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)

The production of collagen and glycosaminoglycans (GAG) was studied in cultured human synovial cells exposed to four cytokines, alone or in dual combination, namely interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and transforming growth factor-beta (TGF-beta). Among these cytokines, only TGF-beta (0.1-10 ng/ml) induced a significant and dose-dependent increase of collagen synthesis in a 24-h incubation. This effect was reversed when the factor was associated with either IL-1 beta (100-500 pg/ml), TNF-alpha (1-100 ng/ml) or IFN-gamma (100 U/ml). Except IFN-gamma which clearly inhibits the collagen production, the other cytokines IL-1 and TNF-alpha were not very effective when tested separately, although they generally induced a small reduction in collagen amount. IL-1 beta and TNF-alpha were found to be more efficient than TGF-beta in stimulating the production of GAG by the synovial cells. IFN-gamma exerted an antagonistic effect on the TGF-beta-induced stimulation of GAG synthesis. TNF-alpha and IL-1 beta were shown to have an additive effect on that production. The results indicate that interactions between cytokines present in the inflamed synovial tissue may modulate their respective actions and thus introduce differentials in their effect on collagen and GAG metabolism which are responsible for the alterations of synovial extracellular matrix in rheumatoid arthritis.
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PMID:Effects of associated cytokines (IL-1, TNF-alpha, IFN-gamma and TGF-beta) on collagen and glycosaminoglycan production by cultured human synovial cells. 211

In addition to the induction of tumor regression, tumor necrosis factor (TNF) has been implicated as the causative agent in a number of pathologies, including cachexia, septic shock, rheumatoid arthritis, autoimmunity, and induction of HIV expression. We propose that this complex physiology might be manifest by different forms of TNF: the 17 kd secretory component, the 26 kd transmembrane form, or both. To determine whether the 26 kd form of TNF was biologically active and whether its biology differed from that of the secretory component, we generated uncleavable and solely secretable mutants of TNF and studied their biological activities. We found that an uncleavable mutant of the 26 kd cell surface transmembrane form of TNF kills tumor cells and virus-infected cells by cell-to-cell contact, and that TNF need not be internalized by its target to kill. Thus, the 26 kd integral transmembrane form of TNF may function in vivo to kill tumor cells and other targets locally in contrast to the systemic bioactivity of the secretory component.
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PMID:A nonsecretable cell surface mutant of tumor necrosis factor (TNF) kills by cell-to-cell contact. 220 85

Most studies of immune function in rheumatoid arthritis (RA) patients treated with methotrexate (MTX) show only marginal effects on humoral or cellular immune responses. These include measurements of lymphocyte subsets, proliferative responses to mitogens, immunoglobulin production, rheumatoid factor and immune complexes. The mechanism of action of MTX in RA might be more antiinflammatory than immunosuppressive. This is supported by the rapid clinical response to drug treatment and by data from in vitro and animal studies. The inhibition of interleukin-1 (IL-1) activity or other inflammatory cytokines by MTX may play an important role in the antiinflammatory effect of MTX. MTX effects in RA are not fully understood and further studies are needed to clarify its mechanism of action. MTX has crucial effects on the cascade of events initiated by some cytokines (IL-1, IL-6, tumor necrosis factor), which plays a major role in RA and other inflammatory diseases.
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PMID:Methotrexate: mechanism of action in rheumatoid arthritis. 228 44

The cytotoxic cytokines, tumor necrosis factor-alpha or cachectin and lymphotoxin (LT), are mediators of bone resorption and of inflammation and may have relevance in rheumatoid arthritis. Using mononuclear cells (MC) isolated from matched peripheral blood (PB) and synovial fluid (SF) of 13 patients with rheumatoid arthritis, we examined the generation of cytotoxic activity in a bioassay capable of detecting both TNF and LT. Synovial fluid mononuclear cells (MC) released significantly more cytotoxic activity than did matched PBMC, both spontaneously and following activation with phytohemagglutinin P (PHA). When PB and SFMC were stimulated with the combination of PHA plus phorbol-12-myristate acetate (PMA), the resulting culture supernatants possessed comparable cytotoxic activity. Neutralization studies employing anti-cytokine antibodies indicated that TNF represented 43 and 59% of the cytotoxic activity in the PHA plus PMA-induced culture supernatants from PB and SF, respectively. Since no inhibition was noted with antibodies to LT, the nature of the remaining approximately 50% of the cytotoxic activity was not determined. In PB and SF culture supernatants, obtained both spontaneously and following PHA activation, the concentration of TNF measured by ELISA significantly correlated with the level of cytotoxicity. As with the cytotoxic activity, the concentration of TNF was greater in the PHA-stimulated supernatants from SF than from PB. These observations suggest that TNF in the SF may contribute to the inflammation and bone destruction observed in rheumatoid arthritis.
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PMID:Enhanced cytotoxicity in the rheumatoid joint. 230 43

The biological effects of tumor necrosis factor (TNF) include the enhancement of fibroblast proliferation, the secretion of collagenase and prostaglandin E2 (PGE2) by fibroblasts, and the resorption of bone and cartilage, suggesting a role for this cytokine in arthritic conditions. To investigate this, we measured the levels of TNF in synovial fluids and evaluated its secretion by synovial fluid mononuclear cells and tissues from patients with rheumatoid arthritis, osteoarthritis, and seronegative arthritis and normals. TNF was found to be secreted in all arthritic conditions but not in normals. The levels of TNF were highest in synovial fluid and correlated with interferon-gamma (IFN-gamma) levels but not PGE2. The production of TNF was stable in a single joint for 3 to 6 months. Using immunohistochemical staining, TNF was localized to mononuclear cells in the lining layer, sublining, and perivascular areas of synovial tissue. The secretion of TNF by rheumatoid synovial fluid mononuclear cells was inhibited by PGE2, while IFN-gamma enhanced its production in those cells which were spontaneously secreting TNF. Our data suggest that TNF may play a role in various arthritic diseases.
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PMID:Characteristics of tumor necrosis factor production in rheumatoid arthritis. 247 44

Tumor necrosis factor stimulated prostaglandin E2 synthesis in Swiss 3T3 fibroblasts. Interleukin 1 also stimulated prostaglandin synthesis. Simultaneous addition of tumor necrosis factor and interleukin 1 synergistically stimulated prostaglandin synthesis, even when both growth factors were added at what would be supramaximal concentrations by themselves. Several small peptides and nonpeptides rapidly stimulate prostaglandin synthesis in these cells. Pretreatment with tumor necrosis factor synergistically enhanced prostaglandin synthesis in response to bradykinin, bombesin, thrombin, norepinephrine, and platelet-activating factor. Thus, tumor necrosis factor stimulates prostaglandin synthesis and greatly amplifies prostaglandin synthesis in response to other agonists. This finding may have significance in chronic inflammatory diseases such as rheumatoid arthritis in which several hormones and growth factors may synergistically augment eicosanoid synthesis.
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PMID:Tumor necrosis factor causes amplification of arachidonic acid metabolism in response to interleukin 1, bradykinin, and other agonists. 255 Apr 84

An abnormal immune response towards the Epstein-Barr virus (EBV) has been documented in patients with rheumatoid arthritis (RA). To investigate whether these findings are due to the transformation event caused by EBV, RA blood mononuclear cells and monocyte-enriched preparations were incubated with two different EBV strains: the transforming virus secreted by the cell line B95-8 and the virus released by the P3HR-1 cell line that is not able to transform due to a small deletion in the U2 region of the virus genome. Immunological response was determined by the production of interleukin-1 (IL-1) and tumor necrosis factor (TNF) using ELISA and bioassay systems. There was a striking difference in cytokine measurements with a strong inhibition of IL-1 and TNF production after incubation with the B95-8 virus, but not the P3HR-1 virus. These data indicate that the disturbed reaction of the immune system towards EBV is either dependent on the full transformation of B cells in RA patients or alternatively due to the secretion of a cytokine inhibitor by the B95-8 cell line.
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PMID:Differential immunological response of patients with rheumatoid arthritis towards two different Epstein-Barr virus strains: inhibition of interleukin-1 release by the B95-8, but not the P3HR-1 virus strain. 255 10

We describe here an Nco I restriction fragment length polymorphism of tumor necrosis factor carried by the 8.1 (HLA-A1,B8,BfS,C4AQ0,C4B1,DR3) and the 44.1 (HLA-B44,BfS,C4A3,C4BQ0,DR4) ancestral haplotypes associated with complications of rheumatoid arthritis. By examining multiple examples of these and other ancestral haplotypes it was seen that 8.1 and 44.1 ancestral haplotypes yield fragments of approximately 5.5 kb while many other ancestral haplotypes carry fragments of approximately 10.5 kb. The polymorphism is associated with the ancestral haplotype rather than the HLA-B or -DR allele defined by conventional serology.
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PMID:Some disease-associated ancestral haplotypes carry a polymorphism of TNF. 257 86

Inhibition of interleukin-1 alpha (IL-1 alpha) activity was detected in 7 of 41 serum samples from patients with rheumatoid arthritis (RA). These 7 sera inhibited not only IL-1 alpha-induced endothelial cell adherence to neutrophils, but also IL-1 beta-induced endothelial cell adherence, although to a lesser extent. These sera showed no influence on tumor necrosis factor-induced endothelial cell adherence. No inhibitory activity was found in 40 sera from normal control subjects. Studies to further examine these effects included gel filtration analysis of 2 of the RA sera. The inhibitory activity was eluted near Mr 158 kd and above Mr 250 kd. Analysis by protein A affinity chromatography showed that IL-1-inhibitory activity was present in protein A-binding fractions. Purified IgG (by DE-52 column chromatography) from RA patients was found to be as potent an inhibitor as the protein A-binding fractions, which suggests that the major inhibitory activity in RA sera is attributable to IgG molecules. These purified IgG molecules also inhibited IL-1-induced proliferation of mouse thymocytes but did not influence IL-2-dependent proliferation of the CTLL-2 murine T cell line. The 7 patients whose sera showed IL-1-inhibitory activity had mild RA and low titers of rheumatoid factor. The findings, taken together, suggest a possible regulatory role of IL-1-inhibitory IgG in RA disease activity.
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PMID:Interleukin-1-inhibitory IgG in sera from some patients with rheumatoid arthritis. 259 8

Culture supernatants of B cells from patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) in the active stage enhanced interleukin 2 (IL-2) dependent proliferation of CTLL A/J cells. This activity, designated B cell-derived growth-enhancing factor-2 (BGEF-2), was recovered by gel filtration of a molecular weight between 15,000 and 20,000. BGEF-2 itself did not show IL-2 activity nor IL-1 activity, and BGEF-2 activity was not detected in the following cytokines: Interferon-alpha (IFN-alpha), interferon-gamma (IFN-gamma), tumor necrosis factor (TNF), interleukin 4 (IL-4), interleukin 5 (IL-5) and interleukin 6 (IL-6). Furthermore, BGEF-2 was distinguishable from B cell-derived growth-enhancing factor described in a previous paper [Kang et al. (1987) J. Immunol., 139, 1154-1160]. BGEF-2 was produced by B cells from patients with RA or SLE only when the patients were in the active stage. BGEF-2 enhanced IL-2-dependent growth of peripheral blood T cells from patients with active RA, but did not enhance the growth of T cells from healthy volunteers. These results suggest that BGEF-2 is a B cell-derived lymphokine which plays an important role in the pathogenesis of RA and SLE.
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PMID:IL-2 enhancing factor(s) in B cell supernatants from patients with rheumatoid arthritis or systemic lupus erythematosus. 262 61


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