UMLS:C0003873 - FACTA Search

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Query: UMLS:C0003873 (rheumatoid arthritis)
53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The critical role of tumor necrosis factor (TNF) as a mediator in autoimmune inflammatory processes is evident from in vivo studies with TNF-blocking agents. However, the mechanisms by which TNF, and possibly also its homologue lymphotoxin alpha, contributes to development of pathology in rheumatoid arthritis and Crohn disease and in animal models like experimental autoimmune encephalomyelitis is unclear. Possibilities include regulation of vascular adhesion molecules enabling leukocyte movement into tissues or direct cytokine-mediated effector functions such as mediation of tissue damage. Here we show that administration of a TNF receptor (55 kDa)-IgG fusion protein prevented clinical signs of actively induced experimental autoimmune encephalomyelitis. Significantly, the total number of CD4+ T lymphocytes isolated from the central nervous system of clinically healthy treated versus diseased control animals was comparable. By using a CD45 congenic model of passively transferred experimental autoimmune encephalomyelitis to enable tracking of myelin basic protein-specific effector T lymphocytes, prevention of clinical signs of disease was again demonstrated in treated animals but without quantitative or qualitative impediment to the movement of autoreactive T lymphocytes to and within the central nervous system. Thus, despite the uninterrupted movement of specific T lymphocytes into the target tissue, subsequent disease development was blocked. This provides compelling evidence for a direct effector role of TNF/lymphotoxin alpha in autoimmune tissue damage.
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PMID:Unimpaired autoreactive T-cell traffic within the central nervous system during tumor necrosis factor receptor-mediated inhibition of experimental autoimmune encephalomyelitis. 747 38

The phosphodiesterase inhibitor oxpentifylline (OXP) has a number of potentially important immunomodulatory actions which include a selective inhibition of the Th1 subset of CD4+ cells in vitro and inhibition of tumor necrosis factor (TNF)-alpha mRNA transcription. In vivo, it has a dramatic protective effect against experimental allergic encephalomyelitis. In this animal model, tissue injury is associated with both a Th1 response and with TNF-alpha production, either of which could be targets for the protective action of OXP. In an attempt to clarify the relative importance of the Th cell subsets and TNF-alpha in pathogenesis, we investigated the effect of OXP on a Th2 model of T cell-dependent disease, mercuric chloride (HgCl2)-induced autoimmunity in the Brown Norway rat. The effects of OXP on the Th1:Th2 response, TNF-alpha mRNA transcription in spleen and ankle joints, and on the incidence and severity of arthritis and cecal vasculitis have been examined and the effects in vivo have been compared with those of a soluble TNF receptor-IgG1 fusion protein (sTNFR) that neutralizes rat TNF-alpha. In two separate experiments, OXP significantly enhanced unstimulated levels of splenic interleukin-4 (IL-4) mRNA (median 62%, of an artificial IL-4 mRNA construct, vs. 36.5% in controls) and in one experiment, exaggerated the total IgE response to HgCl2. OXP inhibited HgCl2-induced TNF-alpha mRNA transcription in spleen and ankle joints. In three separate experiments, OXP had a significant protective effect against arthritis, with the mean incidence reduced from 100% to 30% and mean peak score reduced from 7.2 to 2.59 (experiments 1 and 2). The protection against arthritis was indistinguishable from that produced by sTNFR. There was no such protection against cecal vasculitis with either OXP or sTNFR. These results demonstrate that OXP induces a shift towards a Th2 response, inhibits TNF-alpha mRNA transcription locally in joint and systemically in spleen, and has a protective effect against arthritis similar to that produced by sTNFR in the HgCl2-treated BN rat. We conclude that TNF-alpha is a critical cytokine in the pathogenesis of arthritis but not cecal vasculitis in this model, and that inhibition of TNF-alpha transcription is the most important mode of action of OXP in this situation. OXP may be a potential therapeutic agent in the treatment of other arthritides, such as human rheumatoid arthritis, in which TNF-alpha has been implicated in pathogenesis.
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PMID:Oxpentifylline inhibits tumor necrosis factor-alpha mRNA transcription and protects against arthritis in mercuric chloride-treated brown Norway rats. 758 90

We have proposed the hypothesis that tumour necrosis factor alpha (TNF-alpha) has a pivotal role in the pathogenesis of rheumatoid arthritis, based on in vitro observations that in RA synovial joint cell cultures removal of TNF-alpha, inhibited other potentially pathogenic cytokines such as the equally proinflammatory cytokine interleukin 1 (IL-1) and the macrophage activating factor, GM-CSF. Here we describe that in both rheumatoid (RA) and osteoarthritic (OA) synovial cultures there is a homeostatic mechanism to regulate the activities of TNF-alpha. This concept is based on several observations. First in these synovial joint cell cultures the substantial discrepancy between the levels of bioactive and immunoreactive TNF-alpha indicates the presence of an inhibitor. Second, TNF binding proteins are produced spontaneously, which are the soluble variants of surface p75 and p55 TNF receptor. The amount of soluble TNF receptors (sTNF-R) produced varied between cultures; p75 sTNF-R was more abundant than p55 sTNF-R (as detected by ELISA), and both were produced at higher levels by RA synovial joint cells in culture, compared to OA cultures. These TNF binding proteins act as endogenous inhibitors of TNF-alpha, since blocking their activity in synovial joint cell culture supernatants with MoAb to p55 and p75 sTNF-R enhanced their cytotoxic activity in the TNF bioassay. The regulation of production of these sTNF-R in synovial joint cell cultures is important as the balance between TNF-alpha and sTNF-R production may determine the outcome of the inflammatory process.
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PMID:TNF inhibitors are produced spontaneously by rheumatoid and osteoarthritic synovial joint cell cultures: evidence of feedback control of TNF action. 763 Nov 38

Interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF alpha) have been identified as important mediators of chronic immuno-inflammatory disease states such as rheumatoid arthritis. Effector cells are triggered by these cytokines to release molecules involved in synovitis and rheumatoid joint destruction, namely prostanoids, leukotrienes, adhesion molecules and metalloproteinases. Modifications of natural inhibitors of IL-1 and TNF alpha, which have been shown to maintain the homeostasis of the cytokine system, are now available by DNA technology. Monoclonal antibodies to TNF and the TNF receptor fusion proteins TNFR 55-IgG and TNFR 75-IgG are currently under clinical investigation in rheumatoid arthritis, inflammatory bowel disease and septic shock. Preliminary results from clinical trials in rheumatoid arthritis suggest that TNF inhibition represents a promising novel interventional strategy providing anti-inflammatory activity and inhibition of effector molecules of structural joint damage.
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PMID:[TNF inhibitors: a new therapeutic perspective in chronic inflammatory diseases in rheumatology?]. 766 Jun 86

There is increasing evidence that TNF-alpha is a cytokine of major importance in the pathogenesis of rheumatoid arthritis. Since TNF-alpha mediates its effects via high affinity receptors, we were interested in investigating their expression and function in cells from rheumatoid tissue. Synovial fibroblasts derived from rheumatoid synovial tissue are stimulated by TNF-alpha to proliferate and release cytokines, prostaglandins, proteases and protease inhibitors. We have evaluated through which receptor stimulation of DNA synthesis and the release of the proinflammatory agents, IL-6, IL-8 and PGE2 are induced. It was found that rheumatoid synovial fibroblasts express both the p55 and p75 TNF receptor, in a ratio of 4:1. TNF-alpha-stimulated synovial fibroblast DNA synthesis and the release of IL-6, IL-8 and PGE2 was inhibited by antagonist monoclonal antibodies against either the p55 or the p75 TNF receptor, although the blockade of the p55 TNF receptor had a more potent effect than inhibition of the p75 TNF receptor alone. Similarly, specific monoclonal antibodies, agonistic for either the p55 or p75 TNF receptor stimulated synovial fibroblast DNA synthesis, as well as IL-6, IL-8 and PGE2 release. Both p55 and p75 TNF receptors on dermal and gingival fibroblasts were also involved in TNF-alpha-mediated DNA synthesis and IL-6, IL-8 and PGE2 release, although differences in the levels of DNA synthesis and release of inflammatory cytokines and PGE2 were observed between the three fibroblast types.
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PMID:p55 and p75 tumor necrosis factor receptors are expressed and mediate common functions in synovial fibroblasts and other fibroblasts. 788 Sep 74

Two soluble tumour-necrosis-factor-alpha(TNF)-binding proteins are derived from the extracellular domains of the p55 and p75 TNF receptors. They are considered to play a pivotal regulatory role in TNF-mediated inflammatory processes, including diseases such as rheumatoid arthritis, by competing with the cell surface receptors for TNF and lymphotoxin (LT, tumour-necrosis factor beta). The extracellular domains of the two receptors each contain four similar cysteine-rich repeats of about 40 amino acids, in common with several other cell surface proteins including the p75 nerve-growth-factor receptor and the CD40 and Fas antigens. The aim of this study was to characterize the involvement of the four cysteine-rich repeats of the human p55 TNF receptor in TNF and LT binding by both membrane-bound and soluble forms of the receptor. Individual repeats were systematically deleted by PCR mutagenesis and the variants transiently expressed in COS cells. Immunoprecipitated receptor variants exhibited the expected sizes on SDS/PAGE gels, and bound a panel of conformation-dependent anti-(TNF receptor) antibodies. Binding of TNF by the four soluble derivatives was compared with binding by the wild-type soluble receptor using a TNF-affinity column and a BIAcore Biosensor, by measurement of their ability to inhibit TNF cytotoxicity on WEHI cells, and 125I-TNF binding to U937 cells. delta 4, which lacks the fourth cysteine-rich repeat, bound TNF comparably with the full-length soluble receptor. TNF-binding affinity was unaltered by deletion of the fourth membrane-proximal cysteine-rich repeat, as determined by Scatchard analysis of the transmembrane derivatives. We conclude that the fourth cysteine-rich repeat is not required for TNF binding. In contrast, both the soluble and the transmembrane derivatives lacking any one of the first, second or third repeats failed to bind TNF. Although we cannot entirely exclude the possibility that this may be due to indirect conformational change, rather than the removal of essential epitopes, our results suggest that the first three repeats are each required for TNF binding by both the soluble and the cell-surface receptor.
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PMID:Characterization of ligand binding by the human p55 tumour-necrosis-factor receptor. Involvement of individual cysteine-rich repeats. 805 60

Tumor necrosis factor is an important mediator of the pathophysiologic events in synovitis. The expression of the p75 and p55-TNF-receptors in rheumatic diseases was investigated. Synovial mononuclear cells (SMNC) of patients with rheumatoid arthritis and spondylarthropathies express p75 TNF receptors in all cases, whereas SMNC of patients with traumatic synovitis do not. In 4/9 patients with rheumatoid arthritis and in 6/11 patients with spondylarthropathies SMNC also expressed the p55 TNF receptor. Differential analysis of lymphocytes and monocytes/macrophages revealed that both predominantly expressed the p75 TNF receptor. The highest concentrations of both soluble TNF receptors which may act as TNF antagonists were found in synovial fluids of rheumatoid arthritis patients.
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PMID:[Expression of TNF receptors in rheumatoid arthritis and ankylosing spondylitis]. 814 32

Tumour necrosis factor-alpha (TNF-alpha) is involved in diverse biological processes including immune and inflammatory reactions and the response to surgical stress. Two soluble TNF receptor protein fragments, TNF-sR55 (from the p55 kD TNF receptor) and TNF-sR75 (from the p75 kD TNF receptor), are released by cells during inflammation and may modulate the e effects of TNF-alpha. We have studied the kinetics of secretion of TNF-alpha, TNF-sR55 and TNF-sR75 in the sera of patients with rheumatoid arthritis (RA) and control subjects with osteoarthritis (OA) or chronic osteomyelitis (OM) before and after major surgery. Significantly higher pre-operative levels of TNF-sR55 and TNF-sR75 were found in RA and OM as compared with OA (P < 0.02). Following surgery, TNF-sR55 increased within 24 h in RA, OM and OA (P < 0.05), whereas TNF-sR75 increased significantly only in OM and OA patients (P < 0.05). By contrast, no TNF-alpha was detectable before and after surgery in any of the subjects, but this may have been due to impaired detection (by ELISA) of TNF-alpha when it is bound to TNF-sR. These findings suggest that TNF-sR55 and TNF-sR75 may be further markers of the host's reaction to inflammatory insults. They may also play a role in modulating the immune and inflammatory reactions by inhibiting the systemic effects of TNF-alpha.
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PMID:Tumour necrosis factor soluble receptors behave as acute phase reactants following surgery in patients with rheumatoid arthritis, chronic osteomyelitis and osteoarthritis. 838 84

To characterize the role of tumor necrosis factor (TNF)-alpha in regulating synovial T cell growth, cell cycle progression associated with TNF-alpha in mitogen-activated synovial T cells of patients with rheumatoid arthritis (RA) were analyzed. After mitogen stimulation, the majority of synovial T cells in RA patients accumulated in S-phase. Anti-human TNF-alpha monoclonal antibody and soluble recombinant human TNF receptor (rhTNFR) can block S-phase accumulation. Furthermore, synovial fluid (SF) from RA patients was able to inhibit the proliferation of these S-phase-accumulated T cells. These data indicate that TNF-alpha could regulate activated synovial T cell growth by driving them into S-phase. Combined with the activities of other components of SF, TNF-alpha seems to play an important role in down-regulating activated synovial T cells in RA patients. In addition, the elevated level of soluble TNFR in the SFof disease-active RA patients is believed to be associated with the promotion of synovial T cell responses.
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PMID:Role of tumor necrosis factor-alpha in the regulation of activated synovial T cell growth: down-regulation of synovial T cells in rheumatoid arthritis patients. 856 7

We have previously hypothesized that the pro-inflammatory cytokine TNF alpha has a pivotal role in the pathogenesis of rheumatoid arthritis (RA). It mediates its effects by cross-linking surface p55 TNF receptors (TNF-R), which can be proteolytically cleaved to yield soluble fragments. Upon binding TNF alpha soluble TNF-R (sTNF-R) can inhibit its function. We investigated the enzymatic nature of the proteases involved in TNF-R cleavage, and found that this process is blocked by a synthetic inhibitor of matrix metallo-proteinase activity (MMP), BB-2275. Inhibition of TNF-R cleavage was observed in a number of different cell types, as detected by retention of surface bound TNF receptor and by less sTNF-R released into the cell supernatant. The augmentation of surface TNF-R expression was of biological relevance as TNF alpha-mediated necrosis of human KYM.1D4 rhabdosarcoma cells was enhanced approximately 15-fold in the presence of BB-2275. The addition of BB-2275 to rheumatoid synovial membrane cell cultures totally inhibited MMP activity and also significantly reduced the levels of soluble TNF alpha (P < 0.006), p55 sTNF-R (P < 0.006), and p75 sTNF-R (P < 0.004). Paradoxically, despite the reduction in soluble TNF alpha levels, the production of IL-1 beta, IL-6, and IL-8, cytokines whose production was previously demonstrated to be inhibited by the addition of neutralizing anti-TNF alpha antibody were not down-regulated by BB-2275. These results raise the interesting possibility that a close relationship exits between the enzyme(s) which process membrane-bound TNF alpha, and those involved in surface TNF-R cleavage. Furthermore our observations suggest that hydroxamate inhibitors of MMP activity which block TNF alpha secretion and TNF-R cleavage may not modulate down-stream effects of TNA alpha, and as such suggest that the precise specificity of these compounds will be highly relevant to their clinical efficacy in inflammatory diseases.
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PMID:Paradoxical effects of a synthetic metalloproteinase inhibitor that blocks both p55 and p75 TNF receptor shedding and TNF alpha processing in RA synovial membrane cell cultures. 867 95

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