Interleukin-6 (IL-6) is an inflammatory cytokine with diverse functions including regulation of the humoral and cellular immune response and induction of thrombopoiesis. This cytokine can have both therapeutic and pathologic effects depending on the levels found in vivo; abnormally high levels of IL-6 are deleterious and contribute to disease development while physiological levels of IL-6 are required for appropriate immune function and thrombopoiesis. The goal of our work is to elucidate the mechanisms whereby IL-6 levels are controlled in vivo. We have developed a murine pre-clinical model for this purpose. The experimental system involves induction of an inflammatory response that is accompanied by prolonged high levels of IL-6. Our data show that in order for an inflammatory compound to induce PGE2-mediated IL-6 synthesis, it must induce expression of cyclooxygenase-2, which is an inducible prostaglandin synthase isozyme. Currently, IL-6 is under development for three clinical uses: (a) IL-6 is being administered as a therapeutic agent for stimulation of platelet production following chemotherapy; (b) Clinical protocols designed to diminish the activity of IL-6 are being developed as a means to block its action as a tumor promoter; and (c) IL-6 serves as a clinical diagnostic marker for diseases such as multiple myeloma and rheumatoid arthritis. Our research is designed to elucidate the biological mechanisms that control IL-6 synthesis and turnover. These studies involve validation of assays to measure IL-6 levels in biological fluids. Key to our research is the use of a pre-clinical model which allows us to measure control of IL-6 levels and mechanisms of IL-6-induced tumorigenicity in vivo. Our research program contributes to the ability of CBER scientists to regulate IL-6 as a therapeutic agent in that it explores both in vitro methods for testing IL-6 in body fluids and pre-clinical models that help to predict IL-6 regulation in vivo.
