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)

We previously proposed the hypothesis that the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA) based on our observations that it is the dominant inducer of interleukin-1 (IL-1) and granulocyte-macrophage colony-stimulating factor (GM-CSF) production in RA synovial joint mononuclear (MNC) cells in culture. Since TNF-alpha acts via two membrane receptors, we have extended those studies to investigate the distribution of the p55 and p75 TNF receptors (TNF-R) in RA tissue. Surface receptor expression was quantitated by flow cytometry using monoclonal antibodies specific to the p55 (HTR-9) and the p75 (UTR-1) TNF-R. Both receptors were significantly increased on MNC isolated from the synovial membrane of RA patients compared to normal or RA peripheral blood MNC. Interestingly, the p75 TNF-R was increased both on large monocytic/macrophage-type cells and CD3+ lymphocytes. Furthermore, there was a significant increase in the proportion of CD3+ cells in RA synovial fluid expressing the p75 TNF-R, compared to matched peripheral blood MNC. In contrast to RA synovial MNC, p75 or p55 TNF-R expression was not significantly increased in osteoarthritis synovial MNC. In addition, Northern blot analysis indicated abundant expression of both p55 and p75 mRNA in RA synovial joint MNC. This was in contrast to normal peripheral blood MNC cells which contained little or no constitutive TNF-R mRNA; following stimulation with phytohemagglutinin and IL-2, a rapid and transient expression of both receptor mRNA was induced. These results, therefore, indicate that in RA synovial joint tissue there is up-regulation of both p55 and p75 TNF-R mRNA and surface protein expression, and with the presence of TNF-alpha in RA tissues, these results provide support to our hypothesis that TNF-alpha is of critical importance in the pathogenesis of RA.
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PMID:Enhanced expression of tumor necrosis factor receptor mRNA and protein in mononuclear cells isolated from rheumatoid arthritis synovial joints. 132 May 71

An impermeable thiol blocker has been used to investigate the role of sulphydryl (SH) groups in the production of and responsiveness to IL-2 by normal human T lymphocytes. Surface SH blockade of mononuclear cells prior to incubation with mitogen (phytohaemagglutinin, concanavalin A, CD3 MoAb) had no effect on production of IL-2 but markedly impaired cellular responsiveness to exogenous IL-2. Studies using MoAbs indicated that this effect was accompanied by decreased expression of both the CD25 and p75 subunits of the IL-2 receptor. Blocking surface SH groups did not affect binding of IL-2 to p75 on unstimulated mononuclear cells, but inhibited binding to high-affinity receptors on a T lymphoma cell line. The data are consistent with the hypothesis that sulphydryl groups on the IL-2 receptor are required for its function and may be involved in the interaction of the CD25 and p75 subunits leading to generation of the high-affinity binding site. The surface thiol identified on the IL-2 receptor may be a candidate for oxidation on cells from patients with chronic inflammatory diseases such as rheumatoid arthritis and thus contribute to the aberrant function of T cells in these patients.
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PMID:Modulation of human T cell functions by surface sulphydryl groups: differential effects on IL-2 production and responsiveness. 156 2

In vitro analysis of polymorphonuclear neutrophils (PMN) has allowed various stages of cell activation to be distinguished, characterized by the expression level of specific membrane markers and of functional receptors. Among those, TNF-alpha receptors (TNF-R) are modulated by various PMN activators, a mechanism which may be important to control cell responses to TNF in inflammatory reactions such as rheumatoid arthritis (RA). PMN, isolated from the blood of 36 RA patients and from the synovial fluid of 23 of them, were analysed for membrane expression of the two TNF-R (p55 and p75). Soluble p55 and p75 (sTNF-R) and TNF concentrations were measured in the plasma and synovial fluid by specific ELISA assays. Our results show that PMN from the blood of RA patients bear a normal number of TNF-R, with a normal p55/p75 ratio, compared with PMN from normal controls. Soluble TNF-R levels were similar in patients and normal plasma. In spite of high endogenous TNF concentration, patients' circulating PMN were not activated, as shown by a CD11b/CD18 expression similar to that of control resting cells. In contrast with blood neutrophils, PMN from RA patients' synovial fluids had an activated phenotype, characterized by increased expression of CD11b, decreased expression of leukosialin, CD43, and the appearance on the plasma membrane of an azurophil granule protein, CD63. High levels of soluble TNF-R were measured in RA synovial fluids. Nevertheless, membrane TNF-R levels and p55 and p75 proportions were similar to those of PMN from normal blood. These results suggest the existence of regulatory mechanisms which maintain a stable neutrophil expression of TNF-R as well as a balance between both types of receptors in inflammatory situations where neutrophils are strongly activated.
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PMID:Neutrophil expression of tumour necrosis factor receptors (TNF-R) and of activation markers (CD11b, CD43, CD63) in rheumatoid arthritis. 762 89

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

This open label study examines whether methotrexate (MTX) treatment modulates ex vivo synthesis of interleukin-1 receptor antagonist (IL-1ra), soluble tumour necrosis factor receptors (sTNFR p55 and p75), interleukin-1 beta (IL-1 beta), tumour necrosis factor alpha (TNF-alpha), interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) by peripheral blood mononuclear cells (PBMC) and whether changes reflect clinical response. Significant stimulation of IL-1ra and sTNFR p75 as well as inhibition of IL-8 production of PBMC were associated with clinical improvement observed in patients treated with MTX. When defining the characteristics of patients at study entry retrospectively in responders and non-responders, a significantly lower ratio of IL-1ra:IL-1 beta production before and its increase upon treatment was associated with clinical response in 13 patients compared to five patients not responding to MTX. In addition, clinical improvement was associated with decreased synthesis of IL-1 beta, TNF-alpha and IL-8 induced by bacterial lipopolysaccharide, IL-1 alpha and IL-1 beta in PBMC in vitro. These findings suggest that MTX therapy reverses the inflammatory type of rheumatoid arthritis (RA) blood mononuclear cells by stimulating cytokine inhibitor production while inhibiting inflammatory cytokine release at the same time. This may explain the powerful anti-inflammatory properties of low-dose MTX as observed in most RA patients. Pretreatment determination of the IL-1ra:IL-1 beta ratio in PBMC may be predictive with regard to a favourable therapeutic response and therefore may be useful for the selection of RA patients to be treated with MTX.
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PMID:Methotrexate action in rheumatoid arthritis: stimulation of cytokine inhibitor and inhibition of chemokine production by peripheral blood mononuclear cells. 767 Jul 76

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

Our work has shown that TNF alpha is produced by cultured mononuclear cells from rheumatoid arthritis joints and appears to regulate the production of IL-1. Immunohistochemical examination has shown the presence of TNF alpha in the synovium, e.g. in the lining layer, some endothelial cells and most importantly, in the cells in the cartilage pannus junction. TNF receptors (both p55 and p75) have a similar distribution, thereby suggesting that TNF has the potential for autocrine and paracrine activity in the joint. The concept that TNF alpha is pathogenic in inflammatory arthritis has been validated by showing that neutralizing monoclonal anti-TNF antibodies significantly attenuate collagen-induced arthritis in mice. In preliminary trials in rheumatoid patients anti-TNF appears to have an impressive effect on indices of disease activity including C-reactive production and serum amyloid-A production. TNF alpha appears to be a relevant therapeutic target in rheumatoid disease.
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PMID:TNF-alpha in rheumatoid arthritis and prospects of anti-TNF therapy. 839 52

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