Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

In inflammatory diseases such as rheumatoid arthritis, functions of chondrocytes including synthesis of matrix proteins and proteinases are altered through interactions with cells of the infiltrating pannus. One of the major secreted products of mononuclear inflammatory cells is IL-1. In this study we found that recombinant human IL-1 beta suppressed synthesis of cartilage-specific type II collagen by cultured human costal chondrocytes associated with decreased steady state levels of alpha 1 (II) and alpha 1(IX) procollagen mRNAs. In contrast, IL-1 increased synthesis of types I and III collagens and levels of alpha 1(I), alpha 2(I), and alpha 1(III) procollagen mRNAs, as we described previously using human articular chondrocytes and synovial fibroblasts. This stimulatory effect of IL-1 was observed only when IL-1-stimulated PGE2 synthesis was blocked by the cyclooxygenase inhibitor indomethacin. The suppression of type II collagen mRNA levels by IL-1 alone was not due to IL-1-stimulated PGE2, since addition of indomethacin did not reverse, but actually potentiated, this inhibition. Continuous exposure of freshly isolated chondrocytes from day 2 of culture to approximately half-maximal concentrations of IL-1 (2.5 pM) completely suppressed levels of type II collagen mRNA and increased levels of types I and III collagen mRNAs, thereby reversing the ratio of alpha 1(II)/alpha 1(I) procollagen mRNAs from greater than 6.0 to less than 1.0 by day 7. IL-1, therefore, can modify, at a pretranslational level, the relative amounts of the different types of collagen synthesized in cartilage and thereby could be responsible for the inappropriate repair of cartilage matrix in inflammatory conditions.
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PMID:Interleukin 1 suppresses expression of cartilage-specific types II and IX collagens and increases types I and III collagens in human chondrocytes. 326 90

In rheumatoid arthritis there is a chronic immune and inflammatory reaction which can lead to the destruction of the diseased joint. Cytokine gene expression was studied in synovial cells using cDNA probes specific for human interleukin 1 (IL-1), -alpha and IL-1 beta, tumour necrosis factor (TNF), -alpha and TNF beta (lymphotoxin); protein molecules which induce cartilage degradation and bone resorption. In all cases studied, IL-1 mRNA was present in freshly isolated synovial cells from fluid or membrane. Compared to levels of IL-1 mRNA found in optimally activated normal blood mononuclear cells, the levels of IL-1 alpha mRNA were high in seven of the nine patients studied, whereas IL-1 beta mRNA, the dominant form in blood, was relatively lower. TNF alpha and TNF beta mRNA were also detected. Rheumatoid synovial cells, cultured without any stimulus, continued to express high levels of IL-1 alpha mRNA for up to 5 days, compared to the 24 h response of activated blood cells; IL-1 beta mRNA in culture was also prolonged. Cultures of rheumatoid joint cells produced IL-1 bioactivity, with roughly equal amounts of IL-1 alpha and beta, as assessed using neutralizing antibodies. TNF bioactivity was also detected which may be of importance as TNF induces the production of IL-1. The finding of these mediators produced in large amounts in active rheumatoid synovial cells suggests that mutually stimulatory cell interactions, mediated by these molecules, may be important in the chronic inflammation and tissue destruction in rheumatoid arthritis.
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PMID:Interleukin-1 and tumour necrosis factor mRNA expression in rheumatoid arthritis: prolonged production of IL-1 alpha. 326 73

Interleukin-1 beta (IL-1 beta) and proteoglycans have been quantified by radioimmunoassay (IL-1 beta) and enzyme linked immunosorbent assay (proteoglycans) in synovial fluids and sera from patients with rheumatoid arthritis (RA) and reactive arthritis. All fluids were also tested for their ability to influence proteoglycan metabolism in a cartilage explant culture system. Synovial fluid IL-1 beta concentrations were inversely related to proteoglycan concentrations in samples from both RA and reactive arthritis patients (P less than 0.002 for all patients). There was no statistically significant relation between immunoreactive IL-1 beta concentration and proteoglycan synthesis or degradation in explants cultured in synovial fluid containing medium. Synovial fluid IL-1 beta concentrations were not related to erythrocyte sedimentation rate or joint total leukocyte count. IL-1 beta was not detectable (limit 250 pg/ml) in any unextracted sera. Although it appears likely that IL-1 beta is involved in the inflammatory and degenerative processes in joint disease, our findings indicate that there is no simple positive relationship between immunoreactive levels of this cytokine in synovial fluid and liberation of proteoglycans from articular cartilage as reflected in synovial fluid proteoglycan concentration.
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PMID:Synovial fluid concentrations of interleukin-1 beta and proteoglycans are inversely related. 326 94

Balb/3T3 fibroblasts respond to interleukin-1 (IL-1) by proliferating in a dose-dependent fashion. Increasing proliferative responses were observed with increasing IL-1 concentration in serum-free medium when the medium was supplemented with insulin, transferrin, and selenium. This response was evident only if the cell culture medium also contained the cyclooxygenase inhibitor indomethacin. When another fibroblast mitogen, epidermal growth factor (EGF) was cocultured with either purified monocyte-derived IL-1 beta or recombinant IL-1 beta, there was a potentiation of proliferation above the expected additive response. Unexpectedly, the response to recombinant IL-1 alpha was only additive with EGF. This suggests that IL-1-mediated activation of synovial fibroblasts in rheumatoid arthritis may be compounded by EGF as well as by other fibroblast mitogens secreted by cells found in the joint. The results further suggest that IL-1 and EGF interactions may play a significant role in wound healing, scarring, and bone resorption. In addition, these results imply that there may be different cellular activation pathways brought to bear in vivo which may depend, in part, on the IL-1 isotype available.
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PMID:Potentiation of Balb/3T3 fibroblast proliferative response by interleukin-1 and epidermal growth factor. 328 79

Highly purified and cloned preparations of interleukin-1 (IL-1) were found to antagonize the capacity of erythropoietin (Epo) to stimulate the proliferation of mouse spleen and bone marrow erythroid precursor cells (EPC) in culture. Cloned murine IL-1 and purified and cloned human IL-1 alpha and IL-1 beta were approximately equipotent in this assay. IL-1 inhibited the proliferation response of EPC even when added as long as 17 h after Epo, suggesting that IL-1 does not affect binding of Epo to receptors or biochemical events following shortly thereafter. Indomethacin did not influence the inhibitory effect of IL-1 on Epo-induced proliferation, and PGE2 had no demonstrable effect on the process. Tumor-necrosis factor-alpha and interferons beta 1, and gamma did not affect Epo-induced proliferation. It is suggested that IL-1 mediated antagonism of the effects of Epo on erythroid precursors is a factor in the pathogenesis of many types of hypoplastic anaemia, including those associated with infections, rheumatoid arthritis and systemic lupus erythematosus, giant-cell arteritis, graft-versus-host disease and disorders associated with lymphocyte-mediated suppression of erythropoiesis.
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PMID:Inhibition by interleukin-1 of the action of erythropoietin on erythroid precursors and its possible role in the pathogenesis of hypoplastic anaemias. 349 70

Although the cause of rheumatoid arthritis is uncertain, the mechanisms by which destruction of joint tissues may occur have been studied extensively. The inflammatory responses in rheumatoid arthritis are probably mediated by a variety of different agents which include prostaglandins, leukotrienes, kinins and other peptide mediators, complement components, and immune complexes. The ultimate destruction of proteoglycans and collagen within cartilage similarly depend upon the release of the appropriate degradative enzymes. At one time these were thought to be predominantly lysosomal acid proteinases but emphasis has recently shifted to neutral metallo-proteinases which include specific enzymes capable of degrading collagen or proteoglycans at neutral pH. Under normal conditions these proteinases are in latent form due in part to the presence of a tissue inhibitor of metallo-proteinases (TIMP). During studies of human joint tissues in culture, it has become apparent that products of one cell type may influence the behaviour of other cells. Thus, monocytes and macrophages may produce mediators, such as interleukins, one of which has been called mononuclear cell factor (MCF), which when added to cultures of human articular chondrocytes or synovial cells, markedly enhances production of prostaglandins and metallo-proteinases while depressing the amount of TIMP. Cultured human synovial tissue produces factors with similar properties, which may in turn be related to mediators such as catabolin, which can be produced by synovium and other connective tissues and which stimulate chondrocytes to degrade their own matrix. The production of these mediators may not only be relevant to rheumatoid arthritis but also to other diseases. Thus, MCF is capable of stimulating prostaglandin production by gingival cells and cells derived from human bone. Moreover MCF is itself capable of inducing bone resorption. Since both normal and diseased tissues are capable of producing and responding to these mediators, these potential degradative interactions must be kept in check in vivo. Glucocorticosteroids may play a role in the natural suppression of these mechanisms, since in vitro they are capable of inhibiting the production of factors as well as their effects on target tissues. Since these factors probably have anabolic activity as well, they may be involved in connective tissue repair after injury. Such intercellular mediators may play important roles in the control of connective tissue turnover, not only in disease states but also in the normal processes of growth and differentiation.
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PMID:Intercellular messengers in joint tissues in rheumatoid arthritis. How disturbed control mechanisms may contribute to tissue destruction and repair. 610 Sep 20

Resorption of cartilage matrix is usually considered to be due to extrinsic proteases, generally thought to be the neutral metalloproteases, including collagenase. Such enzymes can be secreted from synovial tissue and in acute forms of arthritis they are believed to be the main agents of pannus erosion. However, such enzyme secretion has not been clearly demonstrated to be the causative agent in either rheumatoid arthritis or in osteoarthritis. For example, no specific inhibitors of these proteinases have yet been proved effective in vivo. Recent experiments at the Strangeways Research Laboratory have demonstrated that viable chondrocytes of animal and human articular cartilage are capable of resorbing their surrounding matrix without the aid of extrinsic enzymes. We now know that such resorption can be stimulated by the action of a low molecular weight peptide released from living synovial and other connective tissues. These messengers (catabolins) are capable of stimulating chondrocytes to degrade totally both proteoglycan and collagen. The purification, properties, regulation and action of catabolism are under investigation to determine the role for catabolin in arthritis.
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PMID:Catabolin--a cartilage catabolic factor from synovium. 701 63

In a recent study from our group, the combination of methotrexate and sulphasalazine (MTX + SASP) seemed superior to MTX alone in the treatment of rheumatoid arthritis (RA). To assess the impact of these therapies on the cytokine cascade, the in vitro production and circulating concentrations of several cytokines and endogenous cytokine antagonists were measured in 30 healthy controls and longitudinally in a subset of 26 patients enrolled in this study. Compared to controls, RA patients had significantly higher circulating concentrations of interleukin-6 (IL-6), soluble receptors for tumour necrosis factor (sTNFR), soluble receptors for interleukin-2 (sIL-2R) and interleukin-1 receptor antagonists (IL-1RA), and their peripheral blood mononuclear cells (PBMNC) showed a higher spontaneous production of interleukin-1 beta (IL-1 beta), tumour necrosis factor alpha (TNF alpha) and IL-1RA (both secreted and cell-associated) and a higher stimulated production of cell-associated TNF alpha, IL-1RA and (to a lesser extent) IL-1 beta. Treatment with MTX alone (n = 12) or combined with SASP (n = 14), resulted in significant reductions of circulating IL-6 and sIL-2R but did not alter IL-1 beta, TNF alpha or IL-1RA concentrations. Decreases in circulating levels of sTNFR and in the in vitro production of cell-associated IL-1 beta and IL-1RA after stimulation were only observed in patients treated with MTX + SASP. The concentrations of IL-1RA and sTNFR in the circulation exceeded moderately those of IL-1 beta and TNF alpha but this is probably insufficient to block IL-1 and TNF alpha activity. In conclusion, therapy with MTX alone or with SASP modulates IL-6 and sIL-2R concentrations in RA. Decreased production of IL-1 beta and IL-1RA and circulating sTNFR levels were only observed during therapy with MTX + SASP. Whether this relates to the better clinical effect observed with the combination therapy remains to be investigated. Circulating levels of IL-6, sIL-2R and sTNFR seem useful markers of disease activity in RA.
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PMID:Effect of methotrexate alone or in combination with sulphasalazine on the production and circulating concentrations of cytokines and their antagonists. Longitudinal evaluation in patients with rheumatoid arthritis. 755 60

Rheumatoid synovitis is characterized by an infiltration of mononuclear cells and by the proliferation of synoviocytes. Monocytes and synoviocytes are major producers of cytokines, growth factors, and enzymes that contribute to the rheumatoid arthritis (RA) process. Since they are in close contact in vivo, we engaged in an in vitro study of the functional consequences of their interactions. Coculture of unstimulated elutriated normal blood monocytes over RA synoviocytes resulted in a synergistic increase of the production of IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), leukemia inhibitory factor (LIF), and IL-8, when compared with their respective production in culture alone. In contrast, cytokines such as IL-10, IL-1 beta, IL-1 alpha, and TNF-alpha could not be detected. The IL-6 production in coculture was further increased by the addition of IL-1 beta, GM-CSF, IFN-gamma, or TNF-alpha, but was inhibited by the addition of IL-10, IL-4, IL-13, or IL-1Ra, an effect reverted by the addition of IL-1 beta. Moreover, an inhibition was also observed with anti-CD14 mAb and newly raised mAbs directed against RA synoviocytes. Under reducing conditions, the mAb SY12 precipitated a 150-kDa surface membrane protein, identified as amino-peptidase N (CD13/AP-N). Collectively, these results indicate that 1) monocytes and synoviocytes interact with each other to produce proinflammatory cytokines, 2) pro- and antiinflammatory cytokines have opposite effects on IL-6 production, and 3) molecules such as IL-1, CD14, and CD13 are involved.
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PMID:Contribution of IL-1, CD14, and CD13 in the increased IL-6 production induced by in vitro monocyte-synoviocyte interactions. 756 Oct 64

Leukocyte recruitment is critical in the inflammation seen in rheumatoid arthritis (RA). To determine whether the chemokine growth-related gene product alpha (gro alpha) plays a role in this process, we examined synovial tissue (ST), synovial fluid (SF), and plasma samples from 102 patients with arthritis. RA SF contained more antigenic gro alpha (mean 5.3 +/- 1.9 ng/ml) than did SFs from either osteoarthritis (OA) or other forms of arthritis (mean 0.1 ng/ml) (p < 0.05). RA plasma contained more gro alpha (mean 4.3 +/- 1.8 ng/ml) than normal plasma (mean 0.1 ng/ml) (p < 0.05). RA ST fibroblasts (1.2 x 10(5)/cells/mI RPMI 1640/24 h) produced antigenic gro alpha (mean 0.2 +/- 0.1 ng/ml), and this production was increased significantly upon incubation with TNF-alpha (mean 1.3 +/- 0.3 ng/ml) or IL-1 beta (mean 2.3 +/- 0.6 ng/ml) (p < 0.05). Cells from RA SF also produced gro alpha: neutrophils (PMNs) (10(7) cells/mI/24 h) produced 3.7 +/- 0.7 ng/ml. RA SF mononuclear cells produced gro alpha, particularly upon incubation with LPS or PHA. Immunoreactive ST gro alpha was found in greater numbers of RA compared with either OA or normal lining cells, as well as in RA compared with OA subsynovial macrophages (p < 0.05). IL-8 accounted for a mean of 36% of the RA SF chemotactic activity for PMNs, while epithelial neutrophil-activating peptide-78 accounted for 34%, and gro alpha for 28%, of this activity. Combined neutralization of all three chemokines in RA SFs resulted in a mean decrease of 50% of the chemotactic activity for PMNs present in the RA SFs. These results indicate that gro alpha plays an important role in the ingress of PMNs into the RA joint.
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PMID:Growth-related gene product alpha. A chemotactic cytokine for neutrophils in rheumatoid arthritis. 756 Oct 66


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