title: Interleukin-17A Promotes Aortic Endothelial Cell Activation via Transcriptionally and Post-translationally Activating p38 Mitogen-activated Protein Kinase (MAPK) Pathway.
abstract: Interleukin-17 (IL-17)-secreting T helper 17 cells were recently identified as a CD4(+) T helper subset and implicated in various inflammatory and autoimmune diseases. The issues of whether and by what mechanism hyperlipidemic stress induces IL-17A to activate aortic endothelial cells (ECs) and enhance monocyte adhesion remained largely unknown. Using biochemical, immunological, microarray, experimental data mining analysis, and pathological approaches focused on primary human and mouse aortic ECs (HAECs and MAECs) and our newly generated apolipoprotein E (ApoE)(-/-)/IL-17A(-/-) mice, we report the following new findings. 1) The hyperlipidemia stimulus oxidized low density lipoprotein up-regulated IL-17 receptor(s) in HAECs and MAECs. 2) IL-17A activated HAECs and increased human monocyte adhesion in vitro. 3) A deficiency of IL-17A reduced leukocyte adhesion to endothelium in vivo. 3) IL-17A activated HAECs and MAECs via up-regulation of proinflammatory cytokines IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), chemokine CXC motif ligand 1 (CXCL1), and CXCL2. 4) IL-17A activated ECs specifically via the p38 mitogen-activated protein kinases (MAPK) pathway; the inhibition of p38 MAPK in ECs attenuated IL-17A-mediated activation by ameliorating the expression of the aforementioned proinflammatory cytokines, chemokines, and EC adhesion molecules including intercellular adhesion molecule 1. Taken together, our results demonstrate for the first time that IL-17A activates aortic ECs specifically via p38 MAPK pathway.
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research and Departments of Pharmacology and.
authors.forename: Jietang
authors.initials: J
authors.lastname: Mai
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research and.
authors.forename: Gayani
authors.initials: G
authors.lastname: Nanayakkara
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research and.
authors.forename: Jahaira
authors.initials: J
authors.lastname: Lopez-Pastrana
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research and Departments of Pharmacology and.
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Li
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research and.
authors.forename: Ya-Feng
authors.initials: YF
authors.lastname: Li
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research and.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research and.
authors.forename: Ai
authors.initials: A
authors.lastname: Song
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research and Departments of Pharmacology and.
authors.forename: Anthony
authors.initials: A
authors.lastname: Virtue
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research and.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shao
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research and.
authors.forename: Huimin
authors.initials: H
authors.lastname: Shan
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research and.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Physiology, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania 19140 and.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Autieri
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research and Physiology, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania 19140 and.
authors.forename: Satya P
authors.initials: SP
authors.lastname: Kunapuli
authors.affiliation: Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research and.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Jiang
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research and Departments of Pharmacology and.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research and Departments of Pharmacology and xfyang@temple.edu.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Yang
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006949:Hyperlipidemias / Q000378:metabolism*; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism / Q000502:physiology; D053722:Receptors, Interleukin-17 / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D054360:Chemokine CXCL1; C098680:Il17a protein, mouse; D020381:Interleukin-17; D015850:Interleukin-6; D053722:Receptors, Interleukin-17; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D048051:p38 Mitogen-Activated Protein Kinases
keywords: cardiovascular disease; endothelial cell; endothelial cell activation; inflammation; interleukin 17A (IL-17 or IL-17A); monocyte adhesion; p38 MAPK