Autocrine production of IL-1 beta by human osteoarthritis-affected cartilage and differential regulation of endogenous nitric oxide, IL-6, prostaglandin E2, and IL-8.

Interleukin-1 beta (IL-1 beta) plays a central role in the pathophysiology of cartilage damage and degradation in arthritis. In noninflammatory 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 ex vivo conditions spontaneously releases detectable amounts of autocrine IL-1 beta, nitric oxide (NO), and prostaglandin E2 (PGE2), known to be involved in cartilage damage and inflammation, that cannot be detected in normal cartilage. The autocrine IL-1 beta released by the OA-affected cartilage (for at least 72 hr in ex vivo conditions) is present in sufficient quantities to modulate NO and PGE2 production because addition of recombinant soluble IL-1 beta receptor (but not soluble tumor necrosis factor-alpha receptor) and cytokine-suppressive antiinflammatory drugs (CSAIDs) significantly attenuates the spontaneous release of NO and PGE2. Furthermore, OA-affected cartilage releases significant 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 functionally active autocrine IL-1 beta that can modulate endogenous NO, PGE2, 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 mediators in OA-affected cartilage may be sufficient to facilitate or augment cartilage degradation and inhibit cartilage repair, and therefore lead the cartilage into an autodestructive pathway in osteoarthritis.