IL-13 dampens human airway epithelial innate immunity through induction of IL-1 receptor-associated kinase M.

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 TH2 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 TH2 cytokine milieu remain unclear. We sought to evaluate the role of IRAK-M in IL-13–inhibited TLR2 signaling in human airway epithelial cells. Methods: 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 TH2 cytokine–exposed airways inhibits TLR2 signaling, providing a novel mechanism for the increased susceptibility of infections in asthmatic patients.

气道黏膜免疫受损可导致哮喘患者呼吸道感染增加，但相关分子机制尚未完全阐明。气道上皮细胞作为呼吸道黏膜防御的第一道防线，通过多种机制（包括Toll样受体（TLR）通路）清除吸入的病原体。我们先前的研究表明，暴露于TH2细胞因子的气道中TLR2功能受损可能会降低对病原体的免疫反应，进而加剧过敏性炎症。白细胞介素 - 1受体相关激酶M（IRAK - M）对TLR信号传导起负调节作用。然而，哮喘患者气道上皮中IRAK - M的表达及其在TH2细胞因子环境下的功能仍不清楚。 我们试图评估IRAK - M在白细胞介素 - 13抑制的人气道上皮细胞中TLR2信号传导中的作用。方法：我们检测了哮喘患者上皮细胞与正常气道上皮细胞中IRAK - M蛋白的表达。此外，在有或无白细胞介素 - 13刺激的培养人气道上皮细胞中，研究了IRAK - M在调节先天免疫（例如TLR2信号传导）中的调节作用和功能。 哮喘患者气道上皮中IRAK - M蛋白水平升高。此外，在原代人气道上皮细胞中，白细胞介素 - 13持续上调IRAK - M的表达，主要是通过激活磷脂酰肌醇3 - 激酶通路。具体而言，磷脂酰肌醇3 - 激酶的激活导致c - Jun与人类IRAK - M基因启动子结合，从而使IRAK - M上调。在功能上，白细胞介素 - 13诱导的IRAK - M抑制了气道上皮TLR2信号传导的激活（例如TLR2和人β - 防御素2），部分是通过抑制核因子κB的激活。 我们的数据表明，暴露于TH2细胞因子的气道中上皮IRAK - M的过度表达抑制了TLR2信号传导，这为哮喘患者感染易感性增加提供了一种新的机制。