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首页> 外文期刊>American Journal of Physiology >Exposure to TARC alters beta2-adrenergic receptor signaling in human peripheral blood T lymphocytes.
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Exposure to TARC alters beta2-adrenergic receptor signaling in human peripheral blood T lymphocytes.

机译：暴露于TARC会改变人外周血T淋巴细胞中的β2-肾上腺素能受体信号。

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The beta(2)-adrenergic receptor (beta(2)-AR) negatively regulates T cell activity through the activation of the G(s)/adenylyl cyclase/cAMP pathway. beta(2)-AR desensitization, which can be induced by its phosphorylation, may have important consequences for the regulation of T cell function in asthma. In the present study we demonstrate that the C-C chemokine thymus and activation-regulated chemokine (TARC) impairs the ability of beta(2)-agonist fenoterol to activate the cAMP downstream effector cAMP-responsive element binding protein (CREB) in freshly isolated human T cells. The TARC-induced activation of Src kinases resulted in membrane translocation of both G protein-coupled receptor kinase (GRK) 2 and beta-arrestin. Moreover, TARC was able to induce Src-dependent serine phosphorylation of the beta(2)-AR as well as its association with GRK2 and beta-arrestin. Finally, in contrast to CREB, phosphorylation of Src and extracellular signal-regulated kinase was enhanced by fenoterol upon TARC pretreatment. In summary, we show for the first time that TARC exposure impairs beta(2)-AR function in T cells. Our data suggest that this is mediated by Src-dependent activation of GRK2, resulting in receptor phosphorylation, binding to beta-arrestin, and a switch from cAMP-dependent signaling to activation of the MAPK pathway. We propose that aberrant T cell control in the presence of endogenous beta-agonists promotes T cell-mediated inflammation in asthma.
机译：β（2）-肾上腺素能受体（β（2）-AR）通过激活G（s）/腺苷酸环化酶/ cAMP途径负调节T细胞活性。 beta（2）-AR脱敏，可以由其磷酸化诱导，可能对哮喘T细胞功能的调节具有重要意义。在本研究中，我们证明了CC趋化因子胸腺和激活调节趋化因子（TARC）会损害β（2）-激动剂非诺特罗在新鲜分离的人T中激活cAMP下游效应子cAMP响应元件结合蛋白（CREB）的能力。细胞。 TARC诱导的Src激酶激活导致G蛋白偶联受体激酶（GRK）2和β-arrestin的膜易位。此外，TARC能够诱导β（2）-AR的Src依赖性丝氨酸磷酸化以及其与GRK2和β-arrestin的缔合。最后，与CREB相比，非诺特罗在TARC预处理后增强了Src和细胞外信号调节激酶的磷酸化。总之，我们首次表明TARC暴露会损害T细胞中的beta（2）-AR功能。我们的数据表明，这是由GRK2的Src依赖性激活介导的，导致受体磷酸化，与β-arrestin结合以及从cAMP依赖性信号转为激活MAPK途径。我们提出在存在内源性β-激动剂的情况下异常T细胞控制可促进哮喘中T细胞介导的炎症。

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