title: Adiponectin inhibits the production of CXC receptor 3 chemokine ligands in macrophages and reduces T-lymphocyte recruitment in atherogenesis.
abstract: 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 (MPhi) suppressing T-lymphocyte accumulation in atherogenesis. RNA profiling of lipopolysaccharide-stimulated human MPhi identified CXC chemokine ligands (CXCLs), such as IP-10 (interferon [IFN]-inducible protein 10) (CXCL10), I-TAC (IFN-inducible T-cell alpha chemoattractant) (CXCL11), and Mig (monokine induced by IFN-gamma) (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 MPhi 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 MPhi but did not change IP-10 mRNA stability. In lipopolysaccharide-stimulated MPhi, reduction of IFN-beta 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-beta 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.
authors.affiliation: Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass 02115, USA.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Eduardo J
authors.initials: EJ
authors.lastname: Folco
authors.forename: Manabu
authors.initials: M
authors.lastname: Minami
authors.forename: A K
authors.initials: AK
authors.lastname: Wara
authors.forename: Mark W
authors.initials: MW
authors.lastname: Feinberg
authors.forename: Galina K
authors.initials: GK
authors.lastname: Sukhova
authors.forename: Richard A
authors.initials: RA
authors.lastname: Colvin
authors.forename: Shinji
authors.initials: S
authors.lastname: Kihara
authors.forename: Tohru
authors.initials: T
authors.lastname: Funahashi
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Luster
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
mesh_terms: D052242:Adiponectin / Q000494:pharmacology*; D001161:Arteriosclerosis / Q000276:immunology*; D002478:Cells, Cultured; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003920:Diabetes Mellitus; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007109:Immunity / Q000187:drug effects; D008264:Macrophages; D024821:Metabolic Syndrome; D009765:Obesity; D054367:Receptors, CXCR3 / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects*; D014162:Transfection
chemical_list: D052242:Adiponectin; D019743:Chemokines, CXC; D054367:Receptors, CXCR3