COMPARATIVE AND COMBINED EFFECTS OF INTERLEUKIN-6, INTERLEUKIN-1-BETA, AND TUMOR-NECROSIS-FACTOR-ALPHA ON PROTEOGLYCAN METABOLISM OF HUMAN ARTICULAR CHONDROCYTES CULTURED IN AGAROSE

Objective. To study the effects of recombinant tumor necrosis factor a lpha (TNF-alpha), interleukin 1 beta (IL-1 beta) and interleukin 6 (IL -6) on proteoglycan metabolism of isolated chondrocytes. Methods. Huma n articular cartilage cells were cultured in agarose gel. In these cul ture conditions, chondrocytes keep their phenotypic stability. They re lease cartilage specific proteoglycans into the surrounding artificial matrix. Proteoglycan synthesis was measured by the incorporation of ( 35)sulfate (S-35). Results. TNF-alpha and IL-1 beta depressed proteogl ycan synthesis and induced proteoglycan degradation. The effects of bo th cytokines were additive, when used in submaximal doses. No mutual i nduction of TNF-alpha and IL-1 beta was shown, but both cytokines stim ulated the chondrocytes to release IL-6, up to 100,000 pg/ml. Equal am ounts of human recombinant IL-6 did not affect proteoglycan synthesis. IL-6 did not alter proteoglycan quality, nor did it modulate the IL-1 beta activities on proteoglycan metabolism. Conclusion. These finding s illustrate the role of IL-1 beta and TNF-alpha in cartilage degradat ion and suggest that the role of the large amounts of IL-6 released in response to IL-1 in chronic arthritis is not directly protective with regard to proteoglycan metabolism.