Abstract 1735: Adiponectin, an Anti-Inflammatory Adipocytokine, Regulates T Lymphocytes Recruitment by Inhibiting T Lymphocytotropic CXC Chemokines in LPS-Stimulated Macrophages: A Potential Anti-Atherogenic Function of Adiponectin
Objective: Chronic inflammation characterizes both obesity and atherosclerotic cardiovascular diseases. Individuals with obesity and coronary artery disease frequently have low plasma adiponectin (APN) levels. The current study sought anti-inflammatory mechanisms of APN by cDNA microarray assessment of genes suppressed by APN in LPS-stimulated human monocyte-derived macrophages (Mϕ).
Methods and Results: A cDNA microarray analysis of LPS-stimulated human Mϕ (LPS: 5ng/ml) indicated the T lymphocytotropic CXC chemokines IP-10 (CXCL10), Mig (CXCL9) and I-TAC (CXCL11) among the top 15 genes down-regulated by APN (10μg/ml)(99.1%, p<0.01; 97.1% ,p<0.05; 90.7% ,p<0.01,vs LPS alone, respectively, n=4). Real-time quantitative RT-PCR and ELISA verified that APN significantly inhibited the expression of these inflammatory chemokines at both the mRNA and protein levels in a concentration-dependent manner. APN did not change IP-10 mRNA stability after actinomycin D stimulation indicating that APN suppresses IP-10 gene transcription. Promoter analysis with promoter-transfected THP-1 Mϕ showed APN decreased LPS-inducible IP-10 promoter activity by 48.8% (p<0.0001 vs LPS alone, n=4). In early time points after LPS stimulation in Mϕ, APN significantly suppressed the expression of IFN-β through a MyD88-independent pathway of Toll-like Receptor 4 signaling, which subsequently induces IFN-inducible genes including IP-10. Furthermore, APN significantly inhibited the release of chemotactic activity for CXC chemokine receptor 3 (receptor for IP-10, Mig and I-TAC)-transfected lymphocytes from LPS-stimulated Mϕ by 71% (p < 0.05 vs LPS alone, n=4).
Conclusion: This study documented that APN strongly inhibits T lymphocytotropic CXC chemokines in LPS-stimulated Mϕ and indirectly regulates T lymphocyte recruitment, an important feature in the pathogenesis of atherosclerotic cardiovascular disease.