Prevention and reversal of cartilage degradation in rheumatoid arthritis by interleukin‐10 and interleukin‐4

Abstract

Objective. Inflammation‐induced articular cartilage degradation is a major problem in rheumatoid arthritis (RA). Type 1 T cell activity (characterized by interferon‐γ/interleukin‐2 [IL‐2] production), and consequently, the production of the proinflammatory cytokines IL‐1 and tumor necrosis factor α (TNFα), have been reported to play a major role in cartilage damage. IL‐10 and IL‐4, both produced by type 2 T cells, are cytokines with the capacity to down‐regulate proinflammatory responses. The present study was undertaken to investigate the way in which these cytokines affect activated mononuclear cells (MNC) of RA patients in relation to human articular cartilage degradation in vitro. Methods. MNC from synovial fluid and peripheral blood of RA patients were stimulated with bacterial antigen and treated with IL‐10 and/or IL‐4. Bacterial antigen is known to activate type 1 T cells and to induce proinflammatory IL‐1/TNFα–dependent cartilage damage. Cytokine production and effects of conditioned media, as well as effects of IL‐10 and IL‐4 on proteoglycan (PG) turnover (as a measure for cartilage damage), were determined. Results. IL‐10 and IL‐4 inhibited proinflammatory cytokine production of stimulated RA MNC and completely reversed inhibition of cartilage PG synthesis induced by these stimulated RA MNC. IL‐10 was more potent than IL‐4 in this respect, and the combination of IL‐10 and IL‐4 had an additive effect. In addition, IL‐10 directly stimulated cartilage PG synthesis. Conclusion. IL‐10 reverses the cartilage degradation induced by antigen‐stimulated MNC, and IL‐4 has an additive effect on this process. Furthermore, IL‐10 has a direct stimulatory effect on PG synthesis, and IL‐4, as a growth factor for type 2 T cells, can reduce the ratio of type 1 to type 2 T cell activity. These results provide evidence in favor of the use of a combination of the two cytokines in the treatment of RA.

Accumulation of advanced glycation end products as a molecular mechanism for aging as a risk factor in osteoarthritis

“…Shark cartilage chondroitin sulfate (Sigma) served as a standard. GAG release was normalized to the wet weight of the cartilage samples (46). Proteoglycan synthesis.…”

Interleukins and interleukin receptors in rheumatoid arthritis: Research, diagnostics and clinical implications

“…Some antiinflammatory effects are also naturally provided by the presence of IL-1RN, IL-1R2 decoy receptor and soluble TNF receptor. In vitro, IL-10 and IL-4 inhibit the production of inflammatory cytokines including IL-1, IL-6 and TNF-α RA [189,190] , furthermore IL-10 has been shown to reverse the cartilage degradation seen in RA [189] . In vivo, however, they are inherently weak and proved inadequate.…”

Aseptic loosening

“…In particular, IL-1 receptor antagonist protein (IL-1Ra or IRAP) has been successful in reducing inflammation, 72,73 and the antiinflammatory cytokine IL-10 appears to possess the capacity to reduce cell-mediated reactions in inflammation. 74,75 The delivery of appropriate doses of proinflammatory cytokine inhibitors to the periprosthetic tissue remains a problem. However, recent advances in gene therapy techniques 76,77 suggest that viral vectors may be capable of delivering anti-inflammatory cytokine genes to the periprosthetic tissues, which could control the local reaction and extend the life of the prosthesis.…”