Department of Medicine, National Jewish Health and the University of Colorado Denver, Denver, CO 80206, USA.
J Allergy Clin Immunol. 2012 Mar;129(3):825-833.e2. doi: 10.1016/j.jaci.2011.10.043. Epub 2011 Dec 9.
Impaired airway mucosal immunity can contribute to increased respiratory tract infections in asthmatic patients, but the involved molecular mechanisms have not been fully clarified. Airway epithelial cells serve as the first line of respiratory mucosal defense to eliminate inhaled pathogens through various mechanisms, including Toll-like receptor (TLR) pathways. Our previous studies suggest that impaired TLR2 function in T(H)2 cytokine-exposed airways might decrease immune responses to pathogens and subsequently exacerbate allergic inflammation. IL-1 receptor-associated kinase M (IRAK-M) negatively regulates TLR signaling. However, IRAK-M expression in airway epithelium from asthmatic patients and its functions under a T(H)2 cytokine milieu remain unclear.
We sought to evaluate the role of IRAK-M in IL-13-inhibited TLR2 signaling in human airway epithelial cells.
We examined IRAK-M protein expression in epithelia from asthmatic patients versus that in normal airway epithelia. Moreover, IRAK-M regulation and function in modulating innate immunity (eg, TLR2 signaling) were investigated in cultured human airway epithelial cells with or without IL-13 stimulation.
IRAK-M protein levels were increased in asthmatic airway epithelium. Furthermore, in primary human airway epithelial cells, IL-13 consistently upregulated IRAK-M expression, largely through activation of phosphoinositide 3-kinase pathway. Specifically, phosphoinositide 3-kinase activation led to c-Jun binding to human IRAK-M gene promoter and IRAK-M upregulation. Functionally, IL-13-induced IRAK-M suppressed airway epithelial TLR2 signaling activation (eg, TLR2 and human β-defensin 2), partly through inhibiting activation of nuclear factor κB.
Our data indicate that epithelial IRAK-M overexpression in T(H)2 cytokine-exposed airways inhibits TLR2 signaling, providing a novel mechanism for the increased susceptibility of infections in asthmatic patients.
气道黏膜免疫功能受损可能导致哮喘患者呼吸道感染增加，但涉及的分子机制尚未完全阐明。气道上皮细胞作为呼吸黏膜防御的第一道防线，通过各种机制（包括 Toll 样受体 [TLR] 途径）消除吸入的病原体。我们之前的研究表明，T(H)2 细胞因子暴露的气道中 TLR2 功能受损可能会降低对病原体的免疫反应，进而加重过敏炎症。白介素 1 受体相关激酶 M（IRAK-M）负调节 TLR 信号。然而，哮喘患者气道上皮细胞中的 IRAK-M 表达及其在 T(H)2 细胞因子环境下的功能仍不清楚。
我们旨在评估 IRAK-M 在人气道上皮细胞中 IL-13 抑制 TLR2 信号中的作用。
我们检测了哮喘患者气道上皮细胞中 IRAK-M 蛋白的表达与正常气道上皮细胞中的表达。此外，我们还研究了在有无 IL-13 刺激的情况下，培养的人气道上皮细胞中 IRAK-M 的调节和功能对固有免疫（如 TLR2 信号）的影响。
在哮喘气道上皮细胞中 IRAK-M 蛋白水平增加。此外，在原代人气道上皮细胞中，IL-13 一致地上调了 IRAK-M 的表达，主要是通过激活磷脂酰肌醇 3-激酶途径。具体来说，磷脂酰肌醇 3-激酶的激活导致 c-Jun 结合到人类 IRAK-M 基因启动子上，从而上调 IRAK-M。功能上，IL-13 诱导的 IRAK-M 抑制气道上皮 TLR2 信号激活（如 TLR2 和人 β-防御素 2），部分通过抑制核因子 κB 的激活。
我们的数据表明，T(H)2 细胞因子暴露的气道上皮中 IRAK-M 的过度表达抑制了 TLR2 信号，为哮喘患者感染易感性增加提供了一种新的机制。
