Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: DrugBank:BIOD00017 (IFN-gamma)
 28,919 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mononuclear inflammatory cells (MC) isolated from the livers and spleens of mice with chronic graft-vs-host disease (CGVHD) to minor histocompatibility antigens (B10.D2----BALB/c) show defective proliferation when stimulated with Con A and LPS. In turn, both CGVHD liver and spleen cells suppress the proliferation of mitogen-stimulated normal spleen cells in a genetically unrestricted manner. The suppressor activity of CGVHD spleen cells is mediated by plastic nonadherent null (natural suppressor) cells and involves a soluble suppressor factor(s). In contrast, the suppressor activity of CGVHD liver cells is mediated by macrophages (M phi). In the current studies we show that the suppressor activity of CGVHD liver cells is also mediated by soluble factors and compare the roles of prostaglandins and interferon (IFN)-gamma in mediating defective proliferation and suppressor activities of CGVHD liver and spleen MC. Monoclonal antibody to IFN-gamma partially reversed the defective mitogen-stimulated proliferation of CGVHD spleen MC but had no effect on proliferative response of CGVHD liver MC. Indomethacin did not alter the low proliferative response of either CGVHD liver or spleen MC. Anti-IFN-gamma inhibited the ability of CGVHD spleen cells to suppress proliferation of Con A and LPS-stimulated B10.D2 spleen cells. In contrast, anti-IFN-gamma resulted in a small decrease in the ability of liver MC to suppress Con A (but not LPS)-stimulated cell proliferation. Indomethacin decreased the ability of both CGVHD liver and spleen cells to suppress Con A-stimulated proliferation but had inconsistent effects on LPS-stimulated proliferation. These results show that IFN-gamma and prostaglandins partially mediate the suppressor activity of CGVHD spleen MC. The suppressor activity of CGVHD liver MC also involves prostaglandins but is relatively independent of IFN-gamma.
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PMID:Suppressor function of liver mononuclear cells isolated during murine chronic graft-vs-host disease. II. Role of prostaglandins and interferon-gamma. 153 54

During the last few years, several observations outline that the impaired T lymphocyte proliferative capacity in the elderly is due to a reduced interleukin 2 (IL-2) release. To further investigate the activation process during lectin stimulation, aged peripheral blood mononuclear cells (PBMC) were stimulated with phytohemagglutinin (PHA) and assessed for CD25 (IL-2 receptor) and CD71 (transferrin receptor) expression at different intervals of time. Our results provided evidence for a significant decline of both structure induction, above all in the later phase of culture. Indomethacin (INDO) treatment gave rise to an enhancement of CD71 antigen expression only, while prostaglandin E2 (PGE2) supplementation to culture media further decreased either CD25 or CD71 receptor induction. Interferon (IFN)-alpha and IFN-gamma treatment failed to modulate the frequency of CD25+ and/or CD71+ cells. Finally, the expression of CD71 receptor was increased by deferoxamine supplementation, this suggesting a partial involvement of iron overload in the depressed function. Although further studies are required to evaluate at a molecular level the decreased antigen expression, these findings indicate that several mechanism are involved in the elderly-related decline of T lymphocyte activation structures during lectin stimulation.
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PMID:Modulating effects on CD25 and CD71 antigen expression by lectin-stimulated T lymphocytes in the elderly. 177 Feb 20

Lymphocyte proliferation in Con A- or LPS-stimulated murine splenic cell (SC) cultures was suppressed by the addition of excess macrophages. In Con A-stimulated cultures, suppression was associated with the expression of nitric oxide-synthesizing pathway (NOSP) activity as demonstrated by the accumulation of nitrite, a degradation product of nitric oxide (NO), in the culture supernatants. That NO, a cytotoxic and anti-proliferative metabolite of l-arginine, or other reactive nitrogen intermediates generated through the NOSP mediated the suppressive effect was suggested by the reversal of suppression brought about by the addition of a specific inhibitor of the NOSP (NG-monomethyl-l-arginine acetate) to the culture media. No NOSP activity was detectable in LPS-stimulated SC/macrophage cocultures. The role of T cell-derived IFN-gamma in the induction of the NOSP was investigated by the use of anti-IFN-gamma-mAb. Antibody-treated Con A supernatants failed to induce the NOSP in macrophages, and the addition of the mAb to Con A-stimulated SC/macrophage cocultures obviated the suppressive effects. Indomethacin and catalase only partially restored proliferation in Con A-stimulated SC/macrophage cocultures but were remarkably efficient in preventing macrophage-dependent suppression when LPS was used as the mitogenic stimulus. These results demonstrate a regulatory system of potential relevance in sites of predominant macrophage infiltration by which T cell-derived IFN-gamma activates the production of the mediator, NO, that suppresses T cell proliferation. In addition, these data demonstrate that, although the suppressive effects of excess macrophages appear to be expressed nonspecifically toward both T and B cells, suppression is mediated through a different mechanism in each case.
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PMID:Nitric oxide production is required for murine resident peritoneal macrophages to suppress mitogen-stimulated T cell proliferation. Role of IFN-gamma in the induction of the nitric oxide-synthesizing pathway. 190 99

Naturally occurring substances capable of the negative regulation of class II molecules on synovial fibroblasts may play an important role in controlling the sustained immune processes ongoing in the rheumatoid joint. We report here that rIL-1 is capable of such a negative regulatory process. The simultaneous addition of rIL-1 and rIFN-gamma to rat synovial fibroblasts resulted in decreased Ia Ag and mRNA expression when compared with synovial fibroblasts treated with IFN-gamma alone. Both rIL-1 alpha and rIL-beta inhibited to a similar degree with the level of inhibition being dependent on both the concentration of IL-1 and IFN-gamma. Other cytokines, including IFN-alpha/beta, IL-2, and TNF, had no antagonistic effect on IFN-gamma-induced Ia expression. Time course experiments showed that IL-1 inhibited when present immediately before addition of IFN-gamma or when added during the first 24 h of IFN-gamma stimulation but not at later time points. Indomethacin failed to reverse the IL-1-mediated inhibition, despite the fact that exogenously added PGE2 also inhibited IFN-gamma-induced Ia expression. IL-1 treatment of synovial cells did not alter the ability of IFN-gamma to bind to the cells. These findings provide evidence for a negative regulatory role for IL-1 on synovial fibroblasts independent of PGE2 production and thus suggest that IL-1 is capable of both pro- and antiinflammatory actions within the rheumatoid joint.
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PMID:Inhibition of IFN-gamma-induced Ia antigen expression on synovial fibroblasts by IL-1. 250 58

The suppressive effect of normal rat peritoneal exudate cells (PEC) on concanavalin A (Con-A)-induced lymphocyte proliferation was studied. Partial suppression of proliferation was obtained by adding 3% PEC and complete suppression was observed with 6% PEC. The suppressive effect was mediated by W3/25+ plastic-adherent macrophages, which constitute about 60% of normal PEC. Addition of PEC prior to, simultaneously with, or 24 h after, but not 48 h after, the stimulation of lymphocytes with Con A resulted in suppression. Suppressed cultures produced normal or slightly increased amounts of interleukin 2 (IL-2), but the expression of the IL-2 receptor on lymphocytes was decreased. Pre-exposure of PEC to gamma interferon (IFN-gamma) resulted in decreased suppression, whereas IFN-gamma added simultaneously with the lymphocytes had no effect. Catalase reversed PEC-induced suppression and significant synergistic effects were recorded when combined with IFN-gamma. Even completely suppressed cultures were effectively protected from suppression. Indomethacin and combinations of indomethacin with catalase or IFN-gamma did not result in additional protection from PEC-mediated suppression.
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PMID:Synergistic action of gamma interferon and catalase to reverse the suppressive effect of peritoneal macrophages on concanavalin A-induced lymphocyte proliferation. 308 21

Lipopolysaccharide (LPS) induces high levels of gamma interferon (IFN-gamma) in the circulation of mice pretreated with heat-killed Propionibacterium acnes. The following results were obtained in the present study. LPS, as well as interleukin-2 (IL-2), was also able to induce IFN-gamma in vitro in peritoneal exudate cells (PEC) from such mice. Splenocytes and lymph node cells from these mice or resident peritoneal cells from control mice produced trace or undetectable amount of IFN-gamma upon exposure to LPS. A synergistic effect on IFN-gamma induction was observed when LPS was added to a culture of PEC together with IL-2. Indomethacin augmented the induction of IFN-gamma by LPS or IL-2, and prostaglandin E2 reversed its effect. Deprivation of plastic-adherent or nylon wool-adherent cells abolished the induction by LPS or IL-2, whereas it did not affect that by concanavalin A. Culture supernatant of plastic-adherent cells incubated with LPS stimulated the nylon wool-nonadherent cells to produce IFN-gamma in the presence of IL-2, but interleukin-1 or phorbol myristic acetate did not replace the LPS-stimulated supernatant. The ability of PEC to produce IFN-gamma measured as a function of time after P. acnes injection increased in proportion to their natural killer (NK)-like activity against YAC-1 cells. Moreover, treatment of PEC with monoclonal anti-Thy-1 antibody or with anti-asialo GM1 antiserum plus complement eliminated the production of IFN-gamma and the NK-like activity simultaneously, whereas treatment with monoclonal anti-Lyt-2 antibody plus complement did not. These results suggest that IL-2 and some unidentified factor released from plastic-adherent cells by LPS stimulation cooperatively induce IFN-gamma production in activated, Thy-1- and asialo GM1-positive NK-like cells appearing in inflammatory reactions and that prostaglandin E2 regulates IFN-gamma production in these cells.
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PMID:Induction of murine gamma interferon production by lipopolysaccharide and interleukin-2 in Propionibacterium acnes-induced peritoneal exudate cells. 310 Apr 48

Some cytokines are known to affect both proliferation and activation of cultured human endothelial cells (HEC). We compared the extent of these modifications when induced by several cytokines or by the monocyte-derived endothelial cell inhibitory factor (MECIF) activity. We measured as endothelial activation parameters the expression of endothelium-leukocyte adhesion receptor-1 (ELAM-1, E-selectin), major histocompatibility complex (MHC) class II antigens, interleukin 1 (IL-1), interleukin 6 (IL-6), and prostacyclin. To further investigate if a common or distinct intracellular mechanism was involved in the action of these effectors we studied the influence of indomethacin, a cyclooxygenase inhibitor, on the growth inhibition and the activation effects. Our results showed that IL-1 beta, tumor necrosis factor (TNF)alpha, and MECIF activity induced the expression of ELAM-1 on HEC membrane while transforming growth factor beta (TGF beta), IL-6, and gamma-interferon (IFN-gamma) showed no effect. However, MECIF activity did not induce MHC class II antigens on HEC surface. MECIF activity appeared to be immunologically distinct from IL-1 beta, TNF alpha, and TNF beta (lymphotoxin). IL-6 production by HEC was significantly increased only in the presence of IL-1 beta, TNF alpha, or MECIF activity. Intracellular IL-1 alpha and IL-1 beta levels were markedly enhanced by IL-1 beta and TNF alpha. MECIF activity, TNF alpha, and IL-1 beta significantly increased prostacyclin secretion whereas TGF beta, IL-6, and IFN-gamma showed no significant effect. Indomethacin did not significantly modify ELAM-1 induction and reduced in a nonsignificant manner the antiproliferative effect of MECIF activity, TNF alpha, IL-1 beta, and TGF beta. The effectors studied appeared to modulate differently the expression of endothelial products and activation markers in vitro, suggesting that their effects could be mediated through distinct intracellular pathways. The cyclooxygenase pathway of arachidonic acid metabolism could be involved in the growth inhibitory action of MECIF activity, TNF alpha, IL-1 beta, and TGF beta but an additional putative pathway might also be involved.
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PMID:Modulation of human endothelial cell activation by antiproliferative cytokines: exploration of arachidonic acid and intracellular cytokine pathways as possible mechanisms of action. 768 96

Activated antigen-presenting cells and central nervous system microglia produce IL-1 beta, TNF-alpha, IL-6, and PGE-1. These monokines participate in the lymphocyte activation, demyelination, and intrathecal immunoglobulin synthesis seen in multiple sclerosis (MS). Exacerbations of MS are ameliorated by IFN-beta, but provoked by IFN-gamma, possibly through an effect on monocytes (Mo). We studied the effects of IFNs and PG on monokine secretion under stringent low-endotoxin conditions. Spontaneous and IFN-gamma-induced IL-1 beta secretion was greater in MS than in NL Mo. IFN-beta did not inhibit IFN-gamma-induced secretion of monokines, which contrasts with IFN-beta's inhibitory effect on IFN-gamma-induced MHC class II expression. PGE1, a cAMP agonist, caused a 30-fold induction of IL-6 secretion. Indomethacin directly inhibited this induction. Low-dose IFN-beta, through effects on T cells, and cAMP agonists, through effects in T cells and Mo, may ameliorate inflammatory diseases characterized by excessive monokine secretion.
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PMID:IFN-gamma, IFN-beta, and PGE1 affect monokine secretion: relevance to monocyte activation in multiple sclerosis. 806 25

Nonsteroidal anti-inflammatory drugs (NSAIDs) are well known as immunoregulators, but the mechanisms of their action are not fully explained by the inhibition of PG synthesis. We have investigated the effect of NSAIDs on cytokine production in human PBMC and T cell clones (TCC). NSAIDs up-regulated TNF, IFN-gamma and IL-2 production at both the mRNA and protein levels, and IL-12 expression at the mRNA level. In contrast, NSAIDs down-regulated IL-6 production both at the mRNA and protein levels, and down-regulated IL-4 mRNA expression. The modulation at the mRNA level became detectable 1 h after culture. This modulation was also observed at the level of TCC. Indomethacin (IM) enhanced TNF production in all the eight TCC that were established from a patient with human T lymphotrophic virus type 1 uveitis or pulmonary sarcoidosis, and suppressed IL-6 production in six of the eight TCC, without affecting their low levels of PGE2 production. IM also enhanced TNF and suppressed IL-6 production, respectively, in both IL-2-activated PBMC and IL-2-dependent NK cell line, with the inhibition of their high levels of PGE2 production. Culture with PGE2 alone suppressed TNF production by three of the six TCC and NK cell lines, which was neutralized by addition of IM. It had, however, no effect on TNF production by the remaining three TCC or IL-2-activated PBMC. The effects of PGE2 on IL-6 production also varied among TCC.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nonsteroidal anti-inflammatory drugs differentially regulate cytokine production in human lymphocytes: up-regulation of TNF, IFN-gamma and IL-2, in contrast to down-regulation of IL-6 production. 858 68

We investigated the utility of the oxidant-reactive probe dichlorofluorescin (DCFH) for measurement of NO synthase (NOS) activity in rat alveolar macrophages (AMs) activated by culture for 18 h with interferon-gamma (IFN-gamma, 25 U/ml). Using both microplate-based fluorometry and flow cytometric analysis, AMs treated with l (but not d)-arginine showed a dose- and time-dependent increase in DCFH oxidation above buffer control (e.g., DCF production (nM): control, d-arginine 100 microM, l-arginine 100 microM respectively; 91+/-9, 76+/-11, 396+/-45, mean +/- SE, n = 6, 120 min). Furthermore, the NOS inhibitor (nitro-l-arginine) showed complete inhibition of the l-arginine-dependent DCF production. Parallel assays showed a strong correlation in DCFH oxidation with nitrite production in the same samples (e.g., DCF production (nM): 143, 222, 409; nitrite (microM): 2.2, 3.6, 7.1; for 5, 10, 50 microM l-arginine, respectively). In contrast, the alternate oxidant-reactive probes hydroethidine (HE) and dihydrorhodamine (DHR) did not report increased oxidant production in activated AMs incubated with l-arginine, despite their ability to easily detect intracellular superoxide anion production in cells treated with menadione (100 microM). We conclude that DCFH is a useful probe for quantitation of NOS-2 activity in activated rat lung macrophages.
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PMID:Fluorescence-based measurement of nitric oxide synthase activity in activated rat macrophages using dichlorofluorescin. 944 7


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