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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a FADD-like interferon converting enzyme or caspase 8 (FLICE) inhibitory protein (vFLIP) that prevents death receptor-mediated apoptosis by inhibiting the recruitment and activation of FLICE. Since vFLIP physically interacts with tumor necrosis factor receptor associated factor 2 (TRAF2) and TRAF2 mediates activation of the jun NH(2)-terminal kinase (JNK)/activation protein 1 (AP1) pathway, we hypothesized that vFLIP might also activate this pathway. To evaluate this hypothesis, we transiently and stably transfected a vFLIP expression construct and performed several complementary assays to document that vFLIP activates the JNK/AP1 pathway and does so in a TRAF-dependent fashion. As vFLIP also activates the nuclear factor kappaB (NF-kappaB) signaling pathway and the NF-kappaB and JNK/AP1 pathways both modulate cellular interleukin-6 (cIL-6) expression, we postulated that vFLIP induces expression of this cytokine. We show that vFLIP induces cIL-6 expression and activates the cIL-6 promoter, and maximal activation of the cIL-6 promoter by vFLIP requires NF-kappaB and AP1 activation. In addition, vFLIP and latency-associated nuclear antigen (LANA), another KSHV-encoded latent protein, potentiate each other's ability to activate the cIL-6 promoter. Gene silencing experiments by RNA interference demonstrate that vFLIP in BCBL-1 endogenously infected primary effusion lymphoma (PEL) cells mediates JNK/AP1 activation and cIL-6 expression. Thus, we conclude that vFLIP, in addition to its known effects on NF-kappaB activation, also modulates the JNK/AP1 pathway and induces gene expression from the cIL-6 promoter in a JNK/AP1-dependent fashion.
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PMID:Kaposi's sarcoma-associated herpesvirus encoded vFLIP induces cellular IL-6 expression: the role of the NF-kappaB and JNK/AP1 pathways. 1277 88

Analysis of the genome of human herpesvirus 8 (HHV-8) led to the discovery of several novel genes, unique among the characterized gammaherpesviruses. These include cytokines (interleukin-6 and chemokine homologues), two putative signal-transducing transmembrane proteins encoded by genes K1 and K15 at the genome termini, and an OX-2 (CD200) receptor homologue that had not previously been identified in a gammaherpesvirus. HHV-8 also specifies a diverged version of the gammaherpesvirus-conserved G protein-coupled chemokine receptor (vGCR) and a latently expressed protein unique to HHV-8 specified by open reading frame (ORF) K12. These cytokine and receptor homologues mediate signal transduction or modulate the activities of other endogenous cytokines and receptors to enhance viral productive replication, regulate latent-lytic switching, evade host attack, or mediate cell survival. The viral signalling ligands and receptors are also potential contributors to virus-associated diseases, Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease, and so represent potentially important targets for therapeutic and antiviral drugs. Understanding these proteins' modes of action and functions in viral biology and disease is therefore of considerable importance, and the subject of this review.
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PMID:Human herpesvirus-8-encoded signalling ligands and receptors. 1292 88

Kaposi's sarcoma-associated herpesvirus (KSHV, or HHV-8) encodes a pathogenic viral homologue of human interleukin-6 (IL-6). In contrast to human IL-6 (hIL-6), viral IL-6 (vIL-6) binds directly to, and activates, the shared human cytokine signaling receptor gp130 without the requirement for pre-complexation to a specific alpha-receptor. Here, we dissect the biochemical and functional basis of vIL-6 mimicry of hIL-6. We find that, in addition to the "alpha-receptor-independent" tetrameric vIL-6/gp130 complex, the viral cytokine can engage the human alpha-receptor (IL-6Ralpha) to form a hexameric vIL-6/IL-6Ralpha/gp130 complex with enhanced signaling potency. In contrast to the assembly sequence of the hIL-6 hexamer, the preformed vIL-6/gp130 tetramer can be decorated with IL-6Ralpha, post facto, in a "vIL-6-dependent" fashion. A detailed comparison of the viral and human cytokine/gp130 interfaces indicates that vIL-6 has evolved a unique molecular strategy to interact with gp130, as revealed by an almost entirely divergent structural makeup of its receptor binding sites. Viral IL-6 appears to utilize an elegant combination of both convergent, and unexpectedly divergent, molecular strategies to oligomerize gp130 and activate similar downstream signaling cascades as its human counterpart.
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PMID:Molecular mechanisms for viral mimicry of a human cytokine: activation of gp130 by HHV-8 interleukin-6. 1467 70

Idiopathic plasmacytic lymphadenopathy (IPL) with polyclonal hyperimmunoglobulinemia is considered identical to multicentric Castleman's disease (MCD) reported in western countries. Clinically, both IPL and MCD are characterized by multicentric lymphadenopathy, prominent polyclonal hypergammaglobulinemia, elevated erythrocyte sedimentation rate, elevated serum interleukin-6 concentration, bone marrow plasmacytosis, and various abnormal laboratory data such as anemia and positive autoantibodies. However, IPL has a significantly better 5-year survival rate than that of MCD. Moreover, none of the present 16 cases developed Kaposi's sarcoma or B-cell lymphoma. Histologically, the interfollicular area contains a sheet of polytypic mature plasma cells in both IPL and MCD. In MCD, the majority of lymphoid follicles had hyaline-vascular germinal centers. However, lymphoid follicles of IPL usually exhibit a hyperplastic germinal center. Immunostaining also demonstrated a normal/reactive follicular dendritic cell network pattern in the germinal center of IPL. Moreover, there were no human herpes virus-8-positive cells detected by immunohistochemistry. The overall clinicopathologic and immunohistochemical findings of our 16 cases suggest that IPL is distinct from MCD reported in Western countries.
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PMID:Clinical implication of idiopathic plasmacytic lymphadenopathy with polyclonal hypergammaglobulinemia: a report of 16 cases. 1573 69

Kaposi's sarcoma-associated herpesvirus interleukin-6 (vIL-6) is a structural and functional homologue of the human cytokine IL-6 (hIL-6). hIL-6 and vIL-6 exhibit similar biological functions and both act via the gp130 receptor subunit to activate the Janus tyrosine kinase (JAK)1 and signal transducer and activator of transcription (STAT)1/3 pathway. Here we show that vIL-6 is N-linked glycosylated at N78 and N89 and demonstrate that N-linked glycosylation at site N89 of vIL-6 markedly enhances binding to gp130, signaling through the JAK1-STAT1/3 pathway and functions in a cytokine-dependent cell proliferation bioassay. Although hIL-6 is also N-glycosylated at N73 and multiply O-glycosylated, neither N-linked nor O-linked glycosylation is necessary for IL-6 receptor alpha-dependent binding to gp130 or signaling through JAK1-STAT1/3. As distinct from vIL-6, unglycosylated hIL-6 is as potent as glycosylated hIL-6 in stimulating B cell proliferation. These findings highlight distinct functional roles of N-linked glycosylation in viral and cellular IL-6.
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PMID:N-linked glycosylation is required for optimal function of Kaposi's sarcoma herpesvirus-encoded, but not cellular, interleukin 6. 1497 Jan 77

It is widely accepted that there is a causal association between Kaposi sarcoma-associated herpesvirus (KSHV) and Kaposi sarcoma (KS). However, the majority of individuals infected with KSHV never develop KS. Here, we present a unique familial case of classic KS, in which the disease occurs in 4 siblings who have no recognized underlying immunodeficiency. We examine risk factors that could play a role in this condition, including KSHV infection, KSHV DNA load, genetic variants of KSHV, infection with additional viruses, interleukin-6-promoter polymorphism, and HLA genotype. We hypothesize that a genetic susceptibility to KS, in combination with KSHV infection, may play an important role in the presented familial case.
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PMID:Familial clustering of classic Kaposi sarcoma. 1514 69

Castlemans disease (CD) was described from Benjamin Castleman in 1954. The disease today is enumerated among lymphoproliferative disorders and has unknown etiology, but a interleukin-6 (IL-6) dysregulation and a reaction to viral antigens (HHV8) especially in patients with immunodeficiency is suspected. It is observed in adult and young people, in male or female with equal frequency; the appearance in childhood is extremely rare. The disease shows various clinical and histological pictures, with a localized type (involvement of one lymph node group) described more frequently than the multicentric one. Histological examination distinguish a "hyaline-vascular type" that represents approximately the 91%, a plasma cell type" that represents approximately the 9% has an aggressive clinical outcome, and the "mixed types". Initial symptoms are nearly absent, but not for the plasma cell type. We describe the clinical case of a female patient 21 years old. She reached our observation in May 1999, referring us for pelvic pains and amenorrhoea from four years. During 1996 she underwent to a laparoscopy that diagnosed an endometrial cyst on left ovary. A year later a new retroperitoneal mass was discovered and a second laparoscopy was performed with a little partial excision of the tumor. In our Institute the us and the TC showed a retroperitoneal mass of 4.5 cm of diameter, next to the uterus and the iliac left vessels. The patient underwent surgical laparotomic excision and histological examination showed hyaline vascular type of CD. Three years after surgery the patient is still free of any symptoms.
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PMID:[Castleman's disease: a case report]. 1520 15

A 32-year-old HIV-1 positive man was diagnosed with Castleman's disease following a long history of constitutional symptoms. Primary therapy with single agent rituximab was associated with a near complete response. During this time, his KSHV (Kaposi's sarcoma-associated herpesvirus) viral load decreased and we also observed immediate, large and sustained decreases in interleukin-6 (IL-6) and tumor necrosis factor-alpha levels (TNF-alpha). This highlights the close association between circulating cytokines such as IL-6 and virally-induced malignancy.
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PMID:Resolution of AIDS-related Castleman's disease with anti-CD20 monoclonal antibodies is associated with declining IL-6 and TNF-alpha levels. 1522 59

Kaposi sarcoma (KS) is a multifocal angioproliferative neoplasm strictly dependent on angiogenic growth factors and cytokines and invariably associated with infection by the Kaposi sarcoma-associated herpesvirus (KSHV or HHV8). A G protein-coupled receptor encoded by KSHV (vGPCR) is able to initiate KS-like tumors when targeted to the vascular endothelium of mice. Analogous to human KS, vGPCR sarcomagenesis involves the paracrine secretion of angiogenic growth factors and proinflammatory molecules from vGPCR-expressing cells. Here we demonstrate that vGPCR up-regulates expression and secretion of critical KS cytokines by stimulating key transcription factors, including nuclear factor-kappaB (NF-kappaB), activator protein-1 (AP-1), and nuclear factor of activated T cells (NFAT), through the activation of the small G protein Rac1. Inhibition of Rac1 blocked vGPCR-induced transcription and secretion of KS cytokines, including interleukin-6 (IL-6), IL-8, and growth-regulated oncogene alpha (GROalpha), in vitro and reduced vGPCR tumorigenesis in vivo. Moreover, endothelial-specific infection with the constitutively active Rac1QL induced vascular lesions in mice that were remarkably similar to early vGPCR experimental lesions. These results identify Rac1 as a key mediator of vGPCR paracrine neoplasia, suggesting that this small G protein and its downstream effectors may represent suitable therapeutic targets for the treatment of KS.
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PMID:The small GTPase Rac1 links the Kaposi sarcoma-associated herpesvirus vGPCR to cytokine secretion and paracrine neoplasia. 1523 71

Viral interleukin-6 (vIL-6) is a homolog of cellular IL-6 that is encoded by the Kaposi's sarcoma-associated herpesvirus (KSHV) genome. vIL-6 binds to the IL-6 signal transducer gp130 without the cooperation of the IL-6 high affinity receptor to induce STAT3 DNA binding and cell proliferation. Although vIL-6 is believed to be important in the pathogenesis of KSHV-induced diseases, its secretion and post-translational modifications have not previously been characterized. Pulse-chase analysis revealed that the half-time of vIL-6 secretion is approximately 8-fold longer than that of human IL-6. Yet, the vIL-6 signal sequence targets human IL-6 secretion to nearly wild-type levels. Surprisingly, vIL-6 was not secreted from a cell line that does not express gp130 but expression of human gp130 in these cells enabled the secretion of vIL-6. Consistent with this observation, complete maturation of gp130 N-glycans is inhibited by vIL-6 coexpression, suggesting that the binding of the receptor to vIL-6 occurs intracellularly in early or pre-Golgi compartments. Furthermore, a vIL-6 mutant containing an endoplasmic reticulum retention signal is not secreted but does still induce receptor activation and signaling. Secreted vIL-6 is completely glycosylated at both possible N-glycosylaton sites and contains a large proportion of immature high-mannose glycans that is not typical of cytokines. These findings suggest that vIL-6 may induce gp130 signaling by an exclusively autocrine mechanism that relies on intracellular binding to its receptor. During KSHV infection, vIL-6 may only induce signaling in KSHV-infected cells to benefit the viral life cycle and promote oncogenic transformation.
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PMID:Kaposi's sarcoma-associated herpesvirus-encoded viral interleukin-6 is secreted and modified differently than human interleukin-6: evidence for a unique autocrine signaling mechanism. 1525 50


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