title: Interleukin-18 enhances IL-18R/Nox1 binding, and mediates TRAF3IP2-dependent smooth muscle cell migration. Inhibition by simvastatin.
abstract: We investigated the role of TRAF3 interacting protein 2 (TRAF3IP2), a redox-sensitive adapter protein and an upstream regulator of IKK and JNK in interleukin (IL)-18 induced smooth muscle cell migration, and the mechanism of its inhibition by simvastatin. The pleiotropic cytokine IL-18 induced human coronary artery SMC migration through the induction of TRAF3IP2. IL-18 induced Nox1-dependent ROS generation, TRAF3IP2 expression, and IKK/NF-κB and JNK/AP-1 activation. IL-18 induced its own expression and that of its receptor subunit IL-18Rα. Using co-IP/IB and GST pull-down assays, we show for the first time that the subunits of the IL-18R heterodimer physically associate with Nox1 under basal conditions, and IL-18 appears to enhance their binding. Importantly, the HMG-coA reductase inhibitor simvastatin attenuated IL-18-induced TRAF3IP2 induction. These inhibitory effects were reversed by mevalonate and geranylgeranylpyrophosphate (GGPP), but not by farnesylpyrophosphate (FPP). Interestingly, simvastatin, GGPP, FPP, or Rac1 inhibition did not modulate ectopically expressed TRAF3IP2. These results demonstrate that the promigratory effects of IL-18 are mediated through TRAF3IP2 in a redox-sensitive manner, and this may involve IL-18R/Nox1 physical association. Further, Simvastatin inhibits inducible, but not ectopically-xpressed TRAF3IP2. Targeting TRAF3IP2 may blunt progression of hyperplastic vascular diseases in vivo.
authors.affiliation: Medicine, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, TX 78229, United States.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Valente
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Reza
authors.initials: R
authors.lastname: Izadpanah
authors.forename: Patrice
authors.initials: P
authors.lastname: Delafontaine
authors.forename: Ulrich
authors.initials: U
authors.lastname: Siebenlist
authors.forename: Bysani
authors.initials: B
authors.lastname: Chandrasekar
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000494:pharmacology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects*; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D053724:Receptors, Interleukin-18 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D012717:Sesquiterpenes / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000924:Anticholesteremic Agents; D020382:Interleukin-18; D016328:NF-kappa B; D011106:Polyisoprenyl Phosphates; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D053724:Receptors, Interleukin-18; D011994:Recombinant Proteins; D012717:Sesquiterpenes; C414202:TRAF3IP2 protein, human; D018808:Transcription Factor AP-1; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; C004808:farnesyl pyrophosphate; D019821:Simvastatin; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases; C402799:NOX1 protein, human; D020830:rac1 GTP-Binding Protein; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid
references.citation: Mol Cell Biol. 2012 Oct;32(19):3925-37
references.pmid: 22851696
references.citation: Circ Res. 1995 Jun;76(6):996-1002
references.pmid: 7758171
references.citation: J Biol Chem. 2006 Aug 4;281(31):21857-21868
references.pmid: 16762923
references.citation: J Immunol. 2009 Feb 1;182(3):1617-30
references.pmid: 19155511
references.citation: Am J Cardiol. 2005 Sep 5;96(5A):24F-33F
references.pmid: 16126020
references.citation: Nat Rev Immunol. 2009 Aug;9(8):556-67
references.pmid: 19575028
references.citation: J Cell Physiol. 2011 Dec;226(12):3303-15
references.pmid: 21321938
references.citation: Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10494-9
references.pmid: 10962033
references.citation: Circulation. 1992 Sep;86(3):723-9
references.pmid: 1516183
references.citation: J Biol Chem. 2006 Jun 2;281(22):15099-109
references.pmid: 16554298
references.citation: Circ Res. 2005 May 27;96(10):1064-71
references.pmid: 15860756
references.citation: Circulation. 2001 Oct 2;104(14):1598-603
references.pmid: 11581135
references.citation: J Mol Cell Cardiol. 2010 Oct;49(4):655-63
references.pmid: 20538003
references.citation: Arterioscler Thromb Vasc Biol. 2007 Jan;27(1):42-8
references.pmid: 17082491
references.citation: Circ Res. 2012 Apr 27;110(9):1217-25
references.pmid: 22456182
references.citation: Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10489-93
references.pmid: 10962024
references.citation: Antioxid Redox Signal. 2010 Mar 1;12(5):583-93
references.pmid: 19737091
references.citation: Cell Signal. 2013 Jan;25(1):359-71
references.pmid: 23085260
references.citation: Am J Physiol Heart Circ Physiol. 2012 Aug 1;303(3):H282-96
references.pmid: 22636674
references.citation: Nat Immunol. 2011 Aug 07;12(9):844-52
references.pmid: 21822257
references.citation: Circulation. 2000 Jan 18;101(2):207-13
references.pmid: 10637210
references.citation: N Engl J Med. 1992 Jan 23;326(4):242-50
references.pmid: 1727977
references.citation: Arterioscler Thromb Vasc Biol. 2007 Aug;27(8):1736-43
references.pmid: 17541028
references.citation: J Biol Chem. 2009 May 22;284(21):14414-27
references.pmid: 19339243
references.citation: Circ Res. 2002 Feb 8;90(2):E34-8
references.pmid: 11834721
references.citation: J Mol Cell Cardiol. 2012 Jul;53(1):113-24
references.pmid: 22575763
references.citation: J Clin Invest. 2001 Nov;108(10):1429-37
references.pmid: 11714734