title: Adiponectin inhibits endothelial synthesis of interleukin-8.
abstract: Adiponectin is an antiatherogenic adipokine that inhibits inflammation by mechanisms that are not completely understood. We explored the effect of adiponectin on endothelial synthesis of interleukin-8 (IL-8), a pro-inflammatory chemokine that plays a role in atherogenesis. Adiponectin decreased the secretion of IL-8 from human aortic endothelial cells (HAEC) stimulated with tumor necrosis factor-alpha (TNF-alpha). Adiponectin also inhibited IL-8 mRNA expression induced by TNF-alpha. Phosphorylation of IkappaB-alpha was decreased by adiponectin, but phosphorylation of ERK, SAPK/JNK, and p38MAPK were unaffected. Adiponectin increased intra-cellular cAMP levels in HAEC in a dose-dependent manner; PKA activity was also increased. The inhibitory effect of adiponectin on TNF-alpha-induced IL-8 synthesis was inhibited by pretreatment with Rp-cAMP, a PKA inhibitor. These observations suggest that adiponectin inhibits IL-8 synthesis through inhibition of a PKA dependent NF-kappaB signaling pathway. We also showed that adiponectin enhances Akt phosphorylation. The inhibitory effect of adiponectin on TNF-alpha-induced IL-8 synthesis was abrogated in part by pretreatment with the PI3 kinase inhibitor LY294002 or by Akt siRNA transfection, suggesting that Akt activation might inhibit IL-8 synthesis induced by TNF-alpha. We conclude that inhibition of NF-kappaB and activation of Akt phosphorylation may mediate adiponectin inhibition of atherosclerosis.
authors.affiliation: First Department of Internal Medicine, School of Medicine, Toyama Medical and Pharmaceutical University, Japan.
authors.forename: Chikaaki
authors.initials: C
authors.lastname: Kobashi
authors.forename: Masaharu
authors.initials: M
authors.lastname: Urakaze
authors.forename: Mika
authors.initials: M
authors.lastname: Kishida
authors.forename: Etsuko
authors.initials: E
authors.lastname: Kibayashi
authors.forename: Hideki
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Shinji
authors.initials: S
authors.lastname: Kihara
authors.forename: Tohru
authors.initials: T
authors.lastname: Funahashi
authors.forename: Michiyo
authors.initials: M
authors.lastname: Takata
authors.forename: Rie
authors.initials: R
authors.lastname: Temaru
authors.forename: Akira
authors.initials: A
authors.lastname: Sato
authors.forename: Katsuya
authors.initials: K
authors.lastname: Yamazaki
authors.forename: Norio
authors.initials: N
authors.lastname: Nakamura
authors.forename: Masashi
authors.initials: M
authors.lastname: Kobayashi
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D052242:Adiponectin / Q000494:pharmacology* / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D050197:Atherosclerosis / Q000188:drug therapy; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology
chemical_list: D052242:Adiponectin; D000893:Anti-Inflammatory Agents; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D000263:Adenylate Kinase