title: Interleukin-35 Inhibits Endothelial Cell Activation by Suppressing MAPK-AP-1 Pathway.
abstract: Vascular response is an essential pathological mechanism underlying various inflammatory diseases. This study determines whether IL-35, a novel responsive anti-inflammatory cytokine, inhibits vascular response in acute inflammation. Using a mouse model of LPS-induced acute inflammation and plasma samples from sepsis patients, we found that IL-35 was induced in the plasma of mice after LPS injection as well as in the plasma of sepsis patients. In addition, IL-35 decreased LPS-induced proinflammatory cytokines and chemokines in the plasma of mice. Furthermore, IL-35 inhibited leukocyte adhesion to the endothelium in the vessels of lung and cremaster muscle and decreased the numbers of inflammatory cells in bronchoalveolar lavage fluid. Mechanistically, IL-35 inhibited the LPS-induced up-regulation of endothelial cell (EC) adhesion molecule VCAM-1 through IL-35 receptors gp130 and IL-12Rβ2 via inhibition of the MAPK-activator protein-1 (AP-1) signaling pathway. We also found that IL-27, which shares the EBI3 subunit with IL-35, promoted LPS-induced VCAM-1 in human aortic ECs and that EBI3-deficient mice had similar vascular response to LPS when compared with that of WT mice. These results demonstrated for the first time that inflammation-induced IL-35 inhibits LPS-induced EC activation by suppressing MAPK-AP1-mediated VCAM-1 expression and attenuates LPS-induced secretion of proinflammatory cytokines/chemokines. Our results provide insight into the control of vascular inflammation by IL-35 and suggest that IL-35 is an attractive novel therapeutic reagent for sepsis and cardiovascular diseases.
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research, Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140 and.
authors.forename: Xiaojin
authors.initials: X
authors.lastname: Sha
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research, Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140 and.
authors.forename: Shu
authors.initials: S
authors.lastname: Meng
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research, Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140 and.
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Li
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research, Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140 and.
authors.forename: Hang
authors.initials: H
authors.lastname: Xi
authors.affiliation: the Department of Infectious Diseases & Pathology, College of Veterinary Medicine, University of Florida, Gainesville, Florida 32608.
authors.forename: Massimo
authors.initials: M
authors.lastname: Maddaloni
authors.affiliation: the Department of Infectious Diseases & Pathology, College of Veterinary Medicine, University of Florida, Gainesville, Florida 32608.
authors.forename: David W
authors.initials: DW
authors.lastname: Pascual
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research, Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140 and.
authors.forename: Huimin
authors.initials: H
authors.lastname: Shan
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research, Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140 and.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Jiang
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research, Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140 and.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: From the Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research, Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140 and xfyang@temple.edu.
authors.forename: Xiao-feng
authors.initials: XF
authors.lastname: Yang
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000276:immunology / Q000378:metabolism; D016022:Case-Control Studies; D002448:Cell Adhesion; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000473:pathology; D004927:Escherichia coli Infections / Q000097:blood / Q000276:immunology; D005260:Female; D006801:Humans; D007378:Interleukins / Q000502:physiology*; D007962:Leukocytes / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D018805:Sepsis / Q000097:blood / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D007378:Interleukins; D008070:Lipopolysaccharides; D018808:Transcription Factor AP-1; D019010:Vascular Cell Adhesion Molecule-1; C532417:interleukin-35, human
keywords: cytokine; endothelial cell; endothelial cell activation; inflammation; interleukin-35; lipopolysaccharide (LPS); sepsis; vascular cell adhesion molecule-1 (VCAM-1); vascular inflammation