SYNTHESIS OF METALLOPROTEASES AND INTERLEUKIN-6 (IL-6) IN HUMAN OSTEOARTHRITIC SYNOVIAL-MEMBRANE IS AN IL-1 MEDIATED PROCESS

We investigated the nature of cytokines synthesized by human osteoarth ritic (OA) synovium, par particularly interleukin 1 alpha (IL-1 alpha) , interleukin 1 beta (IL-1 beta), and tumor necrosis factor alpha (TNF alpha). We examined the capacity of recombinant human interleukin 1 r eceptor antagonist (rhIL-1ra) to block the synthesis of metalloproteas es (collagenase and stromelysin), IL-1 beta, and IL-6 in osteoarthriti s (OA) synovium. Human OA synovium were incubated in the presence or a bsence of lipopolysaccharide (LPS)or increasing concentrations of rhIL -1ra. The determinations of IL-1 alpha, IL-1 beta, TNF alpha, IL-6, an d IL-1ra in culture medium were carried out using specific ELISA. Alth ough both IL-1 isoforms and TNF alpha could be produced by OA synovium , IL-1 beta was the predominant cytokine synthesized either in the pre sence or absence of LBS. Treatment of the OA synovium with an increasi ng concentration of rhIL-1ra (0-10 mu g/ml) showed a dose dependent re duction of both metalloproteases and IL-6. Maximal inhibition was 70% for collagenase, 80% for stromelysin, and 76% for IL-6. LPS treated sy novium also showed a consistent suppression of metalloproteases and IL -6, although a higher IL-1ra concentration was required. Conversely, I L-1 beta production was not inhibited by IL-1ra, irrespective of the c oncentration used and whether the membranes were LPS stimulated. These data showed that IL-1 appears to be the major autocrine cytokine invo lved in the stimulation of metalloproteases and IL-6 synthesis in OA s ynovium.