Weckmann Markus, Collison Adam, Simpson Jodie L, Kopp Matthias V, Wark Peter A B, Smyth Mark J, Yagita Hideo, Matthaei Klaus I, Hansbro Nicole, Whitehead Bruce, Gibson Peter G, Foster Paul S, Mattes Joerg
Department of Paediatrics and Adolescent Medicine, Albert Ludwigs University Freiburg, 79106 Freiburg, Germany.
Nat Med. 2007 Nov;13(11):1308-15. doi: 10.1038/nm1660. Epub 2007 Oct 14.
The role of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in immune responses mediated by T-helper 2 (T(H)2) lymphocytes is unknown. Here we characterize the development of allergic airway disease in TRAIL-deficient (Tnfsf10(-/-)) mice and in mice exposed to short interfering RNA targeting TRAIL. We show that TRAIL is abundantly expressed in the airway epithelium of allergic mice and that inhibition of signaling impairs production of the chemokine CCL20 and homing of myeloid dendritic cells and T cells expressing CCR6 and CD4 to the airways. Attenuated homing limits T(H)2 cytokine release, inflammation, airway hyperreactivity and expression of the transcriptional activator STAT6. Activation of STAT6 by interleukin-13 restores airway hyperreactivity in Tnfsf10(-/-) mice. Recombinant TRAIL induces pathognomic features of asthma and stimulates the production of CCL20 in primary human bronchial epithelium cells. TRAIL is also increased in sputum of asthmatics. The function of TRAIL in the airway epithelium identifies this molecule as a target for the treatment of asthma.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）在辅助性T细胞2（Th2）淋巴细胞介导的免疫反应中的作用尚不清楚。在此，我们对TRAIL缺陷（Tnfsf10-/-）小鼠以及暴露于靶向TRAIL的小干扰RNA的小鼠中过敏性气道疾病的发展进行了表征。我们发现，TRAIL在过敏性小鼠的气道上皮中大量表达，信号传导的抑制会损害趋化因子CCL20的产生以及表达CCR6和CD4的髓样树突状细胞和T细胞向气道的归巢。归巢减弱限制了Th2细胞因子的释放、炎症、气道高反应性以及转录激活因子STAT6的表达。白细胞介素-13对STAT6的激活可恢复Tnfsf10-/-小鼠的气道高反应性。重组TRAIL可诱导哮喘的典型特征，并刺激原代人支气管上皮细胞中CCL20的产生。哮喘患者痰液中的TRAIL也会增加。TRAIL在气道上皮中的功能表明该分子是哮喘治疗的一个靶点。
