哮喘联盟

    摘要
    背景：哮喘患者的气道粘膜免疫受损可导致呼吸道感染增加，但其中的分子机制尚未完全了解。气道上皮细胞为呼吸道粘膜防御的第一线，通过各种不同机制清除吸入的病原体，其中就包括通过Toll样受体（TLR）途径发挥作用。前期研究显示，气道暴露于Th2细胞因子后导致的TLR2功能受损可能降低了针对病原体的免疫反应，导致随后过敏性炎症恶化。IL-1受体相关激酶M（IRAK-M）能负向调节TLR信号通路。然而，在Th2细胞因子环境下，哮喘患者气道上皮细胞IRAK-M的表达及其功能尚不清楚。
    目的：本研究旨在人气道上皮细胞中评价IRAK-M在IL-13抑制的TLR2信号通路中的作用。
    方法：检测哮喘患者气道上皮细胞和正常气道上皮细胞内IRAK-M的蛋白表达。同时，在有或无IL-13刺激条件下，评价IRAK-M在调节人气道上皮细胞固有免疫中的作用。
    结果：哮喘患者气道上皮细胞的IRAK-M蛋白表达增加。此外，对于原人气道上皮细胞，IL-13可能通过活化肌醇磷脂3激酶信号途径上调IRAK-M表达。特别是肌醇磷脂3激酶信号途径的活化，可使c-Jun结合至人IRAK-M基因启动子，最终导致IRAK-M上调。在功能上，IL-13诱导的IRAK-M能抑制气道上皮细胞TLR2信号途径活化（如：TLR2和人β-防御素-2），这与抑制核因子κB活化部分相关。
    结论：该项结果显示，Th2细胞因子暴露的气道上皮细胞存在IRAK-M过表达，后者能抑制TLR2信号途径。该研究结果为哮喘患者容易发生感染提供了一个新的机制解释。

（苏楠 审校）
                    J Allergy Clin Immunol. 2011 Dec 7. [Epub ahead of print]

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

Wu Q, Jiang D, Smith S, Thaikoottathil J, Martin RJ, Bowler RP, Chu HW.

Source
Departments of Medicine, National Jewish Health and the University of Colorado Denver, Denver, CO.

Abstract 
BACKGROUND: 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.
OBJECTIVES: 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.
RESULTS: 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.
CONCLUSIONS: 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

J Allergy Clin Immunol. 2011 Dec 7. [Epub ahead of print]