressive ATLL have a poor prognosis because the leukemic cells are resistant to conventional chemotherapy. We have investigated the therapeutic efficacy of a biphosphinic cyclopalladated complex {Pd2 [S(−C2, N-dmpa]2 (μ-dppeCl2}, termed C7a, in a patient-derived xenograft model of ATLL, and investigated the mechanism of C7a action in HTLV-1-positive and negative transformed T cell lines in vitro. In vivo survival studies in immunocompromised mice inoculated with human RV-ATL cells and intraperitoneally treated with C7a led to significantly increased survival of the treated mice. We investigated the mechanism of C7a activity in vitro and found that it induced mitochondrial release of cytochrome c, caspase activation, nuclear condensation and DNA degradation. These results suggest that C7a triggers apoptotic cell death in both HTLV-1 infected and uninfected human transformed T-cell lines. Significantly, C7a was not cytotoxic to peripheral blood mononuclear cells (PBMC from healthy donors and HTLV-1-infected individuals. C7a inhibited more than 60% of the ex vivo spontaneous proliferation of PBMC from HTLV-1-infected individuals. These results support a potential therapeutic role for C7a in both ATLL and HTLV-1-negative T-cell lymphomas.

  20. Paradoxical expression of IL-28B mRNA in peripheral blood in human T-cell leukemia virus Type-1 mono-infection and co-infection with hepatitis C Virus

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    Kamihira Shimeru

    2012-02-01

    Full Text Available Abstract Background Human T-cell leukemia virus type-1 (HTLV-1 carriers co-infected with and hepatitis C virus (HCV have been known to be at higher risk of their related diseases than mono-infected individuals. The recent studies clarified that IL-28B polymorphism rs8099917 is associated with not only the HCV therapeutic response by IFN, but also innate immunity and antiviral activity. The aim of our research was to clarify study whether IL-28B gene polymorphism (rs8099917 is associated with HTLV-1/HCV co-infection. Results The genotyping and viral-serological analysis for 340 individuals showed that IL-28B genotype distribution of rs8099917 SNP did not differ significantly by respective viral infection status. However, the IL-28B mRNA expression level was 3.8 fold higher in HTLV-1 mono-infection than HTLV-1/HCV co-infection. The high expression level was associated with TT (OR, 6.25, whiles the low expression was associated with co-infection of the two viruses (OR, 9.5. However, there was no association between down-regulation and ATL development (OR, 0.8. Conclusion HTLV-1 mono-infection up-regulates the expression of IL-28B transcripts in genotype-dependent manner, whiles HTLV-1/HCV co-infection down-regulates regardless of ATL development.

  1. Comparison of seropositivity of human T lymphotropic virus type 1 in mycosis fungoides patients and normal volunteers: A case-control study and review of literature

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    Seirafi Hassan

    2009-01-01

    Full Text Available Background: There have been controversial reports about the possible association between mycosis fungoides (MF, its leukemic variant Sιzary syndrome (SS and human T lymphotropic virus type 1 (HTLV-1 in different geographical regions. Aims: The purpose of this study was to explore any association between MF and presence of HTLV-1 infection in Iran. Methods: In a case-control setting, 150 clinically and histopathologically proven MF patients had been admitted to the tertiary referral skin center during a 10-year period and another 150 normal volunteers had been compared with each other for the presence of HTLV-1 infection. Enzyme-linked immunosorbent assay (ELISA was used to detect antibodies against HTLV-1, and positive results were confirmed with western blotting. Results: Only three MF patients had HTLV-1 infection, whereas two cases of normal subjects had the infection ( P > 0.05. The only three seropositive MF patients were male and from North-Eastern Iran . Conclusion: This study showed that MF does not correlate with HTLV-1 infection in Iran.

  2. Inferences about the global scenario of human T-cell lymphotropic virus type 1 infection using data mining of viral sequences

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    Thessika Hialla Almeida Araujo

    2014-07-01

    Full Text Available Human T-cell lymphotropic virus type 1 (HTLV-1 is mainly associated with two diseases: tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM and adult T-cell leukaemia/lymphoma. This retrovirus infects five-10 million individuals throughout the world. Previously, we developed a database that annotates sequence data from GenBank and the present study aimed to describe the clinical, molecular and epidemiological scenarios of HTLV-1 infection through the stored sequences in this database. A total of 2,545 registered complete and partial sequences of HTLV-1 were collected and 1,967 (77.3% of those sequences represented unique isolates. Among these isolates, 93% contained geographic origin information and only 39% were related to any clinical status. A total of 1,091 sequences contained information about the geographic origin and viral subtype and 93% of these sequences were identified as subtype “a”. Ethnicity data are very scarce. Regarding clinical status data, 29% of the sequences were generated from TSP/HAM and 67.8% from healthy carrier individuals. Although the data mining enabled some inferences about specific aspects of HTLV-1 infection to be made, due to the relative scarcity of data of available sequences, it was not possible to delineate a global scenario of HTLV-1 infection.

  3. Seroprevalence and correlates of human T-cell lymphoma/leukemia virus type 1 antibodies among pregnant women at the University of Nigeria Teaching Hospital, Enugu, Nigeria.

    Science.gov (United States)

    Okoye, Augustine Ejike; Ibegbulam, Obike Godswill; Onoh, Robinson Chukwudi; Ezeonu, Paul Olisaemeka; Ugwu, Ngozi I; Lawani, Lucky Osaheni; Anigbo, Chukwudi Simon; Nonyelu, Charles E

    2014-01-01

    Human T-cell lymphoma/leukemia virus (HTLV)-1 is a retrovirus transmitted vertically from mother to child parenterally and sexually by infected lymphocytes. The objective of this study was to determine the seroprevalence of HTLV-1 antibodies and associated risk factors for HTLV-1 infection among pregnant women in University of Nigeria Teaching Hospital, Enugu, southeast Nigeria. A cross-sectional study was carried out from July to October 2010. Two hundred pregnant women were recruited consecutively from the antenatal clinic. Five milliliters of blood was collected from each of the participants into a plain sterile bottle and allowed to clot. The serum obtained was stored at -20°C until required for analysis. The serum samples were then analyzed for antibodies to HTLV-1 using a one-step incubation double-antigen sandwich enzyme-linked immunosorbent assay kit. Participants' demographic characteristics and degree of exposure to the risk factors associated with HTLV-1 infection were captured using a questionnaire. Statistical analysis of results was done using SPSS version 17. The average age of the pregnant women was 28.94 years (standard deviation 4.17). The age-group with the highest representation was those between the ages of 26 and 30 years. Thirty-six percent of the population was above 30 years old. The result of the tests showed that only one respondent, a 31-year-old pregnant woman tested positive for HTLV-1 antibodies. Therefore, the seroprevalence of HTLV-1 antibodies among pregnant women attending the antenatal clinic at University of Nigeria Teaching Hospital was 0.5%, with a 95% confidence interval of 0%-2.8%. Some of the sociodemographic risk factors of HTLV-1 infection found to be applicable to the 31-year-old woman who tested positive included positive history of previous sexually transmitted diseases, high parity, low socioeconomic status, female sex, and age above 30 years. The pregnant women that participated in this study were exposed to risk

  4. Human T-Lymphotropic Virus Type 1-Induced Overexpression of Activated Leukocyte Cell Adhesion Molecule (ALCAM) Facilitates Trafficking of Infected Lymphocytes through the Blood-Brain Barrier.

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    Curis, Céline; Percher, Florent; Jeannin, Patricia; Montange, Thomas; Chevalier, Sébastien A; Seilhean, Danielle; Cartier, Luis; Couraud, Pierre-Olivier; Gout, Olivier; Gessain, Antoine; Ceccaldi, Pierre-Emmanuel; Afonso, Philippe V

    2016-08-15

    Human T-lymphotropic virus type 1 (HTLV-1) is the etiological agent of a slowly progressive neurodegenerative disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This disease develops upon infiltration of HTLV-1-infected lymphocytes into the central nervous system, mostly the thoracic spinal cord. The central nervous system is normally protected by a physiological structure called the blood-brain barrier (BBB), which consists primarily of a continuous endothelium with tight junctions. In this study, we investigated the role of activated leukocyte cell adhesion molecule (ALCAM/CD166), a member of the immunoglobulin superfamily, in the crossing of the BBB by HTLV-1-infected lymphocytes. We demonstrated that ALCAM is overexpressed on the surface of HTLV-1-infected lymphocytes, both in chronically infected cell lines and in primary infected CD4(+) T lymphocytes. ALCAM overexpression results from the activation of the canonical NF-κB pathway by the viral transactivator Tax. In contrast, staining of spinal cord sections of HAM/TSP patients showed that ALCAM expression is not altered on the BBB endothelium in the context of HTLV-1 infection. ALCAM blockade or downregulation of ALCAM levels significantly reduced the migration of HTLV-1-infected lymphocytes across a monolayer of human BBB endothelial cells. This study suggests a potential role for ALCAM in HAM/TSP pathogenesis. Human T-lymphotropic virus type 1 (HTLV-1) is the etiological agent of a slowly progressive neurodegenerative disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This disease is the consequence of the infiltration of HTLV-1-infected lymphocytes into the central nervous system (CNS), mostly the thoracic spinal cord. The CNS is normally protected by a physiological structure called the blood-brain barrier (BBB), which consists primarily of a continuous endothelium with tight junctions. The mechanism of migration of lymphocytes into the CNS is unclear

  5. Human T-cell leukemia virus type 1 Tax oncoprotein represses the expression of the BCL11B tumor suppressor in T-cells

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    Takachi, Takayuki; Takahashi, Masahiko; Takahashi-Yoshita, Manami; Higuchi, Masaya; Obata, Miki; Mishima, Yukio; Okuda, Shujiro; Tanaka, Yuetsu; Matsuoka, Masao; Saitoh, Akihiko; Green, Patrick L; Fujii, Masahiro

    2015-01-01

    Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T cell leukemia (ATL), which is an aggressive form of T-cell malignancy. HTLV-1 oncoproteins, Tax and HBZ, play crucial roles in the immortalization of T-cells and/or leukemogenesis by dysregulating the cellular functions in the host. Recent studies show that HTLV-1-infected T-cells have reduced expression of the BCL11B tumor suppressor protein. In the present study, we explored whether Tax and/or HBZ play a role in downregulating BCL11B in HTLV-1-infected T-cells. Lentiviral transduction of Tax in a human T-cell line repressed the expression of BCL11B at both the protein and mRNA levels, whereas the transduction of HBZ had little effect on the expression. Tax mutants with a decreased activity for the NF-κB, CREB or PDZ protein pathways still showed a reduced expression of the BCL11B protein, thereby implicating a different function of Tax in BCL11B downregulation. In addition, the HTLV-2 Tax2 protein reduced the BCL11B protein expression in T-cells. Seven HTLV-1-infected T-cell lines, including three ATL-derived cell lines, showed reduced BCL11B mRNA and protein expression relative to an uninfected T-cell line, and the greatest reductions were in the cells expressing Tax. Collectively, these results indicate that Tax is responsible for suppressing BCL11B protein expression in HTLV-1-infected T-cells; Tax-mediated repression of BCL11B is another mechanism that Tax uses to promote oncogenesis of HTLV-1-infected T-cells. PMID:25613934

  6. Human T-lymphotropic virus type 1-infected cells secrete exosomes that contain Tax protein.

    Science.gov (United States)

    Jaworski, Elizabeth; Narayanan, Aarthi; Van Duyne, Rachel; Shabbeer-Meyering, Shabana; Iordanskiy, Sergey; Saifuddin, Mohammed; Das, Ravi; Afonso, Philippe V; Sampey, Gavin C; Chung, Myung; Popratiloff, Anastas; Shrestha, Bindesh; Sehgal, Mohit; Jain, Pooja; Vertes, Akos; Mahieux, Renaud; Kashanchi, Fatah

    2014-08-08

    Human T-lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis. The HTLV-1 transactivator protein Tax controls many critical cellular pathways, including host cell DNA damage response mechanisms, cell cycle progression, and apoptosis. Extracellular vesicles called exosomes play critical roles during pathogenic viral infections as delivery vehicles for host and viral components, including proteins, mRNA, and microRNA. We hypothesized that exosomes derived from HTLV-1-infected cells contain unique host and viral proteins that may contribute to HTLV-1-induced pathogenesis. We found exosomes derived from infected cells to contain Tax protein and proinflammatory mediators as well as viral mRNA transcripts, including Tax, HBZ, and Env. Furthermore, we observed that exosomes released from HTLV-1-infected Tax-expressing cells contributed to enhanced survival of exosome-recipient cells when treated with Fas antibody. This survival was cFLIP-dependent, with Tax showing induction of NF-κB in exosome-recipient cells. Finally, IL-2-dependent CTLL-2 cells that received Tax-containing exosomes were protected from apoptosis through activation of AKT. Similar experiments with primary cultures showed protection and survival of peripheral blood mononuclear cells even in the absence of phytohemagglutinin/IL-2. Surviving cells contained more phosphorylated Rb, consistent with the role of Tax in regulation of the cell cycle. Collectively, these results suggest that exosomes may play an important role in extracellular delivery of functional HTLV-1 proteins and mRNA to recipient cells. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  7. Human T-lymphotropic Virus Type 1-infected Cells Secrete Exosomes That Contain Tax Protein*

    Science.gov (United States)

    Jaworski, Elizabeth; Narayanan, Aarthi; Van Duyne, Rachel; Shabbeer-Meyering, Shabana; Iordanskiy, Sergey; Saifuddin, Mohammed; Das, Ravi; Afonso, Philippe V.; Sampey, Gavin C.; Chung, Myung; Popratiloff, Anastas; Shrestha, Bindesh; Sehgal, Mohit; Jain, Pooja; Vertes, Akos; Mahieux, Renaud; Kashanchi, Fatah

    2014-01-01

    Human T-lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis. The HTLV-1 transactivator protein Tax controls many critical cellular pathways, including host cell DNA damage response mechanisms, cell cycle progression, and apoptosis. Extracellular vesicles called exosomes play critical roles during pathogenic viral infections as delivery vehicles for host and viral components, including proteins, mRNA, and microRNA. We hypothesized that exosomes derived from HTLV-1-infected cells contain unique host and viral proteins that may contribute to HTLV-1-induced pathogenesis. We found exosomes derived from infected cells to contain Tax protein and proinflammatory mediators as well as viral mRNA transcripts, including Tax, HBZ, and Env. Furthermore, we observed that exosomes released from HTLV-1-infected Tax-expressing cells contributed to enhanced survival of exosome-recipient cells when treated with Fas antibody. This survival was cFLIP-dependent, with Tax showing induction of NF-κB in exosome-recipient cells. Finally, IL-2-dependent CTLL-2 cells that received Tax-containing exosomes were protected from apoptosis through activation of AKT. Similar experiments with primary cultures showed protection and survival of peripheral blood mononuclear cells even in the absence of phytohemagglutinin/IL-2. Surviving cells contained more phosphorylated Rb, consistent with the role of Tax in regulation of the cell cycle. Collectively, these results suggest that exosomes may play an important role in extracellular delivery of functional HTLV-1 proteins and mRNA to recipient cells. PMID:24939845

  8. Quantification of HTLV-I proviral load in experimentally infected rabbits

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    Kindt Thomas J

    2005-05-01

    Full Text Available Abstract Background Levels of proviral load in HTLV-1 infected patients correlate with clinical outcome and are reasonably prognostic. Adaptation of proviral load measurement techniques is examined here for use in an experimental rabbit model of HTLV-1 infection. Initial efforts sought to correlate proviral load with route and dose of inoculation and with clinical outcome in this model. These methods contribute to our continuing goal of using the model to test treatments that alleviate virus infection. Results A real-time PCR assay was used to measure proviral load in blood and tissue samples from a series of rabbits infected using HTLV-1 inocula prepared as either cell-free virus particles, infected cells or blood, or by naked DNA injection. Proviral loads from asymptomatically infected rabbits showed levels corresponding to those reported for human patients with clinically silent HTLV-1 infections. Proviral load was comparably increased in 50% of experimentally infected rabbits that developed either spontaneous benign or malignant tumors while infected. Similarly elevated provirus was found in organs of rabbits with experimentally induced acute leukemia/lymphoma-like disease. Levels of provirus in organs taken at necropsy varied widely suggesting that reservoirs of infections exist in non-lymphoid organs not traditionally thought to be targets for HTLV-1. Conclusion Proviral load measurement is a valuable enhancement to the rabbit model for HTLV-1 infection providing a metric to monitor clinical status of the infected animals as well as a means for the testing of treatment to combat infection. In some cases proviral load in blood did not reflect organ proviral levels, revealing a limitation of this method for monitoring health status of HTLV-1 infected individuals.

  9. Human T-Lymphotropic virus (HTLV type I in vivo integration in oral keratinocytes

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    Martha C Domínguez

    2011-03-01

    Full Text Available Although the infection of HTLV-1 to cell components of the mouth have been previously reported, there was not until this report, a detailed study to show the characteristics of such infection. From 14 Tropical Spastic Paraparesis/ HTLV-1-Associated Myelopathy (HAM/TSP patients and 11 asymptomatic carrier individuals (AC coming from HTLV-1 endemic areas of southwest Pacific of Colombia, infected oral mucosa cells were primary cultured during five days. These cell cultures were immunophenotyped by dual color fluorescence cell assortment using different lymphocyte CD markers and also were immunohistochemically processed using a polyclonal anti-keratin antibody. Five days old primary cultures were characterized as oral keratinocytes, whose phenotype was CD3- /CD4-/CD8-/CD19-/CD14-/CD45-/A575-keratin+. From DNA extracted of primary cultures LTR, pol, env and tax HTLV-1 proviral DNA regions were differentially amplified by PCR showing proviral integration. Using poly A+ RNA obtained of these primary cultures, we amplify by RT-PCR cDNA of tax and pol in 57.14% (8/14 HAM/TSP patients and 27.28% (3/11 AC. Tax and pol poly A+ RNA were expressed only in those sIgA positive subjects. Our results showed that proviral integration and viral gene expression in oral keratinocytes are associated with a HTLV-1 specific local mucosal immune response only in those HTLV-1 infected individuals with detectable levels of sIgA in their oral fluids. Altogether the results gave strong evidence that oral mucosa infection would be parte of the systemic spreading of HTLV-1 infection.

  10. Integration Site and Clonal Expansion in Human Chronic Retroviral Infection and Gene Therapy

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    Niederer, Heather A.; Bangham, Charles R. M.

    2014-01-01

    Retroviral vectors have been successfully used therapeutically to restore expression of genes in a range of single-gene diseases, including several primary immunodeficiency disorders. Although clinical trials have shown remarkable results, there have also been a number of severe adverse events involving malignant outgrowth of a transformed clonal population. This clonal expansion is influenced by the integration site profile of the viral integrase, the transgene expressed, and the effect of the viral promoters on the neighbouring host genome. Infection with the pathogenic human retrovirus HTLV-1 also causes clonal expansion of cells containing an integrated HTLV-1 provirus. Although the majority of HTLV-1-infected people remain asymptomatic, up to 5% develop an aggressive T cell malignancy. In this review we discuss recent findings on the role of the genomic integration site in determining the clonality and the potential for malignant transformation of cells carrying integrated HTLV-1 or gene therapy vectors, and how these results have contributed to the understanding of HTLV-1 pathogenesis and to improvements in gene therapy vector safety. PMID:25365582

  11. Repression of tax expression is associated both with resistance of human T-cell leukemia virus type 1-infected T cells to killing by tax-specific cytotoxic T lymphocytes and with impaired tumorigenicity in a rat model.

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    Nomura, Machiko; Ohashi, Takashi; Nishikawa, Keiko; Nishitsuji, Hironori; Kurihara, Kiyoshi; Hasegawa, Atsuhiko; Furuta, Rika A; Fujisawa, Jun-ichi; Tanaka, Yuetsu; Hanabuchi, Shino; Harashima, Nanae; Masuda, Takao; Kannagi, Mari

    2004-04-01

    Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL). Although the viral transactivation factor, Tax, has been known to have apparent transforming ability, the exact function of Tax in ATL development is still not clear. To understand the role of Tax in ATL development, we introduced short-interfering RNAs (siRNAs) against Tax in a rat HTLV-1-infected T-cell line. Our results demonstrated that expression of siRNA targeting Tax successfully downregulated Tax expression. Repression of Tax expression was associated with resistance of the HTLV-1-infected T cells to Tax-specific cytotoxic-T-lymphocyte killing. This may be due to the direct effect of decreased Tax expression, because the Tax siRNA did not alter the expression of MHC-I, CD80, or CD86. Furthermore, T cells with Tax downregulation appeared to lose the ability to develop tumors in T-cell-deficient nude rats, in which the parental HTLV-1-infected cells induce ATL-like lymphoproliferative disease. These results indicated the importance of Tax both for activating host immune response against the virus and for maintaining the growth ability of infected cells in vivo. Our results provide insights into the mechanisms how the host immune system can survey and inhibit the growth of HTLV-1-infected cells during the long latent period before the onset of ATL.

  12. Chronic adult T-cell Leukemia in a young male after blood transfusion as a newborn

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    Magali Colucci

    2016-06-01

    Full Text Available Human T-cell Lymphotropic virus type 1 (HTLV-1 is the etiological agent of Adult T-cell Leukemia/Lymphoma (ATLL and HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HTM/TSP. Areas of extremely high HTLV-1 prevalence are surrounded by areas of middle or very low prevalence. ATLL is an aggressive lymphoproliferative malignancy of peripheral T cells, with an incidence of less than 5% in HTLV-1-infected individuals. ATLL developed in the majority of cases in individuals who were infected with HTLV-1 by their mothers due to prolonged breastfeeding. In non-endemic areas, ATLL is usually limited to immigrants, their sexual partners and descendants from endemic regions. Very few cases of ATLL have been diagnosed in recipient patients few years after an organ transplantation or blood transfusion worldwide. Achieving an accurate and fast diagnosis of ATLL can be challenging due to the lack of professional experience, delayed consultation and difficulty in its sub-classification. We present a case of a delayed onset of a chronic ATLL in an 18-years-old male who was transfused with blood components as a premature newborn in Buenos Aires, a non-endemic city of South America.

  13. [HTLV and "donating" milk].

    Science.gov (United States)

    Rigourd, V; Meyer, V; Kieffer, F; Aubry, S; Magny, J-F

    2011-08-01

    In France, the screening for human T-cell leukemia/ lymphoma virus type 1 and 2 (HTLV-1 and HTLV-2) during the donation of human milk has been carried out from 1992 with the application of the circular DGS 24 November 1992. The screening for antibodies against these viruses is regulated and done systematically during every donation of milk. Breast feeding being the main mode of transmission of the HTLV-1, the last ministerial decree of 25 August 2010 has made the screening test compulsory for the anonymous donation and for the personalized donation (of a mother for her own child) from all women including those affected by the infection. The milk delivered by milk banks is pasteurized (62.5 °C for 30 minutes) before freezing at -18 °C, which inactivates the pathogens. This double means of prevention of the transmission of the HTLV-1 paradoxically seems disproportionate in the absence of any precautionary measure in the case of direct breast-feeding and the use of mother's raw milk. Indeed, in most neonatal intensive care units in maternity hospitals, unpasteurized milk is administered to the neonates without any systematic preliminary testing of the serological HTLV-1 status of the mother. An increased sensitization of the community of the obstetricians, midwives and neonatologists by the Association of the Milk Banks of France (ADLF) and the Société de pathologie exotique could address the issue of screening for HTLV-1 in "donated" milk and breast-feeding.

  14. Development of neurologic diseases in a patient with primate T lymphotropic virus type 1 (PTLV-1).

    Science.gov (United States)

    Enose-Akahata, Yoshimi; Caruso, Breanna; Haner, Benjamin; Charlip, Emily; Nair, Govind; Massoud, Raya; Billioux, Bridgette J; Ohayon, Joan; Switzer, William M; Jacobson, Steven

    2016-08-12

    Virus transmission from various wild and domestic animals contributes to an increased risk of emerging infectious diseases in human populations. HTLV-1 is a human retrovirus associated with acute T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 originated from ancient zoonotic transmission from nonhuman primates, although cases of zoonotic infections continue to occur. Similar to HTLV-1, the simian counterpart, STLV-1, causes chronic infection and leukemia and lymphoma in naturally infected monkeys, and combined are called primate T-lymphotropic viruses (PTLV-1). However, other clinical syndromes typically seen in humans such as a chronic progressive myelopathy have not been observed in nonhuman primates. Little is known about the development of neurologic and inflammatory diseases in human populations infected with STLV-1-like viruses following nonhuman primate exposure. We performed detailed laboratory analyses on an HTLV-1 seropositive patient with typical HAM/TSP who was born in Liberia and now resides in the United States. Using a novel droplet digital PCR for the detection of the HTLV-1 tax gene, the proviral load in PBMC and cerebrospinal fluid cells was 12.98 and 51.68 %, respectively; however, we observed a distinct difference in fluorescence amplitude of the positive droplet population suggesting possible mutations in proviral DNA. A complete PTLV-1 proviral genome was amplified from the patient's PBMC DNA using an overlapping PCR strategy. Phylogenetic analysis of the envelope and LTR sequences showed the virus was highly related to PTLV-1 from sooty mangabey monkeys (smm) and humans exposed via nonhuman primates in West Africa. These results demonstrate the patient is infected with a simian variant of PTLV-1, suggesting for the first time that PTLV-1smm infection in humans may be associated with a chronic progressive neurologic disease.

  15. Human endogenous retrovirus K(HML-2) Gag and Env specific T-cell responses are not detected in HTLV-I-infected subjects using standard peptide screening methods.

    Science.gov (United States)

    Jones, R Brad; Leal, Fabio E; Hasenkrug, Aaron M; Segurado, Aluisio C; Nixon, Douglas F; Ostrowski, Mario A; Kallas, Esper G

    2013-01-10

    An estimated 10-20 million individuals are infected with the retrovirus human T-cell leukemia virus type 1 (HTLV-1). While the majority of these individuals remain asymptomatic, 0.3-4% develop a neurodegenerative inflammatory disease, termed HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP results in the progressive demyelination of the central nervous system and is a differential diagnosis of multiple sclerosis (MS). The etiology of HAM/TSP is unclear, but evidence points to a role for CNS-inflitrating T-cells in pathogenesis. Recently, the HTLV-1-Tax protein has been shown to induce transcription of the human endogenous retrovirus (HERV) families W, H and K. Intriguingly, numerous studies have implicated these same HERV families in MS, though this association remains controversial. Here, we explore the hypothesis that HTLV-1-infection results in the induction of HERV antigen expression and the elicitation of HERV-specific T-cells responses which, in turn, may be reactive against neurons and other tissues. PBMC from 15 HTLV-1-infected subjects, 5 of whom presented with HAM/TSP, were comprehensively screened for T-cell responses to overlapping peptides spanning HERV-K(HML-2) Gag and Env. In addition, we screened for responses to peptides derived from diverse HERV families, selected based on predicted binding to predicted optimal epitopes. We observed a lack of responses to each of these peptide sets. Thus, although the limited scope of our screening prevents us from conclusively disproving our hypothesis, the current study does not provide data supporting a role for HERV-specific T-cell responses in HTLV-1 associated immunopathology.

  16. T Cell Receptor Vβ Staining Identifies the Malignant Clone in Adult T cell Leukemia and Reveals Killing of Leukemia Cells by Autologous CD8+ T cells.

    Directory of Open Access Journals (Sweden)

    Aileen G Rowan

    2016-11-01

    Full Text Available There is growing evidence that CD8+ cytotoxic T lymphocyte (CTL responses can contribute to long-term remission of many malignancies. The etiological agent of adult T-cell leukemia/lymphoma (ATL, human T lymphotropic virus type-1 (HTLV-1, contains highly immunogenic CTL epitopes, but ATL patients typically have low frequencies of cytokine-producing HTLV-1-specific CD8+ cells in the circulation. It remains unclear whether patients with ATL possess CTLs that can kill the malignant HTLV-1 infected clone. Here we used flow cytometric staining of TCRVβ and cell adhesion molecule-1 (CADM1 to identify monoclonal populations of HTLV-1-infected T cells in the peripheral blood of patients with ATL. Thus, we quantified the rate of CD8+-mediated killing of the putative malignant clone in ex vivo blood samples. We observed that CD8+ cells from ATL patients were unable to lyse autologous ATL clones when tested directly ex vivo. However, short in vitro culture restored the ability of CD8+ cells to kill ex vivo ATL clones in some donors. The capacity of CD8+ cells to lyse HTLV-1 infected cells which expressed the viral sense strand gene products was significantly enhanced after in vitro culture, and donors with an ATL clone that expressed the HTLV-1 Tax gene were most likely to make a detectable lytic CD8+ response to the ATL cells. We conclude that some patients with ATL possess functional tumour-specific CTLs which could be exploited to contribute to control of the disease.

  17. Human T-lymphotropic virus type 1 infection is frequent in rural communities of the southern Andes of Peru.

    Science.gov (United States)

    Ita, Fanny; Mayer, Erick F; Verdonck, Kristien; Gonzalez, Elsa; Clark, Daniel; Gotuzzo, Eduardo

    2014-02-01

    To evaluate the presence of human T-lymphotropic virus type 1 (HTLV-1) infection in isolated rural communities in the southern Andes of Peru. We conducted a cross-sectional study in five communities located in three provinces in Ayacucho, Peru. The five communities are located at >3000 meters above sea level and are mainly rural, and more than 85% of the population speaks Quechua. Volunteers aged 12 years and older were included. Clinical and epidemiological data were collected, along with a blood sample for serological testing. We included 397 participants; their median age was 41 years (interquartile range 31-57 years) and 69% were women. According to our definitions, 98% were of Quechua origin. HTLV-1 was diagnosed in 11 people: 0/164 in Cangallo, 3/154 (2%) in Vilcashuaman, and 8/79 (10%) in Parinacochas. There were no cases of HTLV-2. All the HTLV-1-positive participants were born in Ayacucho and were of Quechua origin; they ranged in age from 29 to 87 years (median 56 years) and 10/11 were women. Ten were apparently healthy, and one woman was diagnosed with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Three out of 11 had a family member with a lower limb impairment compatible with HAM/TSP. The fact that HTLV-1 infection was present in two out of three provinces suggests that HTLV-1 could be highly endemic in the southern Andes in the Quechua population. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

  18. Seroprevalence of HIV, HBV, HCV, and HTLV among Pregnant Women in Southwestern Nigeria.

    Science.gov (United States)

    Opaleye, Oluyinka Oladele; Igboama, Magdalene C; Ojo, Johnson Adeyemi; Odewale, Gbolabo

    2016-01-01

    Sexually transmitted infections (STIs) are major public health challenge especially in developing countries. This study was designed to determine the prevalence of Hepatitis B virus (HBV), Hepatitis C Virus (HCV), Human immunodeficiency virus (HIV), and Human T-cell lymphotropic Virus type I (HTLV-I) among pregnant women attending antenatal clinic, in Ladoke Akintola University Teaching Hospital, Osogbo, and South-Western Nigeria. One hundred and eighty two randomly selected pregnant women were screened for HBsAg, anti-HCV, anti-HIV and HTLV-1 IgM antibodies using commercially available ELISA kit. Of the 182 blood samples of pregnant women screened whose age ranged from 15-49 years, 13 (7.1%), 5 (2.7%), 9 (4.9%), and 44 (24.2%) were positive for HBsAg, anti-HCV, anti-HIV, and HTLV-1 IgM antibodies, respectively. The co-infection rate of 0.5% was obtained for HBV/HCV, HBV/HIV, HIV/HTLV-1, and HCV/HTLV-1 while 1.1% and 0% was recorded for HBV/HTLV-1 and HCV/HIV co-infections, respectively. Expected risk factors such as history of surgery, circumcision, tattooing and incision showed no significant association with any of the viral STIs (P > 0.05). This study shows that there is the need for a comprehensive screening of all pregnant women for HBsAg, anti-HCV, anti-HIV and HTLV-1 to prevent mother to child transmission of these viral infections and its attending consequences.

  19. Rate of positive autoimmune markers in Human T lymphotropic virus type 1 carriers: a case-control study from Iran.

    Science.gov (United States)

    Ahmadi Ghezeldasht, Sanaz; Hedayati-Moghaddam, Mohammad Reza; Habibi, Meysam; Mollahosseini, Farzad; Rafatpanah, Houshang; Miri, Rahele; Hatef Fard, MohammadReza; Sahebari, Maryam

    2018-01-01

    Human T lymphotropic virus type 1 (HTLV-1) infection with high prevalence in the north-east of Iran, particularly in Mashhad, can lead to adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and a variety of autoimmune diseases. The aim of the study was to examine the presence of autoimmune markers in HTLV carries. Serum samples were obtained from blood donors in Mashhad, northeastern Iran. One hundred and five HTLV-1 positive (cases) and 104 age- and sex-matched HTLV-1 negative donors (controls) were assessed for presence of serum autoimmune markers by enzyme-linked immunosorbent assay. The mean ages of cases and controls were 40.8 ± 9.4 and 41.5 ± 9.3 years, respectively (P = 0.5). In the case group, 81.9% and in the control group 83.7% were male (P = 0.74). The frequency of positive antinuclear antibodies and anticyclic citrullinated peptide antibodies in the serum of the two groups were not significantly different (P = 0.68 and P = 0.62, respectively). Only one antineutrophil cytoplasmic antibody-positive case (1%) was observed in the group and no anti-phospholipid immunoglobulin G positivity was observed. The frequency of rheumatoid factor (RF) was greater in case group than in the control group, although the difference was not significant (P = 0.08). The amount of RF in all 12 RF positive sera were higher than normal levels (33-37 IU/mL). Because we failed to detect any significant relation between serum autoimmune markers and HTLV-1 infection, and because of the relatively low prevalence of autoimmune diseases, it could be concluded that healthy HTLV-1 carriers do not produce rheumatologic-related auto-antibodies more than the healthy population. © 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

  20. Immunological aspects of adult T-cell leukemia/lymphoma (ATLL), a possible neoplasm of regulatory T-cells

    OpenAIRE

    Yamada, Yasuaki; Kamihira, Shimeru

    2008-01-01

    Adult T-cell leukemia/lymphoma (ATLL) is a distinct disease caused by the first discovered human oncogenic retrovirus, human T-cell leukemia virus type-1 (HTLV-1). The peculiarity of this disease is not only in its causative agent HTLV-1 but also in the character of leukemia cells. ATLL cells express the mature helper/inducer T-cell antigens, CD2, CD3, CD4 and CD5 but usually lacking CD8. Despite CD4 expression, it has long been known that ATLL cells exhibit strong immunosuppressive activity ...

  1. Enhancement of retroviral infection in vitro by anti-Le(y) IgG: reversal by humanization of monoclonal mouse antibody

    DEFF Research Database (Denmark)

    Hansen, J E; Sørensen, A M; Arendrup, M

    1993-01-01

    Monoclonal mouse IgG3 antibody (ABL 364) against the carbohydrate Le(y) antigen enhanced infection in vitro with HTLV-1 and with HIV-1 when propagated in both transformed and normal lymphocytes. Enhancement was independent of complement, occurred with both lymphocytes and monocytes as target cells...... with no indication of any alternative pathway of infection, as evidenced by abrogation of enhancement by anti-CD4 MAb or soluble recombinant CD4, and also the inability of anti-Le(y) MAb to mediate HIV infection of HSB-2 cells in which HTLV-1/HIV pseudovirus infection was enhanced. While F(ab)2 fragments of ABL 364...

  2. Cohort Profile

    DEFF Research Database (Denmark)

    Jespersen, Sanne; Hønge, Bo Langhoff; Oliveira, Inés

    2014-01-01

    The West African country Guinea-Bissau is home to the world’s highest prevalence of HIV-2, and its HIV-1 prevalence is rising. Other chronic viral infections like human T-lymphotropic virus type 1 (HTLV-1) and hepatitis B virus are common as well. The Bissau HIV Cohort was started in 2007 to gain...... new insights into the overall effect of introducing antiretroviral treatment in a treatment-naı ̈ve population with concomitant infection with three retroviruses (HIV-1, HIV-2 and HTLV-1) and tuberculosis. The cohort includes patients from the HIV clinic at Hospital Nacional Sima ̃ o Mendes, the main...

  3. Potential contribution of a novel Tax epitope-specific CD4+ T cells to graft-versus-Tax effect in adult T cell leukemia patients after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Tamai, Yotaro; Hasegawa, Atsuhiko; Takamori, Ayako; Sasada, Amane; Tanosaki, Ryuji; Choi, Ilseung; Utsunomiya, Atae; Maeda, Yasuhiro; Yamano, Yoshihisa; Eto, Tetsuya; Koh, Ki-Ryang; Nakamae, Hirohisa; Suehiro, Youko; Kato, Koji; Takemoto, Shigeki; Okamura, Jun; Uike, Naokuni; Kannagi, Mari

    2013-04-15

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for adult T cell leukemia/lymphoma (ATL) caused by human T cell leukemia virus type 1 (HTLV-1). We previously reported that Tax-specific CD8(+) cytotoxic T lymphocyte (CTL) contributed to graft-versus-ATL effects in ATL patients after allo-HSCT. However, the role of HTLV-1-specific CD4(+) T cells in the effects remains unclear. In this study, we showed that Tax-specific CD4(+) as well as CD8(+) T cell responses were induced in some ATL patients following allo-HSCT. To further analyze HTLV-1-specific CD4(+) T cell responses, we identified a novel HLA-DRB1*0101-restricted epitope, Tax155-167, recognized by HTLV-1-specific CD4(+) Th1-like cells, a major population of HTLV-1-specific CD4(+) T cell line, which was established from an ATL patient at 180 d after allo-HSCT from an unrelated seronegative donor by in vitro stimulation with HTLV-1-infected cells from the same patient. Costimulation of PBMCs with both the identified epitope (Tax155-167) and known CTL epitope peptides markedly enhanced the expansion of Tax-specific CD8(+) T cells in PBMCs compared with stimulation with CTL epitope peptide alone in all three HLA-DRB1*0101(+) patients post-allo-HSCT tested. In addition, direct detection using newly generated HLA-DRB1*0101/Tax155-167 tetramers revealed that Tax155-167-specific CD4(+) T cells were present in all HTLV-1-infected individuals tested, regardless of HSCT. These results suggest that Tax155-167 may be the dominant epitope recognized by HTLV-1-specific CD4(+) T cells in HLA-DRB1*0101(+)-infected individuals and that Tax-specific CD4(+) T cells may augment the graft-versus-Tax effects via efficient induction of Tax-specific CD8(+) T cell responses.

  4. Seroprevalence and correlates of human T-cell lymphoma/leukemia virus type 1 antibodies among pregnant women at the University of Nigeria Teaching Hospital, Enugu, Nigeria

    Directory of Open Access Journals (Sweden)

    Okoye AE

    2014-09-01

    Full Text Available Augustine Ejike Okoye,1 Obike Godswill Ibegbulam,2 Robinson Chukwudi Onoh,3 Paul Olisaemeka Ezeonu,3 Ngozi I Ugwu,1 Lucky Osaheni Lawani,3 Chukwudi Simon Anigbo,2 Charles E Nonyelu21Department of Haematology and Immunology, Federal Teaching Hospital, Abakaliki, 2Department of Haematology and Immunology, University of Nigeria Teaching Hospital (UNTH, Ituku-Ozalla, 3Department of Obstetrics and Gynaecology, Federal Teaching Hospital, Abakaliki, NigeriaBackground: Human T-cell lymphoma/leukemia virus (HTLV-1 is a retrovirus transmitted vertically from mother to child parenterally and sexually by infected lymphocytes.Objective: The objective of this study was to determine the seroprevalence of HTLV-1 antibodies and associated risk factors for HTLV-1 infection among pregnant women in University of Nigeria Teaching Hospital, Enugu, southeast Nigeria.Materials and methods: A cross-sectional study was carried out from July to October 2010. Two hundred pregnant women were recruited consecutively from the antenatal clinic. Five milliliters of blood was collected from each of the participants into a plain sterile bottle and allowed to clot. The serum obtained was stored at -20°C until required for analysis. The serum samples were then analyzed for antibodies to HTLV-1 using a one-step incubation double-antigen sandwich enzyme-linked immunosorbent assay kit. Participants' demographic characteristics and degree of exposure to the risk factors associated with HTLV-1 infection were captured using a questionnaire. Statistical analysis of results was done using SPSS version 17.Results: The average age of the pregnant women was 28.94 years (standard deviation 4.17. The age-group with the highest representation was those between the ages of 26 and 30 years. Thirty-six percent of the population was above 30 years old. The result of the tests showed that only one respondent, a 31-year-old pregnant woman tested positive for HTLV-1 antibodies. Therefore, the

  5. Root Extract of Polygonum cuspidatum Siebold & Zucc. Ameliorates DSS-Induced Ulcerative Colitis by Affecting NF-kappaB Signaling Pathway in a Mouse Model via Synergistic Effects of Polydatin, Resveratrol, and Emodin

    Directory of Open Access Journals (Sweden)

    Baohai Liu

    2018-04-01

    Full Text Available Background:Polygonum cuspidatum Siebold & Zucc. (PCS has antibacterial properties and may prevent Ulcerative colitis (UC but related molecular mechanism remains unknown. NF-κB signaling pathway is associated with inflammatory responses and its inactivation may be critical for effective therapy of UC.Methods: UC mouse (C57BL/6J model was established by using dextran sulfate sodium (DSS. The extract of PCS (PCSE was prepared by using ethanol and its main ingredients were measured by HPLC. Thirty-two UC mice were evenly assi