PREVENTION AND REVERSAL OF CARTILAGE DEGRADATION IN RHEUMATOID-ARTHRITIS BY INTERLEUKIN-10 AND INTERLEUKIN-4

Objective. Inflammation-induced articular cartilage degradation is a m ajor problem in rheumatoid arthritis (RA). Type 1 T cell activity (cha racterized by interferon- gamma/interleukin-2 [IL-2] production), and consequently, the production of the proinflammatory cytokines IL-1 and tumor necrosis factor alpha (TNF alpha), 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 proinflam matory 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 pa tients were stimulated with bacterial antigen and treated with IL-10 a nd/or IL-4. Bacterial antigen is known to activate type 1 T cells and to induce proinflammatory IL-1/TNF alpha-dependent cartilage damage. C ytokine production and effects of conditioned media, as well as effect s of IL-10 and IL-4 on proteoglycan (PG) turnover (as a measure for ca rtilage damage), were determined. Results. IL-10 and IL-4 inhibited pr oinflammatory cytokine production of stimulated RA MNC and completely reversed inhibition of cartilage PG synthesis induced by these stimula ted RA MNC. IL-10 was more potent than IL-4 in this respect, and the c ombination of IL-10 and IL-4 had an additive effect. In addition, IL-1 0 directly stimulated cartilage PG synthesis. Conclusion. IL-10 revers es the cartilage degradation induced by antigen-stimulated MNC, and IL -4 has an additive effect on this process. Furthermore, IL-10 has a di rect 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 ac tivity. These results provide evidence in favor of the use of a combin ation of the two cytokines in the treatment of RA.