Novel path to activation of vascular smooth muscle cells: Up-regulation ofgp130 creates an autocrine activation loop by IL-6 and its soluble receptor

This study describes a novel path to the activation of smooth muscle cells (SMC) by the IL-6/soluble IL-6 receptor (sIL-6R) system. Human vascular SMC constitutively express only scant amounts of IL-6R and so do not respond t o stimulation with this cytokine, We show that SMC also do not constitutive ly express appreciable levels of gp130, which would render them sensitive t o transsignaling by the IL-6/sIL-6R complex. Because gp130 is generally bel ieved not to be subject to regulation, SMC would thus appear not to qualify as targets for the IL-6/sIL-6R system. However, we report that treatment o f SMC with IL-6/sIL-6R provokes marked up-regulation of gp130 mRNA and surf ace protein expression. This is accompanied by secretion of IL-6 by the cel ls, so that an autocrine stimulation loop is created. In the wake of this s elf-sustaining system, there is a selective induction and secretion of MCP- 1, up-regulation of ICAM-1, and marked cell proliferation. The study identi fies SMC as the first example of cells in which gp130 expression is subject to substantive up-regulation, and discovers a novel amplification loop inv olving IL-6 and its soluble receptor that drives SMC into a proinflammatory state.