Endogenous interleukin-1α promotes a proliferative and proinflammatory phenotype in human vascular smooth muscle cells

Endogenous interleukin-1 alpha promotes a proliferative and proinflammatory phenotype in human vascular smooth Muscle cells. Am J Physiol Heart Circ Physiol 292: H2927-H2934, 2007. First published February 9, 2007; doi: 10.1152/ajpheart.00700.2006. - During vascular disease and following injury, vascular smooth muscle cells (VSMC) proliferate and produce inflammation-promoting, cytokines and chemokines. Similar phenotypic changes can be elicited in vitro by activation of Toll-like receptors (TLR) within VSMC. TLR-activated VSMC also produce IL-1 alpha. but it is Unknown whether endogenous IL-1 alpha stimulates VSMC in an autocrine manner. Here we tested the hypothesis that endogenous IL-1 alpha contributes to TLR-induced proliferation and chemokine release in human VSMC by using RNA interference to knock down IL-1 alpha expression. Knockdown of IL-1 alpha abolished TLR-induced proliferation and Suppressed TLR4-induced release of monocyte chemoattractant protein-1 (MCP-1) by VSMC, indicating that endogenous IL-1 alpha plays a crucial role in both responses. Serum, PDGF, FGF-2, and EGF each increased cellular IL-1 alpha concentrations, and IL-1 alpha knockdown inhibited serum- and PDGF-induced DNA synthesis. further indicating that endogenous IL-1 alpha also contributed to VS,MC responses to growth factors. IL-1 receptor antagonist, a competitive inhibitor of IL-1 receptor I (IL-IRI). also attenuated TLR-induced proliferation and both basal and TLR-induced MCP-1 expression. indicating at least a partial role of the IL-1RI in mediating these responses. The results Support the hypothesis that autocrine actions of endogenous IL-1 alpha, mediated at least in part via TL-1RI signaling contribute to a proproliferative and proinflammatory phenotypic shift in TLR-activated human VSMC, which might play a pathogenic role in vascular disorders.