Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human herpesvirus 8 (HHV-8; Kaposi's sarcoma-associated herpesvirus is linked to Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD), all of which are viewed as cytokine-driven malignancies. In particular, interleukin-6 (IL-6) has been found to promote the growth and proliferation of cells from KS and PEL. HHV-8 encodes a homologue of IL-6 (viral IL-6 [vIL-6]), which functions similarly to the cellular IL-6. Therefore, vIL-6 has been proposed to play an important role in tumor progression. Several groups have reported that vIL-6 is expressed from the HHV-8 genome at higher levels in PEL and MCD lesions than in KS lesions. However, it is not clear how vIL-6 expression is regulated. We characterized the transcription at the vIL-6 gene locus by Northern blot analysis and, in contrast to previous reports, we observed two distinct transcripts from induced PEL cell lines. This observation was confirmed by primer extension, as well as 5' and 3' rapid amplification of cDNA ends. Two transcription initiation sites and putative TATA boxes were mapped. A luciferase reporter system was used to show that each of the two putative TATA boxes contributed to vIL-6 promoter activity. Since virally encoded transcriptional activator Rta potently activates the viral lytic gene expression cascade, we examined the role of Rta in controlling vIL-6 gene expression and found that Rta activated the vIL-6 promoter. The Rta-responsive element was further mapped through a series of deletion constructs. Electrophoretic mobility shift assays demonstrated that Rta binds directly to the vIL-6 Rta-responsive element, and the core Rta-responsive element was mapped to a 26-bp region spanning from nucleotide 18315 to 18290 on the viral genome. We propose that the existence of two vIL-6 promoters offers opportunities for differential regulation of vIL-6 gene expression in different tissue types and may account for the variable vIL-6 levels observed in KS, PEL, and MCD.
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PMID:Transcriptional regulation of the interleukin-6 gene of human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus). 1213 31

Human herpesvirus 8 (HHV-8)/Kaposi sarcoma-associated herpesvirus (KSHV) is linked to a number of malignancies thought to be driven by cytokines, including interleukin-6 (IL-6). Rta, a transcriptional activator encoded by HHV-8/KSHV, activates the viral lytic cycle leading to the expression of several viral genes implicated in viral pathogenesis. However, the effect of HHV-8/KSHV Rta on cellular genes has not been reported. We present evidence that the human IL-6 (hIL-6) gene is up-regulated by Rta. Rta potently activated (up to 164-fold) the hIL-6 promoter in a dose-dependent manner in a transient transfection reporter system. Rta also induced expression of the endogenous hIL-6 gene, as shown by enzyme-linked immunosorbent assays. Activation of the hIL-6 gene by HHV-8/KSHV supports the role of hIL-6 in the development of these malignancies.
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PMID:Rta of the human herpesvirus 8/Kaposi sarcoma-associated herpesvirus up-regulates human interleukin-6 gene expression. 1217 19

Human herpesvirus-8 (HHV-8) is etiologically associated with Kaposi's sarcoma (KS), body cavity-based lymphoma (BCBL), and multicentric Castleman's disease (MCD). These HHV-8-associated diseases arise predominantly in acquired immunodeficiency syndrome (AIDS) patients. Human interleukin-6 (huIL-6) elevated in the serum of AIDS patients is suggested to stimulate the growth of KS and BCBL and to augment the symptoms of MCD. To determine whether huIL-6 stimulates HHV-8 replication directly, expression of the HHV-8 ORF-50 immediate-early gene (transcription activator) and ORF-26 late lytic gene (a capsid protein) was assessed in a BCBL-1 cell line stimulated by huIL-6 by means of real-time reverse transcription-polymerase chain reaction. huIL-6 induced both ORF-50 and ORF-26 expression, and the maximal ORF-50 expression appeared earlier than that of ORF-26. The data indicate that huIL-6 reactivates HHV-8 in BCBL-1 cells through inducing ORF-50. We also confirmed the previously reported activities of HHV-8-encoded huIL-6 homologue (viral interleukin-6 [vIL-6]) on human immunodeficiency virus (HIV) replication in U1 cell line and huIL-6 production by MT-4 T cells, and utilizing monoclonal antibodies to the huIL-6 receptor components, we elucidated that gp130 is the signaling molecule necessary for these vIL-6 activities. These data suggest the possible existence of interaction between HIV and HHV-8 via IL-6, and that the blockade of IL-6 signal by anti-IL-6R antibody or anti-gp130 antibody can constitute a strategy to treat HIV/HHV-8 dually infected patients.
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PMID:Human interleukin-6 induces human herpesvirus-8 replication in a body cavity-based lymphoma cell line. 1222 29

Kaposi sarcoma-associated herpesvirus (KSHV) is known to be associated with 3 distinct lymphoproliferative disorders: primary effusion lymphoma (PEL), multicentric Castleman disease (MCD), and MCD-associated plasmablastic lymphoma. We report 3 cases of a previously undescribed KSHV-associated lymphoproliferative disorder. The disease presented as localized lymphadenopathy and showed a favorable response to chemotherapy or radiotherapy. Histologically, the lymphoproliferation is characterized by plasmablasts that preferentially involved germinal centers of the lymphoid follicles, forming confluent aggregates. They were negative for CD20, CD27, CD79a, CD138, BCL6, and CD10 but showed monotypic kappa or lambda light chain. Clusters of CD10(+)CD20(+) residual follicle center cells were identified in some of the follicles. The plasmablasts were positive for both KSHV and EBV, and most of them also expressed viral interleukin-6 (vIL-6). Unexpectedly, molecular analysis of whole tissue sections or microdissected KSHV-positive aggregates demonstrated a polyclonal or oligoclonal pattern of immunoglobulin (Ig) gene rearrangement. The plasmablasts showed somatic mutation and intraclonal variation in the rearranged Ig genes, and one case expressed switched Ig heavy chain (IgA), suggesting that they originated from germinal center B cells. We propose calling this distinctive entity "KSHV-associated germinotropic lymphoproliferative disorder."
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PMID:KSHV- and EBV-associated germinotropic lymphoproliferative disorder. 1238 45

Lymphoma cells infected with Kaposi's sarcoma-associated herpesvirus are autocrine dependent on virus-derived interleukin-6 (IL-6), but not on cellular IL-6. During viral infection, host cells induce the antiviral factor interferon (IFN) to up-regulate p21, initiate cell cycle arrest, and inhibit virus replication. Viral IL-6, however, blocks IFN signaling. A viral transcriptional program exists in which only the viral IL-6 gene is directly activated by IFN-alpha, allowing the virus to modify its cellular environment by sensing and responding to levels of intracellular IFN signaling. The human cytokine cannot mimic this effect because IFN-alpha down-regulates the IL-6 receptor, gp80. Viral IL-6 bypasses the gp80 regulatory checkpoint by binding directly to the gp130 transducer molecule, resulting in tumor cell autocrine dependence on the viral cytokine for proliferation and survival.
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PMID:Viral IL-6-induced cell proliferation and immune evasion of interferon activity. 1243 62

Kaposi's sarcoma (KS), the most common malignancy associated with HIV infection, is caused by the Kaposi sarcoma herpesvirus (KSHV). Exacerbations of KSHV are associated with increased human interleukin-6 (HuIL-6), and elevated IL-6 could be related to the development of KS. IL-4, a cytokine with pleiotropic effects, suppresses IL-6 in vivo and modestly inhibits AIDS-KS-derived cells in vitro. Suppression of IL-6 by exogenous IL-4 could result in antitumor activity. We report the results of a clinical trial to test this hypothesis. A phase I/II dose escalation safety, tolerance, and efficacy trial was conducted in patients with biopsy-proven AIDS-related KS, at two university medical centers. Patients were scheduled to receive IL-4 (0.5, 1.5, 3.0, or 4.0 microg/kg/day) administered subcutaneously (s.c.) in sequential cohorts. Patients were continued on study as long as the drug was tolerated or the disease progressed. Patients were followed for antitumor activity, effects on viral replication, immune status, and clinical and laboratory toxicity. Seventeen patients were enrolled at two sites over a 21-month period. There were 15 males and 2 females, and 1 patient was Hispanic. All patients had a Karnofsky score >70. Patients enrolled only into the two lower dose cohorts (0.5 and 1.5 microg/kg/day). Both groups had similar baseline characteristics. The median time on treatment was only 7.4 and 8.4 weeks for the 0.5 and 1.5 microg/kg/day dose levels, respectively. There was significant neutropenia, with 6 patients having grade 3 or greater toxicity requiring granulocyte colony-stimulating factor (G-CSF). Three patients on a dose of 1.5 microg/kg/day stopped treatment due to protocol-defined toxicity. There were no appreciable effects on CD4/CD8 counts. HIV viral RNA did not significantly change over time. However, in several people, it appeared to decline with treatment and rebound with discontinuation of treatment. Corresponding changes were noted in the HIV immunocomplex dissociated (ICD) p24 antigen. One patient had a partial response, 11 patients had stable disease, and 5 patients had disease progression during the short period of treatment. The maximum tolerated dose for IL-4 in patients with advanced AIDS-related KS is 1.5 microg/kg/day. At this dose level, IL-4 is poorly tolerated and is not an effective KS treatment. Treatment of the majority of patients is discontinued because of drug-related toxicity or because of disease progression. Future studies of IL-4 should be confined to studies of cytokine manipulation of the underlying HIV infection, as there appears to be little antitumor activity.
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PMID:Lack of antitumor activity and intolerance of interleukin-4 in patients with advanced HIV disease and Kaposi's sarcoma. 1251 14

We describe a 27-year-old female with a mesenterial localisation of the hyaline vascular type of Castleman's disease. A review of the literature is given with emphasis on the different pathogenesis of the subtypes. The hyaline vascular type is a disorder of stromal cells, which can be complicated by the development of soft tissue sarcomas. The plasma cell type is a plasma cell disorder with elevated levels of interleukin-6 (IL-6). In the multicentric type, infection with human herpes virus-8 (HHV-8) plays an important role in the pathogenesis. The development of Kaposi's sarcoma and some lymphomas are related to the presence of HHV-8. As the different subtypes have a different pathogenesis they should be regarded as distinct diseases.
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PMID:Hyaline vascular Castleman's disease: a case report and brief review of the literature. 1268 94

We previously identified retroperitoneal fibromatosis-associated herpesvirus (RFHV) as a simian homolog of Kaposi's sarcoma-associated herpesvirus (KSHV) in a fibroproliferative malignancy of macaques that has similarities to Kaposi's sarcoma. In this report, we cloned 4.3 kb of divergent locus B (DL-B) flanking the DNA polymerase gene from two variants of RFHV from different species of macaque with a consensus degenerate hybrid oligonucleotide primer approach. Within the DL-B region of RFHV, viral homologs of the cellular interleukin-6, dihydrofolate reductase, and thymidylate synthase genes were identified, along with a homolog of the gammaherpesvirus open reading frame (ORF) 10. In addition, a homolog of the KSHV ORF K3, the modulator of immune recognition-1, was identified. Our data show a close similarity in sequence conservation, gene content, and genomic structure between RFHV and KSHV which strongly supports the grouping of these viral species within the same RV-1 rhadinovirus lineage and the hypothesis that RFHV is the macaque homolog of KSHV.
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PMID:Analysis of 4.3 kilobases of divergent locus B of macaque retroperitoneal fibromatosis-associated herpesvirus reveals a close similarity in gene sequence and genome organization to Kaposi's sarcoma-associated herpesvirus. 1269 11

Kaposi's sarcoma-associated herpesvirus, the viral agent of Kaposi's sarcoma, is associated with two lymphoproliferative disorders: primary effusion lymphoma and multicentric Castleman's disease. To identify other lymphoproliferative conditions linked with Kaposi's sarcoma-associated herpesvirus, we studied non-Hodgkin's lymphomas arising in individuals with AIDS-associated Kaposi's sarcoma. Formalin-fixed tissues from 24 such lymphomas were examined. As expected, two primary effusion lymphomas were Kaposi's sarcoma-associated herpesvirus-positive, with immunohistochemistry demonstrating the Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen in the nuclei of all neoplastic cells. Additionally, three of seven evaluable cases of the immunoblastic variant of diffuse large B-cell lymphoma (immunoblastic lymphoma) showed similar latency-associated nuclear antigen staining. These Kaposi's sarcoma-associated herpesvirus-positive immunoblastic lymphomas resembled primary effusion lymphoma histologically but were not known to involve body cavities (sites included lymph nodes, soft tissues of the neck, and spleen). Notably, 5-20% of the neoplastic cells in the Kaposi's sarcoma-associated herpesvirus-positive immunoblastic lymphomas also showed cytoplasmic staining for viral interleukin-6, a biologically active cytokine homologue found in primary effusion lymphoma. We conclude that Kaposi's sarcoma-associated herpesvirus is present in some immunoblastic lymphomas in persons with AIDS-associated Kaposi's sarcoma.
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PMID:Immunoblastic lymphoma in persons with AIDS-associated Kaposi's sarcoma: a role for Kaposi's sarcoma-associated herpesvirus. 1274 48

Immunosuppression associated with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) markedly increases the risk for development of several cancers. Despite its dramatic decrease in frequency after the introduction of highly active antiretroviral therapy (HAART), Kaposi's sarcoma (KS) remains the most common neoplastic manifestation of AIDS. KS is a multicentric angioproliferative tumor, characterized microscopically by spindle cells. KS cells produce and respond to angiogenic factors such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor-A (VEGF-A). In addition to cellular growth factors, the trans-activator HIV protein Tat plays a major role in the pathogenesis of AIDS-related KS by augmenting the angiogenic activities of bFGF and VEGF-A, and activating the VEGF receptor-2. Viral products from the recently described Kaposi's sarcoma-associated herpesvirus (KSHV) also exhibit potent angiogenic activities. KSHV is consistently associated with KS and two lymphoproliferative disorders, primary effusion lymphoma (PEL) and the plasma cell variant of multicentric Castleman's disease (MCD). Several viral genes may contribute to the phenotype of PEL and MCD: among them, a viral homologue of interleukin-6 (vIL-6) has attracted much attention due to its potential to stimulate B cell growth and accelerate angiogenesis via VEGF-A induction. In this review, we summarize current knowledge and hypothesis regarding the cellular and viral angiogenic factors involved in the pathogeneses of AIDS-related malignancies, and discuss novel therapeutic strategies based on targeting pro-angiogenic factors.
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PMID:Targeted inhibition of angiogenic factors in AIDS-related disorders. 1276 89


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