REGULATION OF INTERLEUKIN-6 (IL-6)

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Interleukin-6 (IL-6) is an inflammatory cytokine with diverse functions including regulation of the humoral and cellular immune response and induction of thrombopoiesis. It is presently under development as a therapeutic agent for induction of platelets following chemotherapy. Because IL-6 is a growth factor for some hematopoietic tumors (e.g., multiple myeloma), clinical protocols designed to regulate the synthesis or activity of IL-6 are also being investigated. The goal of the present work is to elucidate the mechanisms whereby IL-6 levels are regulated in vivo. We have developed a murine pre-clinical model for this purpose. The experimental system involves injection of the mineral oil pristane into the peritoneal cavities of BALB/c mice. This treatment induces a chronic peritonitis that is accompanied by dramatically elevated levels of intraperitoneal IL-6 as determined by bioassay and ELISA. Previous studies showed that the elevation in IL-6 can be inhibited by co-administration of the cyclooxygenase inhibitor indomethacin to the mice. We have found that the pristane-induced increase in IL-6 is associated with an elevation in endogenous prostaglandin E2 levels. The results suggest that prostaglandins secreted by inflammatory macrophages might be responsible for stimulating IL-6 production in the same cells through a positive feedback loop. A similar mechanism may contribute to the pathogenesis of human diseases in which both prostaglandins and IL-6 are chronically elevated (e.g., rheumatoid arthritis, Crohn's disease). Our recent data indicate that the source of the PGE2 may be critical in determining whether IL-6 synthesis is turned on or not. That is, when peritoneal macrophages are stimulated to synthesize PGE2 through prostaglandin synthase-1, which is expressed constitutively, little or no IL-6 synthesis is observed. However, when the same macrophages are stimulated to generate PGE2 through induction of prostaglandin synthase-2, IL-6 synthesis is turned on. Current studies are aimed at understanding the cellular mechanisms underlying this phenomenon.