title: Resveratrol blocks interleukin-18-EMMPRIN cross-regulation and smooth muscle cell migration.
abstract: Vascular smooth muscle cell (SMC) migration is an important mechanism in atherogenesis and postangioplasty arterial remodeling. Previously, we demonstrated that the proinflammatory cytokine interleukin (IL)-18 is a potent inducer of SMC migration. Since extracellular matrix metalloproteinase inducer (EMMPRIN) stimulates ECM degradation and facilitates cell migration, we investigated whether IL-18 and EMMPRIN regulate each other's expression, whether their cross talk induces SMC migration, and whether the phytoalexin resveratrol inhibits IL-18-EMMPRIN signaling and SMC migration. Our studies demonstrate that 1) IL-18 induces EMMPRIN mRNA and protein expressions and stimulates EMMPRIN secretion from human aortic SMCs; 2) IL-18 stimulates EMMPRIN expression via oxidative stress and phosphatidylinositol 3-kinase (PI3K)-Akt-ERK signaling; 3) IL-18-stimulated SMC migration is significantly blunted by EMMPRIN knockdown, EMMPRIN function-blocking antibodies, or adenoviral transduction of mutant EMMPRIN; 4) conversely, EMMPRIN stimulates IL-18 expression and secretion via PI3K, Akt, and ERK; and 5) resveratrol attenuates IL-18- and EMMPRIN-mediated PI3K, Akt, and ERK activations; blunts IL-18-mediated oxidative stress; blocks IL-18-EMMPRIN cross-regulation; and inhibits SMC migration. Collectively, our results demonstrate that the coexpression and regulation of IL-18 and EMMPRIN in the vessel wall may amplify the inflammatory cascade and promote atherosclerosis and remodeling. Resveratrol, via its antioxidant and anti-inflammatory properties, has the potential to inhibit the progression of atherosclerosis by blocking IL-18 and EMMPRIN cross-regulation and SMC migration.
authors: Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA.
authors: Balachandar
authors: B
authors: Venkatesan
authors: Anthony J
authors: AJ
authors: Valente
authors: Venkatapuram Seenu
authors: VS
authors: Reddy
authors: Deborah A
authors: DA
authors: Siwik
authors: Bysani
authors: B
authors: Chandrasekar
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001011:Aorta / Q000166:cytology; D050197:Atherosclerosis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D051926:Basigin / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D003432:Cross-Linking Reagents / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D020382:Interleukin-18 / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013267:Stilbenes / Q000494:pharmacology*; D014657:Vasculitis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C497886:BSG protein, human; D003432:Cross-Linking Reagents; D020382:Interleukin-18; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013267:Stilbenes; D051926:Basigin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D000077185:Resveratrol