Endogenous interleukin-1 alpha promotes a proliferative and proinflammatory phenotype in human vascular smooth muscle cells.
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 VSMC responses to growth factors. IL-1 receptor antagonist, a competitive inhibitor of IL-1 receptor I (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-1RI in mediating these responses. The results support the hypothesis that autocrine actions of endogenous IL-1 alpha, mediated at least in part via IL-1RI signaling, contribute to a proproliferative and proinflammatory phenotypic shift in TLR-activated human VSMC, which might play a pathogenic role in vascular disorders.
Schultz
Kelly
K
Molecular Cardiology Research Institute, Tufts-New England Medical Center, Box 8486, 750 Washington St., Boston, MA 02111, USA.
Murthy
Vanishree
V
Tatro
Jeffrey B
JB
Beasley
Debbie
D
D019898:Autocrine Communication; D049109:Cell Proliferation; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004815:Epidermal Growth Factor / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism; D053582:Interleukin-1alpha / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D053573:Receptors, Interleukin-1 Type I / Q000378:metabolism*; D044967:Serum / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*; D014162:Transfection
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D053590:Interleukin 1 Receptor Antagonist Protein; D053582:Interleukin-1alpha; D010982:Platelet-Derived Growth Factor; D034741:RNA, Small Interfering; D053573:Receptors, Interleukin-1 Type I; C495344:TLR3 protein, human; C495345:TLR4 protein, human; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D016222:Fibroblast Growth Factor 2; D004815:Epidermal Growth Factor