THROMBIN INDUCES IL-6 PRODUCTION IN FIBROBLASTS AND EPITHELIAL-CELLS - EVIDENCE FOR THE INVOLVEMENT OF THE 7-TRANSMEMBRANE DOMAIN (STD) RECEPTOR FOR ALPHA-THROMBIN

alpha-Thrombin is a multifunctional serine protease that has an import ant role in the coagulation cascade, wound healing, and inflammatory r esponse. In this study, we show that thrombin induces IL-6 production in human epithelial cells and fibroblasts. ELISA and Northern blot ana lyses showed that physiologic concentrations of thrombin (0.1-1 mu g/m l) induced IL-6 production in human lung fibroblasts, skin fibroblasts , and epithelial cells. Hirudin, a thrombin inhibitor, completely bloc ked IL-6 induction by thrombin. Treatment of fibroblasts with inactiva ted diisopropylphosphofluoridate (DIP)-alpha-thrombin, gamma-thrombin, or trypsin had no effect on IL-6 production. In contrast, treatment w ith the thrombin-tethered ligand receptor peptide TRP-7 (SFLLRNP) indu ced IL-6 production, but at lower levels than that induced by native a lpha-thrombin. Finally, IL-6 pretreatment of lung or skin fibroblasts resulted in the enhanced production of IL-6 following exposure to thro mbin. These results suggest that fibroblasts and epithelial cells may represent a significant source of IL-6 in the inflammatory response to tissue injury, and that cytokine production is an important biologic consequence of thrombin's interaction with its seven-transmembrane dom ain (STD) receptor.