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

In this study we evaluated the effect of human immunodeficiency virus type 1 (HIV-1) recombinant tat-protein on the production of interleukin-6 (IL-6), granulocyte/macrophage colony stimulating factor (GM-CSF) and tumor necrosis factor-alpha (TNF-alpha) by purified peripheral blood monocytes. Whereas no effects were observed on TNF-alpha and GM-CSF production, recombinant tat-protein was able to induce the production of IL-6 by peripheral blood monocytes in a dose-dependent fashion for concentrations ranging from 1 ng/ml to 1 micrograms/ml. Pre-exposure of tat-protein with a polyclonal neutralizing anti-tat antibody (dilution 1:100) completely abrogated the tat-dependent increase in IL-6 production. The ability of tat-protein to selectively stimulate the production of IL-6 by peripheral blood monocytes could help to explain the presence of elevated levels of IL-6 in the serum of HIV-1 seropositive individuals, especially in patients in advanced stages of the disease with an active viral replication.
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PMID:Human immunodeficiency virus type 1 (HIV-1) tat-protein stimulates the production of interleukin-6 (IL-6) by peripheral blood monocytes. 851 May 64

Recombinant human tumor necrosis factor (TNF) binding protein-1 (r-h TBP-1) and recombinant human soluble dimeric TNF receptor (rhu TNFR:Fc) were used to determine the relative contributions of TNF to phorbol myristate acetate (PMA) and cytokine-induced human immunodeficiency virus type 1 (HIV-1) replication in chronically infected cell lines. Treatment of HIV-1-infected promonocytic U1 cells with r-h-TBP-1 or rhu TNFR:Fc reduced PMA-induced HIV-1 p24 antigen production in a concentration-dependent manner, with a maximal inhibition of approximately 90%. Maximal inhibition of p24 antigen production in T-lymphocytic ACH-2 cells was 47% with r-hTBP-1 and 42% with rhu TNFR:Fc. r-hTBP-1 and rhu TNFR:Fc also decreased p24 antigen synthesized by U1 cells in response to other stimuli, including phytohemagglutinin (PHA)-induced supernatant, granulocyte-macrophage colony-stimulating factor, interleukin-6, and TNF. Addition of r-hTBP-1 to U1 cells during the last 4 h of a 24 h incubation with PMA still inhibited p24 antigen production by 15%. U1 cells stimulated with 10(-7) M PMA released approximately 1 ng/ml endogenous TBP-1 with an initial peak observed at 1 h and a second peak at 24 h after PMA stimulation. r-hTBP-1 also partially reversed inhibition of U1 cellular proliferation caused by PMA. Both r-hTBP-1 and rhu TNFR:Fc blocked PMA induction of nuclear factor (NK)- kappa B DNA-binding activity in U1 cells in association with decreases in HIV-1 replication. We conclude that soluble TNF receptors can inhibit stimuli-induced HIV-1 expression and NK- kappa B DNA-binding activity in chronically infected U1 cells.
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PMID:Soluble tumor necrosis factor receptors inhibit phorbol myristate acetate and cytokine-induced HIV-1 expression chronically infected U1 cells. 860 87

Development of Kaposi's sarcoma (KS) after glucocorticoid therapy has been observed in a variety of clinical states including human immunodeficiency virus-1 infection and recent in vitro studies provided evidence for a direct stimulation effect of glucocorticoid hormones on KS cell proliferation. The importance of glucocorticoids in KS pathogenesis is further highlighted by the finding that glucocorticoids synergize with cytokines to promote acquired immune deficiency syndrome (AIDS)-associated KS (AIDS-KS) growth. Furthermore, cytokine effects were abrogated by the glucocorticoid antagonist RU-486. As glucocorticoid action is mediated through activation of their intracellular cognate receptors, we hypothesized that enhanced responsiveness of AIDS-KS cells to glucocorticoids may be due to elevated glucocorticoid receptor (GR) content. Indeed, high expression of GRs in AIDS-KS tumor biopsies was detected both at the level of mRNA and protein. Quantitative measurements of GRs in these specimens by a sensitive immunoassay showed that GR content was significantly elevated in the tumor tissue (4663 fmol/mg protein) compared with the uninvolved skin of the same patients (2777 fmol/mg protein), both of which were markedly above the normal skin of healthy donors (893 fmol/mg protein). Immunocytochemical analysis confirmed the presence of GRs in the cytoplasm and the nucleus of KS cells. Interestingly, four major KS cytokines, namely interleukin-1beta, interleukin-6, tumor necrosis factor-alpha, and oncostatin M, all of which are known autocrine growth factors for AIDS-KS cells, significantly increased the expression of functional GRs in cultured AIDS-KS cells. The latter result may explain, at least in part, the synergistic effect of glucocorticoid and oncostatin M on AIDS-KS cell proliferation. Thus, the high levels of GR expression in AIDS-KS and the up-regulation of GRs by KS-growth-promoting factors may confer enhanced and sustained sensitivity to the stimulatory effects of glucocorticoids. The data presented also provide molecular bases for therapeutic interventions targeting GRs in this disease.
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PMID:Expression and cytokine regulation of glucocorticoid receptors in Kaposi's sarcoma. 866 84

Central nervous system (CNS) involvement is common during human immunodeficiency virus type-1 (HIV-1) infection. The neurologic disease of the CNS most frequently observed during acquired immunodeficiency syndrome (AIDS) is HIV-1-associated cognitive/motor complex or AIDS dementia complex (ADC), which is most likely a direct consequence of HIV-1 infection of the CNS. The peripheral nervous system (PNS) is also affected in HIV-1-infected individuals and there are several features of immune- and cytokine-related pathogenesis in both the CNS and PNS that are reviewed. Several lines of evidence demonstrate aspects of immune activation in the CNS and peripheral nervous system (PNS) of HIV-1-infected individuals. The relative paucity of HIV-1 expression in contrast to widespread functional and pathologic changes in the CNS and PNS of AIDS patients, and the lack of evidence of productive infection of HIV-1 in neuronal cells in vivo lead to the possibility of indirect or immunopathogenic mechanisms for HIV-1-related neurologic diseases. Proposed mechanisms of neuronal and glial cell damage are injury of oligodendrocytes by tumor necrosis factor-alpha (TNF-alpha) released from activated macrophage/microglia, calcium-dependent excitoneurotoxicity induced by gp120 HIV-1 envelope protein, N-methyl-D-aspartate (NMDA) receptor-mediated neurotoxicity by quinolinic acid (a product of activated macrophages), cell injury by HIV-1-specific cytotoxic T cells, and apoptosis of oligodendrocytes or neurons triggered by interaction between cell surface receptors and HIV-1 gp120 protein. Common to those mechanisms is the dependence on cellular activation with expression of proinflammatory cytokines (TNF-alpha, interleukin-1). Amplification of activation signals through the cytokine network by macrophage/astrocyte/endothelial cell interactions, and cell-to-cell contact between activated macrophages and neural cells by upregulation of adhesion molecules dramatically enhances the toxic effect of macrophage products. Expression of immunosuppressive cytokines such as interleukin-4, interleukin-6, and transforming growth factor-beta is also increased in the CNS and PNS of HIV-1-infected patients. This may serve as neuroprotective and regenerative mechanism against insults to nervous system tissue.
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PMID:Role of immune activation and cytokine expression in HIV-1-associated neurologic diseases. 874 77

The interaction between a chronically human immunodeficiency virus type 1 (HIV-1)-infected promonocytic line (U1) and a normal human embryonic lung fibroblast line (MRC-5) on HIV-1 expression was investigated. Coculture of U1 cells with MRC-5 cells induced HIV-1 reverse transcriptase (RT) activities 40- to 50-fold higher than those of parallel control cultures of U1 cells. Culture of U1 cells in the presence of media conditioned by MRC-5 cell culture supernatants resulted in a 30- to 40-fold greater HIV-1 RT activity over a 6-day period. HIV-1 RT activity, however, was not increased in the chronically infected T lymphocyte cell line (ACH-2) by either coculture with MRC-5 cells or when cultured in the MRC-5 cell culture supernatant-conditioned media. A polyclonal antibody against interleukin-6 (IL-6) blocked HIV-1 induction in the U1 cells by MRC-5 culture supernatants, indicating that IL-6 plays an important role in the HIV-1 induction. The magnitude of HIV-1 induction by the MRC-5 cell culture supernatant-conditioned media was proportional to the concentration of IL-6. In addition, the supernatants from three other normal human lung fibroblast (HLF) cell lines induced HIV-1 RT expression in U1 cells. Thus, normal unstimulated HLFs stimulate HIV-1 expression in chronically infected promonocytic cells by secreting IL-6, suggesting that the interaction of HLFs and macrophages may play an important role in the development of HIV-1 infection in the lungs.
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PMID:Induction of HIV-1 expression in chronically infected promonocytic cells cocultured with human lung fibroblasts. 876 62

'Restricted' human immunodeficiency virus type (HIV-1) infection of astrocytes is recognized in vivo in some pediatric and adult AIDS brains and in vitro in a small proportion of transfected primary fetal astrocytes. We investigated the extent of HIV-1JR-FL expression in fetal astrocytes and macrophages cultivated alone or together. Peak HIV-1 p24 antigen titres in supernatant fluids of macrophage cultures were increased with monocyte/macrophages from certain donors and were higher when macrophages were cocultivated with astrocytes. Structural HIV-1 gene (gp 41 and pol) products (protein and mRNA) were observed only in macrophages. Ten days after HIV-1JR-FL infection, astrocytes in a monoculture were stained negative or only weakly positive (1-2+) for Nef, whereas in a coculture up to 100% of astrocytes displayed Nef staining (up to 4+) in the cytoplasm. The streptavidine-biotine-peroxidase technique with certain monoclonal antibodies to Nef (Ovod et al, 1992) was specific for infected astrocytes. The intensity of Nef staining was higher in astrocytes cultivated with monocyte/macrophages from certain donors. In the coculture, tumor necrosis factor-alpha (TNF-alpha) was expressed in the astrocyte cytoplasm earlier after coinfection with HIV-1 and cytomegalovirus (CMV) compared to infection with HIV-1 alone. Interleukin-6 (IL-6) was secreted spontaneously and transiently in uninfected cocultures, but in a prolonged fashion following HIV-1 and HIV-1/CMV infections. The interactions between HIV-1- and CMV-infected macrophages and astrocytes lead to upregulation of TNF-alpha and IL-6 and enhancement of productive HIV-1 infection of macrophages and of 'restricted' HIV-1 infection of astrocytes with implications for the pathogenesis of AIDS dementia.
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PMID:Regulation of HIV-1 infection in astrocytes: expression of Nef, TNF-alpha and IL-6 is enhanced in coculture of astrocytes with macrophages. 879 8

Cytokines are likely involved in hemodialysis-associated complications such as immunodeficiency and beta 2 microglobulin amyloidosis. Because transforming growth factors beta (TGF beta) exert immunosuppressive effects on lymphocytes, down-modulate monocyte functions, and promote fibrosis, we hypothesize that they participate in the deleterious effects of hemodialysis. We investigated the production of TGF beta 1 and TGF beta 2 by monocytes from controls and patients dialyzed with high-flux cellulose triacetate (CT) and polyacrylonitrile (PAN) membranes. The detection of both TGF beta s required an acidification step, suggesting that they are secreted as latent complexes. The spontaneous production of TGF beta 1 and TGF beta 2 was significantly higher in patients dialyzed with CT or PAN than in controls, but the oversecretion of TGF beta 1 was more sustained in CT-treated patients than in PAN-dialyzed patients. The production of interleukin-6 (IL-6) was increased in both patient groups as compared with controls. In contrast to TGF beta 1, the increase was greater in PAN-treated patients than in CT-treated patients, and the release of tumor necrosis factor alpha (TNF alpha) was increased only in PAN-treated patients. Taken together, our results show that hemodialysis is associated with the oversecretion of monocyte cytokines. Moreover, the type of dialysis membrane specifically affects the balance between the secretion of suppressive cytokines such as TGF beta and that of inflammatory cytokines such as IL-6 and TNF alpha.
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PMID:Monocyte production of transforming growth factor beta in long-term hemodialysis: modulation by hemodialysis membranes. 880 38

Since modulation of the glutathione (GSH) level has been implicated in the regulation of human immunodeficiency virus (HIV) transcription and expression, we have undertaken an analysis of the effect of sodium valproate (VPA) on HIV-1 replication. VPA, which is an anti-epileptic drug in widespread use in clinical medicine, has been shown to depress the activity of GSH reductase, an enzyme required for maintaining high cellular levels of reduced GSH. The effect of this drug on HIV-1 replication has been studied in primary infected cells, i.e. peripheral blood mononuclear cells (PBMC) and monocyte/macrophages, in the CEM-SS cell line, and in chronically infected stimulated and non-stimulated U1 cells. We have shown that VPA markedly enhanced viral replication in all infected cells tested. Virus production was induced in U1 cells by VPA treatment and the stimulatory effects of tumour necrosis factor-alpha, interleukin-6 and granulocyte/macrophage colony-stimulating factor were augmented. The LTR-driven gene expression in Jurkat T cells was increased. However, the elevated viral production did not correlate with the effect of VPA on the intracellular GSH level. Thus, VPA stimulated in vitro HIV-1 replication in acutely and chronically infected cells and enhanced LTR-driven gene expression. These effects were observed for concentrations that are reached in the plasma of VPA-treated patients. Therefore, although the clinical significance of these data remains to be demonstrated, these results should be considered in the choice of an anticonvulsant drug in HIV-infected individuals.
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PMID:Sodium valproate, an anticonvulsant drug, stimulates human immunodeficiency virus type 1 replication independently of glutathione levels. 881 Sep 95

Astrocytes respond vigorously to diverse neurological insults. It is still not clear, however, whether this response is stereotypic following different insults or varies according to the injury. We have used a novel immunocytochemical marker of reactive astrocytes, termed M22, together with antibodies to glial fibrillary acidic protein (GFAP), to analyze region- and insult-specific differences in reactive astrocytosis in the murine central nervous system (CNS). Pathology was variously induced by (1) infectious agents, (2) transgenic overexpression of a viral glycoprotein or cytokine, or (3) focal trauma. Scrapie infection induced high levels of both GFAP and M22 epitope expression by hippocampal reactive astrocytes, but neither scrapie nor wild mouse retrovirus infection induced detectable M22 staining in reactive astrocytes of the caudal brain. Focal trauma and human immunodeficiency virus gp120 overexpression induced M22 expression only in the hippocampus, while interleukin-6 overexpression induced it in cerebellar astrocytes. Although M22 expression was limited to areas with extensive damage, GFAP expression was induced in every region of the mouse brain displaying pathology. Staining of routinely fixed human brain tissue demonstrated that M22 also labeled reactive astrocytes in chronic human CNS disease. The restriction of M22 expression to areas of strongly GFAP-positive astrocytosis suggests that the M22 antibody identified highly activated reactive astrocytes. Because of this selective staining of activated astrocytes, the M22 antibody may provide neuropathologists with a good marker for qualitative analysis of the astrocytic response to different injuries.
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PMID:The M22 antibody identifies highly activated reactive astrocytes responding to central nervous system disease. 883 43

The introduction of molecular therapy through the delivery of nucleic acids either as oligonucleotides or genetic constructs holds enormous promise for the treatment of renal disease. Significant barriers remain, however, before successful organ-specific molecular therapy can be applied to the kidney. These include the development of methods to target the kidney selectively, the definition of vectors that transduce renal tissue, the identification of appropriate molecular targets, the development of constructs that are regulated and expressed for long periods of time, the demonstration of efficacy in vivo, and the demonstration of safety in humans. As the genetic and pathophysiologic basis of renal disease is clarified, obvious targets for therapy will be defined, for example, polycystin in polycystic kidney disease, human immunodeficiency virus (HIV) type 1 in HIV-associated nephropathy, alpha-galactosidase A in Fabry's disease, insulin in diabetic nephropathy, and the "minor" collagen IV chains in Alport's syndrome. In addition, several potential mediators of progressive renal disease may be amenable to molecular therapeutic strategies, such as interleukin-6, basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), and transforming growth factor-beta(TGF-beta). To test the in vivo efficacy of molecular therapy, appropriate animal models for these disease states must be developed, an area that has received too little attention. For the successful delivery of genetic constructs to the kidney, both viral and nonviral vector systems will be required. The kidney has a major advantage over other solid organs since it is accessible by many routes, including intrarenal artery infusion, retrograde delivery through the uroexcretory pathways, and ex vivo during transplantation. To further restrict expression to the kidney, tropic vectors and tissue-specific promoters also must be developed. For the purpose of inhibition of endogenous or exogenous genes, current therapeutic modalities include the delivery of antisense oligodeoxynucleotides or ribozymes. For these approaches to succeed, we must gain a much better understanding of the nature of their transport into the kidney, requirements for specificity, and in vivo mechanisms of action. The danger of a rush to clinical application is that superficial approaches to these issues will likely fail and enthusiasm will be lost for an area that should be one of the most exciting developments in therapeutics in the next decade.
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PMID:Molecular therapy for renal diseases. 884 Sep 36


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