Adiponectin inhibits the production of CXC receptor 3 chemokine ligands in macrophages and reduces T-lymphocyte recruitment in atherogenesis
Adiponectin inhibits the production of CXC receptor 3 chemokine ligands in macrophages and reduces T-lymphocyte recruitment in atherogenesis
复制标题
DOI：
10.1161/circresaha.107.164988
复制
发表时间：
2008-02-01
影响因子：
20.1
通讯作者：
Libby, Peter
中科院分区：
文献类型：
--
作者：
Okamoto, Yoshihisa;Folco, Eduardo J.;Libby, Peter
肥胖个体通常具有低血浆脂联素和伴随的慢性炎症，具有易患代谢和心血管疾病的倾向。本研究报告了脂联素在人单核细胞源性巨噬细胞（M Phi）中抑制T淋巴细胞聚集的新的抗动脉粥样硬化作用。脂多糖刺激的人M Phi的RNA分析鉴定了CXC趋化因子配体（CXCL），如IP-10（干扰素[IFN]诱导蛋白10）（CXCL 10）、I-TAC（IFN诱导T细胞α化学引诱物）（CXCL 11）和Mig（IFN-γ诱导的单核因子）（CXCL 9），它们是脂联素抑制的前14种转录物中与动脉粥样硬化发生相关的T淋巴细胞化学引诱物。实时荧光定量RT-PCR和ELISA证实脂联素在mRNA和蛋白水平上均以浓度依赖性方式抑制这些趋化因子的表达。脂联素减少释放脂多糖刺激的M Phi的趋化活性CXC趋化因子受体3转染（IP-10，米格，和I-TAC受体）淋巴细胞。脂联素降低脂多糖诱导的IP-10启动子在启动子转染的THP-1 M Phi的活性，但不改变IP-10 mRNA的稳定性。在脂多糖刺激的M Phi中，脂联素对IFN-β的减少先于IP-10 mRNA表达的抑制。免疫印迹和染色质免疫沉淀分析表明，脂联素减弱了转录因子IFN调节因子3的激活，参与了Toll样受体4信号传导的MyD 88非依赖性途径，以及随后IFN调节因子3与IFN-β启动子的结合。体内研究进一步证实，与apoE单缺陷（apoE（-/-）APN（-/-））小鼠相比，apoE/脂联素双缺陷（apoE（-/-）APN（-/-））小鼠血浆IP-10水平升高，动脉粥样硬化中T淋巴细胞积聚加速，动脉粥样硬化形成增强。本研究证实，低水平脂联素与肥胖、代谢综合征和糖尿病相关，有利于T淋巴细胞募集，并有助于动脉粥样硬化形成过程中的适应性免疫反应。
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 Phi) suppressing T-lymphocyte accumulation in atherogenesis. RNA profiling of lipopolysaccharide-stimulated human M Phi 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 M Phi 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 Phi but did not change IP-10 mRNA stability. In lipopolysaccharide-stimulated M Phi, 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.