The IL-6-soluble IL-6R alpha autocrine loop of endothelial activation as an intermediate between acute and chronic inflammation: An experimental model involving thrombin

Thrombin is a procoagulant and proinflammatory molecule in vivo. In vitro, thrombin has been shown to induce endothelial activation, notably IL-8 secr etion and adhesion molecule expression. In this study, we showed that throm bin may induce a new cascade leading from acute to chronic inflammation. Th rombin was able to induce the production of both IL-6 and monocyte chemotac tic protein-1 (MCP-1) by HUVEC independently of IL-1 alpha beta and TNF-alp ha. Addition of physiological concentrations of exogenous soluble IL-6R alp ha (sIL-6R alpha) to thrombin-activated HUVEC was sufficient to increase th e amounts of MCP-1 produced, but not those of IL-8. These effects could be blocked by anti-IL-6 or anti-sIL-6R alpha blocking mAb, demonstrating the e xistence of an autocrine loop of MCP-1 secretion, involving the IL-6/IL-6R alpha /gp130 complex on HUVEC. In addition, we identified IL-8-activated ne utrophils as a potential source of sIL-6R alpha because IL-8 induced IL-6R alpha shedding from the neutrophil membranes and increased in parallel sIL- 6R alpha concentrations in neutrophil supernatants. Furthermore, addition o f neutrophils to thrombin-activated HUVEC significantly increased MCP-1 sec retion, which could be decreased by blocking IL-6. Thus, thrombin-activated endothelium may induce a cascade of events characterized by IL-8 secretion , neutrophil local infiltration, and the release of IL-6R alpha from neutro phil membranes. sIL-6R alpha may then complex with IL-6 and increase the am ount of MCP-1 produced by thrombin-activated endothelium, favoring monocyte infiltration, and the transformation of acute into chronic inflammation.