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(Circulation Research. 2008;102:218.)
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Molecular Medicine

Adiponectin Inhibits the Production of CXC Receptor 3 Chemokine Ligands in Macrophages and Reduces T-Lymphocyte Recruitment in Atherogenesis

Yoshihisa Okamoto, Eduardo J. Folco, Manabu Minami, A.K. Wara, Mark W. Feinberg, Galina K. Sukhova, Richard A. Colvin, Shinji Kihara, Tohru Funahashi, Andrew D. Luster, Peter Libby

From the Division of Cardiovascular Medicine (Y.O., E.J.F., M.M., A.K.W., M.W.F., G.K.S., P.L.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; Division of Rheumatology (R.A.C., A.D.L.), Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Charlestown; and Department of Metabolic Medicine (S.K., T.F.), Graduate School of Medicine, Osaka University, Suita, Japan.

Correspondence to Peter Libby, MD, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, NRB 741, 77 Ave Louis Pasteur, Boston, MA 02115. E-mail plibby{at}rics.bwh.harvard.edu

Obese individuals often have low plasma adiponectin and concomitant chronic inflammation with a predisposition to metabolic and cardiovascular diseases. The present study reports a novel antiinflammatory action of adiponectin in human monocyte-derived macrophages (M) suppressing T-lymphocyte accumulation in atherogenesis. RNA profiling of lipopolysaccharide-stimulated human M identified CXC chemokine ligands (CXCLs), such as IP-10 (interferon [IFN]-inducible protein 10) (CXCL10), I-TAC (IFN-inducible T-cell chemoattractant) (CXCL11), and Mig (monokine induced by IFN-) (CXCL9), T-lymphocyte chemoattractants associated with atherogenesis, among the top 14 transcripts suppressed by adiponectin. Real-time quantitative RT-PCR and ELISA verified that adiponectin inhibited expression of these chemokines at both the mRNA and protein levels in a concentration-dependent manner. Adiponectin reduced the release by lipopolysaccharide-stimulated M of chemoattractant activity for CXC chemokine receptor 3–transfected (receptor for IP-10, Mig, and I-TAC) lymphocytes. Adiponectin decreased lipopolysaccharide-inducible IP-10 promoter activity in promoter-transfected THP-1 M but did not change IP-10 mRNA stability. In lipopolysaccharide-stimulated M, reduction of IFN-β by adiponectin preceded inhibition of IP-10 mRNA expression. Immunoblot and chromatin immunoprecipitation analyses demonstrated that adiponectin attenuated activation of the transcription factor IFN regulatory factor 3, involved in the MyD88-independent pathway of Toll-like receptor 4 signaling, and subsequent IFN regulatory factor 3 binding to IFN-β promoter. In vivo studies further demonstrated that apolipoprotein E/adiponectin double-deficient (apoE^–/–APN^–/–) mice had increased plasma IP-10 levels, accelerated T-lymphocyte accumulation in atheromata, and augmented atherogenesis compared with apoE single-deficient (apoE^–/–APN^+/+) mice. This study establishes that low levels of adiponectin associated with obesity, the metabolic syndrome, and diabetes favor T-lymphocyte recruitment and contribute to adaptive immune response during atherogenesis.

Key Words: adiponectin • atherogenesis • chemokine • macrophage • T lymphocyte

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Adiponectin and Adaptive Immunity: Linking the Bridge From Obesity to Atherogenesis

Sabine Steffens and Francois Mach
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