AUTOCRINE PRODUCTION OF IL-1-BETA BY HUMAN OSTEOARTHRITIS-AFFECTED CARTILAGE AND DIFFERENTIAL REGULATION OF ENDOGENOUS NITRIC-OXIDE, IL-6, PROSTAGLANDIN E-2, AND IL-8

Interleukin-1 beta (IL-1 beta) plays a central role in the pathophysio logy of cartilage damage and degradation in arthritis. In noninflammat ory arthropathies such as osteoarthritis (OA), the synovial-derived IL -1 beta has been implicated in the disease process. In this study, we report that human OA-affected cartilage demonstrates upregulated IL-1 beta mRNA not seen in normal cartilage. The OA-affected cartilage in e x vivo conditions spontaneously releases detectable amounts of autocri ne IL-1 beta, nitric oxide (NO), and prostaglandin E-2 (PGE(2)), known to be involved in cartilage damage and inflammation, that cannot be d etected in normal cartilage. The autocrine IL-1 beta released by the O A-affected cartilage (for at least 72 hr in ex vivo conditions) is pre sent in sufficient quantities to modulate NO and PGE(2) production bec ause addition of recombinant soluble IL-1 beta receptor (but not solub le tumor necrosis factor-alpha receptor) and cytokine-suppressive anti inflammatory drugs (CSAIDs) significantly attenuates the spontaneous r elease of NO and PGE(2). Furthermore, OA-affected cartilage releases s ignificant amounts of IL-6 and IL-8 in ex vivo conditions. Addition of CSAIDs to OA-affected cartilage differentially regulates IL-6 and IL- 8 production by inhibiting the spontaneous release of IL-6 but not IL- 8 in ex vivo conditions. These experiments demonstrate that the human OA-affected cartilage itself releases sufficient amounts of functional ly active autocrine IL-1 beta that can modulate endogenous NO, PGE(2), and IL-6, but not IL-8, all of which are known to be stimulated by IL -1 beta in vitro. These IL-1 beta induced pleotropic inflammatory medi ators in OA-affected cartilage may be sufficient to facilitate or augm ent cartilage degradation and inhibit cartilage repair, and therefore lead the cartilage into an autodestructive pathway in osteoarthritis.