The transcription factor CREB enhances interleukin-17A production and inflammation in a mouse model of atherosclerosis

• Published in: Science signaling Vol. 6; no. 293; p. ra83
• Main Authors: Kotla, Sivareddy, Singh, Nikhlesh K, Heckle, Mark R, Tigyi, Gabor J, Rao, Gadiparthi N
• Format: Journal Article
• Language: English
• Published: United States 17-09-2013
• Subjects: Animals; Aorta, Thoracic - cytology; Aorta, Thoracic - pathology; Apolipoproteins E - genetics; Arachidonate 15-Lipoxygenase - metabolism; Atherosclerosis - immunology; Azo Compounds; Blotting, Western; Cell Adhesion - physiology; Cell Culture Techniques; Cell Line; Cell Movement - physiology; Cyclic AMP Response Element-Binding Protein - immunology; Diet, High-Fat; Enzyme-Linked Immunosorbent Assay; Fluorescence; Humans; Hydroxyeicosatetraenoic Acids - metabolism; Immunohistochemistry; Interleukin-17 - immunology; Interleukin-17 - metabolism; Mice; Mice, Knockout; Monocytes - physiology; NADPH Oxidases - metabolism; Oligonucleotides, Antisense - genetics; Phosphorylation; Reactive Oxygen Species - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Xanthine Oxidase - metabolism
• ISSN: 1937-9145
• DOI: 10.1126/scisignal.2004214

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.