Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003873 (rheumatoid arthritis)
 53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Macrophages infiltrated into synovium play an important role in joint destruction in inflammatory joint diseases. In this study we focused on the production of monocyte chemoattractant protein-1 (MCP-1), a recently identified monocyte chemotactic protein, by inflammatory synovium. Synovial fluid (SF) from rheumatoid arthritis (RA), osteoarthritis, gout, and traumatic arthritis contained MCP-1. MCP-1 was produced in the synovium of patients with RA and other inflammatory joint disease in in vitro culture systems; differences in the amounts produced were not significant. Synovial MCP-1 production in RA was further investigated. Levels of MCP-1 were significantly correlated with levels of IL-1 beta, IL-6, and IL-8 in the culture supernatants of synovia from RA. Using immunohistochemical techniques, MCP-1 was detected in the lining and sublining cells and in the vascular endothelial cells of rheumatoid synovia. Rheumatoid synovia with active inflammation were stained more intensely by anti-MCP-1 antibody than were those with weak or inactive inflammation. IL-1 beta and TNF-alpha stimulated the expression of MCP-1 mRNA and de novo MCP-1 synthesis by cultured synovial cells. These results suggest the production of MCP-1 by synovium of various inflammatory joint diseases. In rheumatoid synovium, a cytokine network involving MCP-1 and other proinflammatory cytokines (IL-1 beta, IL-6, IL-8, and TNF-alpha) contributes to the immunopathogenesis of RA.
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PMID:Monocyte chemoattractant protein-1 (MCP-1) in inflammatory joint diseases and its involvement in the cytokine network of rheumatoid synovium. 840 45

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

Analysis of cytokine mRNA and protein in rheumatoid arthritis tissue revealed that many proinflammatory cytokines such as TNF alpha, IL-1, IL-6, GM-CSF, and chemokines such as IL-8 are abundant in all patients regardless of therapy. This is compensated to some degree by the increased production of anti-inflammatory cytokines such as IL-10 and TGF beta and cytokine inhibitors such as IL-1ra and soluble TNF-R. However, this upregulation in homeostatic regulatory mechanisms is not sufficient as these are unable to neutralize all the TNF alpha and IL-1 produced. In rheumatoid joint cell cultures that spontaneously produce IL-1, TNF alpha was the major dominant regulator of IL-1. Subsequently, other proinflammatory cytokines were also inhibited if TNF alpha was neutralized, leading to the new concept that the proinflammatory cytokines were linked in a network with TNF alpha at its apex. This led to the hypothesis that TNF alpha was of major importance in rheumatoid arthritis and was a therapeutic target. This hypothesis has been successfully tested in animal models, of, for example, collagen-induced arthritis, and these studies have provided the rationale for clinical trials of anti-TNF alpha therapy in patients with long-standing rheumatoid arthritis. Several clinical trials using a chimeric anti-TNF alpha antibody have shown marked clinical benefit, verifying the hypothesis that TNF alpha is of major importance in rheumatoid arthritis. Retreatment studies have also shown benefit in repeated relapses, indicating that the disease remains TNF alpha dependent. Overall these studies demonstrate that analysis of cytokine expression and regulation may yield effective therapeutic targets in inflammatory disease.
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PMID:Role of cytokines in rheumatoid arthritis. 871 20

We examined the mRNA levels for various cytokines, including IL-1 alpha, IL-1 beta, TNF alpha, TGF-beta 1, GM-CSF, IL-6, IL-8, bFGF, PDGF-A, PDGF-B and IL-1ra, and IL-1 beta converting enzyme, and the protein levels of some of these cytokines in 19 SV40-transformed synovial cell clones. Among those tested, the mRNA levels for IL-6, bFGF and PDGF-A in rheumatoid arthritis (RA) cell clones were greater than those in non-RA cell clones. Moreover, except for one osteoarthritis (OA) cell clone, the mRNA levels for IL-8 in RA cell clones were also greater than those in non-RA cell clones. Although the protein levels were not always correlated with the mRNA levels, the exception being the same OA cell clone, the protein levels of cytokines, such as IL-1 alpha, IL-1 beta, IL-6 and IL-8, in RA cell clones were greater than those in non-RA cell clones. TNF-a was not detected in any cells tested at either the mRNA or the protein level. TNF-alpha upregulated the expression of GM-CSF mRNA in both RA cell clones and one OA cell clone, but not in the other OA cell clone or the normal cell clone. Taken together, these SV-40 transformed synovial cell clones retained many of the original characteristics in terms of cytokine production.
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PMID:Cytokine production by SV40-transformed adherent synovial cells from rheumatoid arthritis patients. 874 72

Normal human polymorphonuclear neutrophils (PMN) can spontaneously produce the third component of complement (C3) in in vitro culture as detected by ELISA. This C3-producing capacity of PMN can be augmented by TNF-alpha (20 ng/ml) and bacterial lipopolysaccharide (100 ng/ml), but not by IL-1 beta or IL-8. The C3 production by PMN was found to be temperature dependent and was suppressed by the addition of protein inhibitor. The C3 mRNA in PMN could be detected by reverse transcription assisted polymerase chain reaction (RT-PCR) after TNF-alpha or LPS stimulation for 6 hours. To further understand C3 production by peripheral blood PMN in rheumatoid arthritis (RA), spontaneous and TNF-alpha stimulated production of C3 by peripheral PMN were compared in 15 cases of active RA, 15 inactive RA and 15 normal individuals. We failed to find any significant difference among the three groups. We conclude that PMN plays a negligible role in C3 hypercomplementemia in patients with active RA.
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PMID:Production of the third component of complement (C3) by peripheral polymorphonuclear neutrophils of the patients with rheumatoid arthritis. 874 20

T-cell infiltration into synovium is a crucial process for rheumatoid arthritis (RA). To investigate the mechanism of T-cell infiltration, we studied T-cell attracting activity in synovial tissue extracts of RA or osteoarthritis (OA) whose synovium lacks T-cell accumulation. RA extracts attracted twofold more T cells than OA extracts. By gel filtration column chromatography the activity of RA extracts was separated into two peaks; one was eluted at the 67-kDa region and the other was at the 12-kDa region, while the latter was absent in OA extracts. The activity eluted at the 12-kDa region was absorbed mostly by an antibody against IL-8/NAP-1, a potent T-cell chemotactic factor. IL-8/NAP-1 concentrations in RA extracts were much higher than those in OA extracts and correlated to T-cell attracting activity eluted at the 12-kDa region. The checkerboard analysis revealed that the 67-kDa activity was chemokinetic but not chemotactic. These results suggest that IL-8/NAP-1 is the major T-cell chemoattractant in RA-synovium.
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PMID:IL-8/NAP-1 is the major T-cell chemoattractant in synovial tissues of rheumatoid arthritis. 876 63

While there is an extensive literature on cytokine regulation in vivo using human cell lines or peripheral blood monocytes, very little is known about cytokine regulation within the multicellular environment of inflammatory sites in vivo. We have previously shown that in rheumatoid synovial membrane cultures, a complex, but pathophysiologically relevant mixture of cells, the addition of a neutralizing anti TNF-alpha antibody inhibits the production of IL-1 and GM-CSF, indicating the presence of a cytokine 'cascade' in this inflammatory tissue. In this paper we demonstrate that the interactivities between cytokines in rheumatoid arthritis also extends to other cytokines, such as IL-6 and IL-8, and that within the IL-1 family it is IL-1 beta in particular which is downregulated by neutralizing TNF-alpha activity. The cytokine interactions are unidirectional, in that neutralization of TNF-alpha reduced IL-1 beta, IL-6 and IL-8 production, whereas treatment of the rheumatoid synovial membrane cells with a neutralizing concentration of the IL-1 receptor antagonist (IL-1ra) reduced IL-6 and IL-8 production but not TNF-alpha production. These results suggest a rationale for the profound anti-inflammatory effects and consequent clinical benefit noted in RA patients treated recently in clinical trials with a chimeric anti-TNF-alpha antibody in vivo.
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PMID:Modulation of proinflammatory cytokine release in rheumatoid synovial membrane cell cultures. Comparison of monoclonal anti TNF-alpha antibody with the interleukin-1 receptor antagonist. 878 87

IL-8 is a potent neutrophil attractant and activator. IL-8 has been reported to be involved in the pathogenesis of several diseases, including rheumatoid arthritis, sepsis, psoriasis, and the adult respiratory distress syndrome (ARDS). Our previous studies demonstrated that high concentrations of IL-8 were present in alveolar fluids from patients with ARDS and were associated with increased mortality. In this study we report that a major portion of IL-8 in bronchoalveolar fluids from patients with ARDS is associated with anti-IL-8 autoantibody (anti-IL-8:IL-8 complexes). Free autoantibodies that recognize IL-8 were also detected in these fluids. Next, we examined the properties of anti-IL-8 autoantibodies present in lung fluids from ARDS patients and compared them with autoantibodies from normal plasma and arthritic synovial fluids. The anti-IL-8 autoantibody was polyclonal, and IgG3 and IgG4 were the primary IgG subclasses. Anti-IL-8:IL-8 complexes consisted of one IgG and one IL-8 molecule. In addition, anti-IL-8 autoantibody bound IL-8 with a high affinity (approximately 10(-12) M) and inhibited IL-8 interaction with its specific receptors on neutrophils. The results suggest that anti-IL-8 autoantibodies may regulate IL-8 activity.
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PMID:Anti-IL-8 autoantibodies in alveolar fluid from patients with the adult respiratory distress syndrome. 880 76

Articular chondrocytes from nine arthritic patients, five infants, and Balb/c neonatal mice were analyzed for the presence of various cytokine mRNAs by a reverse transcriptase polymerase chain reaction (RT-PCR). Four cytokine mRNAs, interleukin (IL)-6, IL-8, IL-11, and macrophage colony stimulating factor (M-CSF), were detected in all human chondrocytes, regardless of source. IL-10, IL-12p35, and tumor necrosis factor alpha (TNF-alpha) transcripts were found in at least 12 of the 14 human samples. IL-13, granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), and TNF-beta mRNAs were found more predominantly in infant samples and in samples from patients with rheumatoid arthritis (RA) compared with samples from patients with osteoarthritis (OA). Another group of cytokine mRNAs, IL-1 (alpha, beta), IL-4, IL-5, and IL-7, were only weakly expressed in some human samples. The cytokine transcripts that were not found were IL-2, IL3, and interferon gamma (IFN-gamma). Because of the large array of cytokine transcripts detected, human chondrocyte preparations were further purified by reacting them with a monoclonal antibody specific to chondrocyte differentiation antigen and subjecting them to fluorescent-activated cell sorting. A similar array of cytokines was found between the sorted and unsorted chondrocytes, although TNF-alpha, G-CSF and GM-CSF transcripts appeared to be upregulated during the sorting process. Human chondrocytes that dedifferentiated into fibroblasts (a 40-day and a 77-day culture) no longer expressed mRNAs for IL-1, G-CSF, GM-CSF, and TNF-alpha, but all other cytokine mRNAs remained detectable. Although certain phenotypic characteristics were lost, including reactivity to chondrocyte-specific monoclonal antibodies and morphological features, chondrocytes in long-term culture still expressed cytokine mRNAs. As expected, more consistent results were obtained when seven preparations of chondrocytes from neonatal Balb/c mice were examined using available cytokine primers. They contained IL-1, IL-5, IL-6, IL-7, IL-12, GM-CSF, M-CSF, transforming growth factor beta (TGF-beta), TNF-alpha, and TNF-beta mRNAs but lacked IL-2, IL-3, IL-4, IL-10, and IFN-gamma mRNAs. Future experiments to define conditions by which these cytokine protein products are expressed are needed to help assess their roles in chondrocyte biology and in disease states.
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PMID:Cytokine mRNA repertoire of articular chondrocytes from arthritic patients, infants, and neonatal mice. 885 28

Elderly-onset rheumatoid arthritis (EORA) is thought to be different from younger-onset disease (YORA) for many reasons, including a more elevated acute phase response and a more abrupt onset; both events are mainly regulated by pro-inflammatory interleukins (ILs), in particular, IL-1, IL-6 and IL-8. To compare the synovial fluid (SF) levels of these ILs, and their relationship to local inflammation as well as the acute phase response, erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP) in the two RA subsets, we determined white blood cell (WBC) number, total protein (TP), IL-1beta, IL-6 and IL-8 concentrations in the SF of 50 patients, 15 with EORA and 35 with YORA. Both ESR and CRP were higher in EORA than in YORA. IL-6 was higher in SF of EORA (2111.37 +/- 1425.03 pg/mL) than YORA (1077.53 +/- 757.62 pg/mL, p = 0.002), while no difference was observed for SF IL-1beta and IL-8. There was a weak correlation between SF IL-6 and IL-1beta in EORA, whereas SF ILs and CRP and/or ESR did not show any correlation in both groups. Our study indicates that in EORA, as in other diseases occurring in the elderly, there are elevated levels of IL-6. Higher SF levels of IL-6 may be, at least in part, responsible for the different behavior of EORA with respect to YORA.
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PMID:Synovial fluid levels of proinflammatory interleukins and their inter-relationships in elderly vs younger onset rheumatoid arthritis. 890 58


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