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 IL-1 receptor I (IL-1RI), or the related Toll-like receptors (TLR), within VSMC. TLR-activated VSMC also produce IL-1, but it is unknown whether endogenous IL-1 stimulates VSMC in an autocrine manner. Here we tested the hypothesis that endogenous IL-1 contributes to TLR-induced proliferation and chemokine release in human VSMC, by using RNA interference to knock down IL-1 expression. Knockdown of IL-1 abolished TLR-induced proliferation and suppressed TLR4-induced release of monocyte chemoattractant protein-1 (MCP-1) by VSMC, indicating that endogenous IL-1? plays a crucial role in both responses. Serum, platelet-derived growth factor (PDGF), fibroblast growth factor-2, and epidermal growth factor each increased cellular IL-1 concentrations, and IL-1 knockdown inhibited serum- and PDGF-induced DNA synthesis, further indicating that endogenous IL-1 also contributed to VSMC responses to growth factors. IL-1 receptor antagonist, a competitive inhibitor of IL-1RI, also attenuated TLR-induced proliferation and both basal and TLR-induced MCP-1 expression, indicating at least a partial role of the IL-RI in mediating these responses. The results support the hypothesis that autocrine actions of endogenous IL-1, mediated at least in part via IL-1RI signaling, contribute to a pro-proliferative and proinflammatory phenotypic shift in TLR-activated human VSMC, which could potentially play a pathogenic role in vascular disorders.