Published online before print November 3, 2005, doi: 10.1161/01.RES.0000194328.57164.36
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© 2005 American Heart Association, Inc.
Molecular Medicine |
Adiponectin Inhibits Endothelial Synthesis of Interleukin-8
From the First Department of Internal Medicine (C.K., M.U., M.K., E.K., M.T., R.T., A.S., K.Y., M. Kobayashi), School of Medicine, Toyama Medical and Pharmaceutical University; Department of Foods and Nutrition (E.K.), School of Human Health, Sonoda Women’s University; Department of Internal Medicine and Molecular Science (H.K., S.K., T.F.), Graduate School of Medicine, Osaka University; Second Department of Internal Medicine (N.N.), Hirosaki University, Japan.
Correspondence to Masaharu Urakaze, MD, PhD, Toyama Medical & Pharmaceutical University, First Department of Internal Medicine, 2630 Sugitani, Toyama 930-0194, Japan. E-mail murakaze{at}ms.toyama-mpu.ac.jp
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-
(TNF-). Adiponectin also inhibited IL-8 mRNA expression induced by TNF-. Phosphorylation of I
B- 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-–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-B signaling pathway. We also showed that adiponectin enhances Akt phosphorylation. The inhibitory effect of adiponectin on TNF-–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-. We conclude that inhibition of NF-B and activation of Akt phosphorylation may mediate adiponectin inhibition of atherosclerosis.
Key Words: adiponectin • Akt • endothelial cells • IL-8 • PKA
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