PDF(Pubmed)
Abstract：
G protein-coupled receptor kinase 2 (GRK2) is an adapter protein that modulates G protein-coupled receptor (GPCR) signaling. It also regulates the functions and activity of other intracellular proteins in many cell types. Accordingly, GRK2 is thought to contribute to disease progression by a variety of mechanisms related to its multifunctional roles. Indeed, GRK2 levels are enhanced in patient samples as well as in preclinical models of several diseases. We have previously shown that GRK2 regulates mast cell functions, and thereby contributes to exacerbated inflammation during allergic reactions. In the current study, we observed that GRK2 levels are enhanced in the lungs of human asthma patients and in mice sensitized to house dust mite extract (HDME) allergen. Consistent with these findings, interleukin (IL)-4 and IL-13 levels were reduced in the lungs of GRK2+/- mice in a HMDE mouse model of asthma. Because Th2 cells are the major source of these cytokines during asthma, we determined the role of GRK2 in regulating T cell-specific responses in our HMDE mouse model. We observed a significant reduction of airway hyperresponsiveness (AHR), lung eosinophil and lymphocyte counts, serum IgE, Th2 cytokines (IL-4 and IL-13), goblet cell hyperplasia and mucus production in mice that had reduced GRK2 expression specifically in T cells. Collectively, our studies reveal an important role for GRK2 in regulating T cell response during asthma pathogenesis and further elucidation of the mechanisms through which GRK2 modulates airway inflammation will lead to the development of new therapeutic strategies for asthma.
摘要：
G蛋白偶联受体激酶2(GRK2)是调节G蛋白偶联受体(GPCR)信号传导的衔接蛋白。它还调节许多细胞类型中其他细胞内蛋白质的功能和活性。因此，GRK2被认为通过与其多功能作用相关的多种机制促进疾病进展。的确,GRK2水平在患者样品中以及在几种疾病的临床前模型中增强。我们之前已经证明GRK2调节肥大细胞功能，从而导致过敏反应期间炎症加剧。在目前的研究中,我们观察到，在人类哮喘患者的肺部和对房尘螨提取物（HDME）变应原致敏的小鼠中，GRK2水平增强。与这些发现一致，在哮喘的HMDE小鼠模型中,GRK2+/-小鼠的肺中白细胞介素(IL)-4和IL-13水平降低。因为Th2细胞是哮喘期间这些细胞因子的主要来源，我们在HMDE小鼠模型中确定了GRK2在调节T细胞特异性应答中的作用.我们观察到气道高反应性（AHR）显着降低，肺嗜酸性粒细胞和淋巴细胞计数，血清IgE,Th2细胞因子（IL-4和IL-13），小鼠杯状细胞增生和粘液产生减少了GRK2表达，特别是在T细胞中。总的来说，我们的研究揭示了GRK2在哮喘发病过程中调节T细胞反应的重要作用,进一步阐明GRK2调节气道炎症的机制将导致哮喘新的治疗策略的开发.
