INTERLEUKIN (IL)-6 AND ITS SOLUBLE RECEPTOR INDUCE TIMP-1 EXPRESSION IN SYNOVIOCYTES AND CHONDROCYTES, AND BLOCK IL-1-INDUCED COLLAGENOLYTIC ACTIVITY

To define the potential role of interleukin-6 (IL-6) and its soluble r eceptor alpha in cartilage metabolism, we analyzed their effects on ti ssue inhibitor of metalloproteases (TIMP) synthesis by synoviocytes an d chondrocytes, TIMP-1 production by isolated human articular synovial fibroblasts and chondrocytes, stimulated by IL-6 and/or its soluble r eceptor, was first assayed by specific enzyme-linked immunosorbent ass ay; the slight stimulatory effect of IL-6 on TIMP-1 production by both types of cells was markedly amplified by the addition of soluble rece ptor, the maximal secretion being observed only at 96 h. TIMP-1 mRNA e xpression, determined by ribonuclease protection assay, was induced by IL-6 together with its soluble receptor, but TIMP-2 and -3 mRNAs were not affected by these factors. A specific neutralizing antibody aboli shed the effects of the soluble receptor. Finally, supernatant from sy noviocytes stimulated by IL-6 plus its soluble receptor blocked almost completely the collagenolytic activity of supernatant from IL-1-induc ed synoviocytes. These observations indicate that IL-6 and its soluble receptor have a protective role in the metabolism of cartilage. Given the high levels of soluble receptor in synovial fluid and the marked induction of IL-6 by IL-1 or TNF-alpha, it is likely that IL-6 and its soluble receptor are critical in controlling the catabolic effects of pro-inflammatory cytokines.