The IL-6-soluble IL-6Rα 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 secretion and adhesion molecule expression. In this study, we showed that thrombin may induce a new cascade leading from acute to chronic inflammation. Thrombin was able to induce the production of both IL-6 and monocyte chemotactic protein-1 (MCP-1) by HUVEC independently of IL-1 alpha beta and TNF-alpha. Addition of physiological concentrations of exogenous soluble IL-6R alpha (sIL-6R alpha) to thrombin-activated HUVEC was sufficient to increase the 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 existence 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 neutrophils 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 of neutrophils to thrombin-activated HUVEC significantly increased MCP-1 secretion, 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 neutrophil membranes. sIL-6R alpha may then complex with IL-6 and increase the amount of MCP-1 produced by thrombin-activated endothelium, favoring monocyte infiltration, and the transformation of acute into chronic inflammation.