β1-Adrenoceptor autoantibodies from DCM patients enhance the proliferation of T lymphocytes through the β1-AR/cAMP/PKA and p38 MAPK pathways.
β1-Adrenoceptor autoantibodies from DCM patients enhance the proliferation of T lymphocytes through the β1-AR/cAMP/PKA and p38 MAPK pathways.
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DOI：
10.1371/journal.pone.0052911
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Liu H
中科院分区：
文献类型：
--
作者：
Du Y;Yan L;Wang J;Zhan W;Song K;Han X;Li X;Cao J;Liu H
抗β1-肾上腺素能受体（β1-AA）细胞外第二环的自身抗体不仅有助于心力衰竭的易感性增加，而且通过其与β1-肾上腺素能受体结合后诱导的交感神经样作用，在心肌重构中起致病作用。然而，它们在T淋巴细胞功能中的作用从未被研究过。本研究旨在确定从扩张型心肌病（DCM）患者血清中分离的β1-AA是否引起T细胞的增殖和细胞因子的分泌。分别采集95例DCM患者和95例健康人的血液，采用ELISA法检测β1-AA。流式细胞术分别筛选CD3+T淋巴细胞，CCK-8试剂盒和CFSE法检测β1-AA对T淋巴细胞增殖的影响。Western blotting分析phospho-VASP和phospho-p38 MAPK的表达。β1-AA促进T淋巴细胞增殖。这种作用可被选择性β1-肾上腺素能受体拮抗剂美托洛尔、PKA抑制剂H89和p38 MAPK抑制剂SB203580阻断。此外，在β1-AA的存在下，磷酸化形式的phospho-VASP和phospho-p38 MAPK的表达显著增加。β1-AA还抑制干扰素-γ (IFN-γ)的分泌，同时促进白细胞介素-4 （IL-4）水平的升高。这些结果表明，从DCM患者分离的β1-AA与T细胞表面的β1-AR结合，通过β1-AR/cAMP/PKA和p38 MAPK途径引起T细胞增殖和分泌的变化。
Autoantibodies against the second extracellular loop of the β1-adrenergic receptor (β1-AA) not only contribute to increased susceptibility to heart failure, but also play a causative role in myocardial remodeling through their sympathomimetic-like effects that are induced upon binding to the β1-adrenergic receptor. However, their role in the function of T lymphocytes has never been previously investigated. Our present study was designed to determine whether β1-AA isolated from the sera of dilated cardiomyopathy (DCM) patients caused the proliferation of T cells and the secretion of cytokines. Blood samples were collected from 95 DCM patients as well as 95 healthy subjects, and β1-AA was detected using ELISA. The CD3+T lymphocytes were selected separately through flow cytometry and the effect of β1-AA on T lymphocyte proliferation was examined by CCK-8 kits and CFSE assay. Western blotting was used to analyze the expressions of phospho-VASP and phospho-p38 MAPK. β1-AA enhanced the proliferation of T lymphocytes. This effect could be blocked by the selective β1-adrenergic receptor antagonist metoprolol, PKA inhibitor H89, and p38 MAPK inhibitor SB203580. Furthermore, the expression of the phosphorylated forms of phospho-VASP and phospho-p38 MAPK were markedly increased in the presence of β1-AA. β1-AA also inhibited the secretion of interferon-γ (IFN-γ) while promoting an increase in interleukin-4 (IL-4) levels. These results demonstrate that β1-AA isolated from DCM patients binds to β1-AR on the surface of T cells, causing changes in T-cell proliferation and secretion through the β1-AR/cAMP/PKA and p38 MAPK pathways.
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