Effects of IL-6 and its soluble receptor on proteoglycan synthesis and NO release by human articular chondrocytes: comparison with IL-1. Modulation by dexamethasone

Contradictory results have been reported on the effects and role of IL-6 on proteoglycan (PG) synthesis. Having shown recently that in vitro IL-6 depe nds on the presence of soluble IL-6 receptor alpha (sIL-6R alpha) to fully exert its effects on chondrocytes, we conducted the present study to analys e the effects of IL-6 on PG synthesis by human articular chondrocytes in th e presence of sIL-6R alpha. PG synthesis was quantified by specific ELISA u sing a monoclonal antibody (MAB) raised against the keratan sulphate region of PG as a capture antibody, and a MAB to the acid binding region as a det ector. It proved specific for PG from primary (differentiated) chondrocytes . In the absence of sIL-6R alpha, IL-6 had a slight inhibitory effect on PG synthesis by articular chondrocytes. sIL-6R alpha alone also had slight bu t consistent inhibitory effects. When adding sIL-6R alpha at concentrations of 50 ng/ml corresponding to levels found in synovial fluid, the effects o f IL-6 increased consistently. However, even at Optimal concentrations (30- 100 ng/ml of IL-6sR per 100 ng/ml of IL-6), maximal inhibition (48%) did no t equal the degree of inhibition achieved by IL-1 at 1 ng/ml (66%). Similar effects, although slightly weaker, were observed on osteoarthritic cells. Dexamethasone, over a wide range of concentrations, markedly enhanced prote oglycan synthesis and completely reversed the downregulatory effects of IL- 1 and IL-6 + sIL-6R alpha. The effects of IL-1 were partially inhibited by an anti-IL-6 antibody. Finally, unlike IL-1, IL-6 + sIL-6R alpha only weakl y stimulated nitric oxide (NO) synthesis. In conclusion, sIL-6R alpha poten tiates the inhibitory effect of IL-6 on PG synthesis by articular chondrocy tes, but the overall effect of IL-6 + IL-6sR is moderate compared to the ef fects of IL-1. (C) 1999 Elsevier Science B.V./International Society of Matr ix Biology. All rights reserved.