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 acts as a growth factor for some hematopoietic tumors (e.g., multiple myeloma), 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 are developing 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. Recently, we have found that the 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). Preliminary results show that induction of cyclooxygenase gene expression is responsible for stimulating macrophage IL-6 synthesis. In addition, to confirming this finding, we will investigate the role of other inflammatory factors (e.g., nitric oxide) that may influence IL-6 levels by modulating protein clearance.
