title: The transcription factor CREB enhances interleukin-17A production and inflammation in a mouse model of atherosclerosis.
abstract: The enzyme 15-lipoxygenase (15-LO) plays a role in atherogenesis (also known as atherosclerosis), but the underlying mechanisms are unclear. We found that 15(S)-hydroxyeicosatetraenoic acid [15(S)-HETE], the major 15-LO-dependent metabolite of arachidonic acid, stimulated the production of reactive oxygen species (ROS) by monocytes through the xanthine oxidase-mediated activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. ROS production led to the Syk-, Pyk2-, and mitogen-activated protein kinase (MAPK)-dependent production of the proinflammatory cytokine interleukin-17A (IL-17A) in a manner that required the transcription factor CREB (cyclic adenosine monophosphate response element-binding protein). In addition, this pathway was required for the 15(S)-HETE-dependent migration and adhesion of monocytes to endothelial cells. Consistent with these observations, we found that peritoneal macrophages from apolipoprotein E-deficient (ApoE-/-) mice fed a high-fat diet (a mouse model of atherosclerosis) exhibited increased xanthine oxidase and NADPH oxidase activities; ROS production; phosphorylation of Syk, Pyk2, MAPK, and CREB; and IL-17A production compared to those from similarly fed ApoE-/-:12/15-LO-/- mice. These events correlated with increased lipid deposits and numbers of monocytes and macrophages in the aortic arches of ApoE-/- mice, which resulted in atherosclerotic plaque formation. Together, these observations suggest that 15(S)-HETE exacerbates atherogenesis by enhancing CREB-dependent IL-17A production and inflammation.
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis, TN 38163, USA.
authors.forename: Sivareddy
authors.initials: S
authors.lastname: Kotla
authors.forename: Nikhlesh K
authors.initials: NK
authors.lastname: Singh
authors.forename: Mark R
authors.initials: MR
authors.lastname: Heckle
authors.forename: Gabor J
authors.initials: GJ
authors.lastname: Tigyi
authors.forename: Gadiparthi N
authors.initials: GN
authors.lastname: Rao
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D050197:Atherosclerosis / Q000276:immunology*; D001391:Azo Compounds; D015153:Blotting, Western; D002448:Cell Adhesion / Q000502:physiology; D018929:Cell Culture Techniques; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000276:immunology*; D059305:Diet, High-Fat; D004797:Enzyme-Linked Immunosorbent Assay; D005453:Fluorescence; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D007150:Immunohistochemistry; D020381:Interleukin-17 / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000502:physiology; D019255:NADPH Oxidases / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000235:genetics; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014969:Xanthine Oxidase / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D001391:Azo Compounds; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D006893:Hydroxyeicosatetraenoic Acids; D020381:Interleukin-17; D016376:Oligonucleotides, Antisense; D017382:Reactive Oxygen Species; D001093:Arachidonate 15-Lipoxygenase; D014969:Xanthine Oxidase; D019255:NADPH Oxidases; C011049:oil red O
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