Abstract 758: Adiponectin Reduces T Lymphocyte Accumulation in Atherosclerotic Lesions by Inhibiting T Lymphocytotropic CXC Chemokines
Objective: Chronic inflammation characterizes both obesity and atherosclerotic cardiovascular disease. Individuals with obesity and coronary artery disease often have low plasma levels of the anti-inflammatory adipocytokine adiponectin (APN). T lymphocyte accumulation in atherosclerotic lesions participates pivotally in atherogenesis. We found that APN strongly inhibits the chemotactic activity of T lymphocytotropic CXC chemokines, including CXCL10 (IP-10) in LPS-stimulated human macrophages (MΦ) . The current study sought the mechanism by which APN suppresses the expression of these chemokines in vitro, and relation of this phenomenon to atherogenesis in vivo.
Methods and Results: Real-time quantitative RT-PCR showed that APN inhibited IFN-β mRNA expression 1–2 hours after LPS stimulation in MΦ preceding inducible IP-10 mRNA expression. Western blot analysis revealed that APN significantly suppresses the phosphorylation of STAT1, a key transcription factor for IP-10, in MΦ stimulated with LPS but not with IFN-β. These findings indicate that APN suppresses IP-10 by inhibiting IFN-β through a MyD88-independent pathway of Toll-like Receptor 4 (TLR4) signaling. In addition, APN suppresses the phosphorylation of IRF3, an essential transcriptional factor for inducing IFN-β in a MyD88-independent pathway of TLR4-signaling in LPS-stimulated MΦ. Moreover, chromatin immunoprecipitation assay demonstrated that APN reduces the binding of IRF3 to the promoter region of IFN-β. Compared to ApoE single-deficient mice (ApoE−/ − APN+/+, n=7), ApoE−/ − APN−/ − mice (n=6) developed larger atherosclerotic lesions by 61%(0.18±0.03 vs. 0.29±0.03 mm2, p < 0.05) and accumulated 63% more T lymphocytes (7.8±1.0 vs. 12.7±1.4 cells/section, p < 0.05) in the aortic root. Plasma IP-10 levels in ApoE−/ − APN−/ − mice (n=8) were 44% higher (32.3±1.6 vs. 46.6±5.8 pg/ml, p <0.05) than in ApoE−/ − APN+/+ mice (n=8).
Conclusion: These results indicate that APN limits atherogenesis in part by inhibiting T lymphocytotropic CXC chemokine expression and subsequent MΦ and T lymphocyte accumulation into atheromata, key steps in the pathogenesis of this inflammatory disease.