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Query: UMLS:C0003864 (arthritis)
 69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inflammatory cytokines have been implicated in the pathogenesis of rheumatoid arthritis. To validate a key role for IL-1 in arthritic processes we have studied the protective effect of neutralizing antimurine IL-1 antibodies in the murine collagen-induced arthritis (CIA) model. Combination of anti-IL-1 alpha and anti-IL-1 beta given before onset of arthritis was shown to prevent disease completely. Remarkably, a single treatment was also highly effective in the established phase of arthritis, reducing both inflammation as well as cartilage destruction. Suppression was most pronounced with the combination, but anti-IL-1 beta alone also induced significant relief. Finally, we studied the protective effect of IL-1 neutralization on cartilage metabolism in a unilateral expression model of collagen arthritis. To this end zymosan was injected in one knee joint before onset of disease, resulting in accelerated expression in that particular joint and the draining paw. Anti-IL-1 treatment started after accelerated expression of arthritis was able to fully normalize chondrocyte synthetic function, which was highly suppressed in the control group. It is concluded that IL-1 is an important determinant in both inflammation and cartilage destruction in collagen arthritis, and this may have implications for therapy in human arthritis.
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PMID:Amelioration of established murine collagen-induced arthritis with anti-IL-1 treatment. 830 98

Injection of lipopolysaccharide (LPS) into rabbit knee joints provoked leucocyte infiltration and loss of proteoglycan (PG) from the cartilage. We investigated the role of IL-1 and IL-1 receptor antagonist (IL-1Ra) and its significance in the pathogenesis of LPS-arthritis. Production of IL-1 beta peaked at 6 h (196.7 +/- 89.4 pg/joint) after injection of 10 ng of LPS, while IL-1Ra peaked at 9 h (34.5 +/- 13.4 ng/joint). The amount of IL-1Ra was 180-200-fold molar excess of IL-1, and a large amount of IL-1Ra was sustained for 1 week. Both IL-1 beta and IL-1Ra were mainly produced by synovial exudate cells. Arthritis was reproduced by rabbit IL-1 beta. LPS-induced leucocyte infiltration was inhibited 70-75% by rabbit IL-1Ra. Loss of PG in LPS-arthritis was prevented by IL-1Ra and also by neutrophil elastase inhibitor, and superoxide dismutase. In leucopenic rabbits, injection of LPS induced neither production of IL-1 beta nor loss of PG. Direct injection of inflammatory exudated cells in leucopenic rabbits reproduced loss of PG, and there was only a partial recovery by IL-1Ra. These results suggest that LPS-initiated IL-1 acts as a key mediator in LPS-arthritis and that endogenous IL-1Ra may suppress a part of IL-1 activity at the site, but its amount was too low for suppression of the produced IL-1. Loss of PG is a sequela of infiltrated leucocytes and leucocyte-derived elastase, and superoxide anion may play a pivotal role in the destruction of cartilage.
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PMID:Production of IL-1 and IL-1 receptor antagonist and the pathological significance in lipopolysaccharide-induced arthritis in rabbits. 834 45

We have developed an extraction method and radioimmunoassay for the measurement of interleukin-1 beta (IL-1 beta) in rat tissues, using an antibody specific for IL-1 beta, IL-1 beta was detected in the spleen and thymus of control rats. Adrenalectomy (ADX) had no effect upon control levels of IL-1 beta. In animals with adjuvant-induced arthritis, IL-1 beta content in the spleen and thymus increased after 14 days. These increases in tissue IL-1 beta contents were not evident in ADX arthritic animals. We conclude that IL-1 beta synthesis is stimulated in tissues of the immune system following the development of adjuvant-induced arthritis. Failure to observe elevated levels of tissue IL-1 beta in ADX arthritic rats may be evidence for tissue depletion due to increased IL-1 beta release in the absence of circulating corticosteroids.
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PMID:Interleukin-1 beta measured by radioimmunoassay in the rat spleen and thymus is increased during chronic inflammatory stress. 835 Sep 80

IL-1ra is the first described naturally occurring receptor antagonist of any cytokine or hormone-like molecule. IL-1ra is a member of the IL-1 family by three criteria: amino acid sequence homology of 26 to 30% to IL-1 beta and 19% to IL-1 alpha; similarities in gene structure; and common gene localization to human chromosome 2q14. Two structural variants of IL-1ra exist: sIL-1ra, a secretory molecule produced by monocytes, macrophages, neutrophils, fibroblasts, and other cells; and icIL-1ra, an intracellular molecule produced by keratinocytes and other epithelial cells, macrophages, and fibroblasts. IL-1ra production by monocytes, macrophages, and neutrophils may be regulated in a differential fashion with IL-1 beta. Human IL-1ra binds to both human IL-1RIs and IL-1RIIs on cell surfaces, although with 100-fold greater avidity to IL-1RIs. IL-1ra may bind preferentially to soluble IL-1RIs and not at all to soluble IL-1RIIs. IL-1ra competitively inhibits binding of both IL-1 alpha and IL-1 beta to cell surface receptors without inducing any discernible intracellular responses. All three forms of IL-1 may bind to IL-1 receptors in a similar fashion but IL-1ra may lack the secondary interactions necessary to trigger cell responses. A 100-fold or greater excess of IL-1ra over IL-1 may be necessary to inhibit biological responses to IL-1 both in vitro and in vivo. The roles of sIL-1ra and icIL-1ra in normal physiology or in host defense mechanisms remain unclear. The administration of IL-1ra blocks the effects of IL-1 in some animal models of septic shock, inflammatory arthritis, graft-versus-host disease, and inflammatory bowel disease. The preliminary results of clinical trials in humans indicate possible efficacy of IL-1ra in sepsis syndrome, rheumatoid arthritis, and GVHD.
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PMID:Interleukin-1 receptor antagonist. 837 62

During septic shock, cytokines produced by host cells play an important role in the pathogenesis of hemodynamic involvement and cellular lesions. Recently, natural inhibitory substances able to neutralize the biological activity of tumor necrosis factor alpha (TNF alpha) and interleukin-1 (IL-1) were described. These inhibitory molecules are involved in the regulation of the production of these cytokines. Thus, an understanding of these mechanisms could lead to new treatments for septic shock. A review of the interactions of TNF alpha with macrophages, neutrophils and endothelium underlines the key role of TNF alpha in 3 important events of septic shock: neutrophil adherence to endothelium, capillary leak syndrome, and development of disseminated intravascular coagulopathy. In clinical studies, circulating TNF alpha concentrations were elevated and correlated with the severity of the disease. Soluble TNF receptors (TNF-sRI and TNF-sRII) neutralize the biological effect of TNF alpha. Their circulating levels are also increased in meningococcemia, but an imbalance between TNF alpha and TNF-sR was found at the beginning of the disease which could determine the severity of the shock in these patients. The IL-1 system is composed of IL-1 alpha and IL-1 beta, two forms of precursors, two distinct receptors, two soluble fragments of the extramembranous regions of these receptors, and a natural antagonist of IL-1 receptors (IL-1 ra) which could be secreted or remain intracellular. IL-1 ra improved the outcome in some experimental diseases (endotoxemic shock, cerebral malaria arthritis, graft-versus-host reaction). The treatment of septic shock with IL-1 ra is currently being assessed in phase I and II clinical studies. Blockade of cytokines by antibodies or naturally occurring inhibitory molecules could lead to new therapies for septic shock.
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PMID:[Cytokines and antagonists in septic shock]. 838 92

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

The magnitude of the response of rat macrophages to group A streptococcal cell wall peptidoglycan-polysaccharide (PG-APS) stimulation is strain-dependent. A comparison of IL-1 expression between macrophages from a PG-APS-resistant (BUF) and PG-APS-sensitive (LEW) rat strain revealed that while mRNA levels for IL-1 alpha and IL-1 beta were equivalent for the two strains, supernatants from BUF macrophages were less potent than LEW supernatants at stimulating thymocyte proliferation and contained less immunoreactive IL-1 alpha and IL-1 beta protein. BUF and LEW macrophages expressed nearly equivalent levels of IL-1 receptor antagonist (IL-1ra) mRNA and secreted IL-1ra protein in supernatants. The ratio of IL-1/IL-1ra produced by macrophages may influence susceptibility versus resistance to PG-APS and is strongly suggestive of a regulatory role for macrophages in the pathogenesis of PG-APS-induced arthritis.
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PMID:Differential regulation of group A streptococcal peptidoglycan-polysaccharide (PG-APS)-stimulated macrophage production of IL-1 by rat strains susceptible and resistant to PG-APS-induced arthritis. 851 8

Leukaemia inhibitory factor (LIF) is a secretory glycoprotein produced by tumour, mesenchymal and haemopoietic cells. LIF has been found to have pleiotropic actions that include the capacity to regulate cell differentiation, promote acute-phase protein synthesis and stimulate calcium release in bone explants. In view of its similarity to other cytokines that affect cartilage metabolism, the effects of LIF on proteoglycan resorption were examined in pig cartilage explants. Endotoxin-free recombinant mouse LIF was found to produce a dose-dependent increase in sulphated glycosaminoglycan (S-GAG) release (ED50 = 123 U/ml, approx. 25-50 pM). Statistically significant stimulation was observed with doses of 100 U/ml or greater. When pig cartilage was stimulated with maximum concentrations of LIF and either interleukin 1 alpha (IL-1 alpha), interleukin 1 beta (IL-1 beta) or tumour necrosis factor alpha (TNF alpha), in each case a significantly greater release of S-GAGs was observed than with the respective cytokines alone (P < 0.05). Comparison of the areas under the curves showed that the action of LIF was additive, and not synergistic with other catabolic cytokines. Dose-response studies showed that transforming growth factor beta (TGF beta) produced a partial inhibition of LIF-stimulated release of S-GAGs (ED50 = 4.5 U/ml). Statistically significant inhibition was observed with doses of 2 U/ml or greater. These results showed that LIF stimulated proteoglycan resorption in vitro and that this effect was modulated by other cytokines. Whether LIF contributes to the progressive destruction of cartilage in septic or chronic inflammatory arthritis remains to be determined.
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PMID:Leukaemia inhibitory factor stimulates proteoglycan resorption in porcine articular cartilage. 851 24

Investigative attempts to identify novel therapy for inflammatory connective tissue diseases continue to evolve. Amiprilose hydrochloride (amiprilose HCl) is a synthetic carbohydrate shown to have anti-inflammatory effects in animal models of inflammatory arthritis and in a multicenter clinical trial. Interleukin-1 (IL-1) is an important mediator of immune regulation, inflammation and joint destruction in arthritis. In the present study, the effects of amiprilose HCl on IL-1 activity, production and receptor distribution were investigated. Drug effects on IL-2 production and receptor distribution on lymphocytes were also explored. Potential regulation of IL-1 activity was determined by monitoring the effects of amiprilose HCl on IL-1 stimulated proliferation of murine thymocytes and human synovial cells. Inhibitory effects on IL-1 beta and IL-2 production by stimulated human peripheral blood monocytes were measured by ELISA and lymphocyte IL-1 beta and IL-2 receptor distribution were analyzed by flow cytometry. The results from in vitro studies demonstrated that low concentrations of amiprilose HCl (1-100 micrograms/ml) stimulated thymocyte proliferation and enhanced the proliferative response of IL-1 stimulated human synovial fibroblasts. IL-1 beta production in cultures of human peripheral blood monocytes was significantly decreased after exposure of the cultures to varying doses of amiprilose HCl as determined by ELISA. Exposure of mitogen activated human peripheral blood lymphocytes to amiprilose HCl resulted in decreased IL-2 production at high concentrations of drug as compared to control. However, at doses of amiprilose HCl previously found to stimulate thymocyte proliferation (1-10 micrograms/ml), increased levels of culture supernatant IL-2 were observed. No amiprilose HCl mediated changes in lymphocyte IL-1 beta or IL-2 receptor expression were observed. The regulatory effects of amiprilose HCl on cytokines support the potential of this drug as a therapeutic agent for the treatment of inflammatory arthritis.
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PMID:Immunoregulatory effects of a synthetic monosaccharide. 857 39

Chronically elevated serum levels of proinflammatory cytokines is a feature of the syndrome known as POEMS (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal [M] protein, skin changes). A patient had a POEMS syndrome with thrombocytosis and biclonal gammopathy and was treated as follows: all-trans-retinoic acid (tretinoin) at 90 mg/day for 50 days, no treatment for 70 days, readministration of tretinoin at 75 mg/day for 180 days. Focal bone lesion irradiation was performed from day 26 to day 50. Serum levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF alpha), and IL-1 beta normalized within 7 days after the first administration of tretinoin, transiently increased at the time of radiotherapy, increased again after withdrawal of the tretinoin, and decreased again after its reintroduction. The platelet count and gammopathy paralleled the changes in the cytokine levels. This study documents in vivo the ability of all-trans-retinoic acid to down-regulate the release of IL-6, IL-1 beta, and TNF alpha, and illustrates its potential as a therapeutic agent in conditions associated with chronic overproduction of proinflammatory cytokines.
Arthritis Rheum 1996 Aug
PMID:All-trans-retinoic acid in POEMS syndrome. Therapeutic effect associated with decreased circulating levels of proinflammatory cytokines. 870 54


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