Zhou Weisong, Zhang Jian, Goleniewska Kasia, Dulek Daniel E, Toki Shinji, Newcomb Dawn C, Cephus Jacqueline Y, Collins Robert D, Wu Pingsheng, Boothby Mark R, Peebles R Stokes
Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; and
Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; and.
J Immunol. 2016 Sep 1;197(5):1577-86. doi: 10.4049/jimmunol.1501063. Epub 2016 Jul 25.
Allergic airway diseases are immune disorders associated with heightened type 2 immune responses and IL-5 and IL-13 production at the site of inflammation. We have previously reported that cyclooxygenase (COX) inhibition by indomethacin augmented allergic airway inflammation in a STAT6-independent manner. However, the key COX product(s) responsible for restraining indomethacin-mediated STAT6-independent allergic inflammation is unknown. In this study, using the mouse model of OVA-induced allergic airway inflammation, we identified that PGI2 receptor (IP) signaling was critical for indomethacin-induced, STAT6-independent proallergic effects. We demonstrated that IP deficiency increased inflammatory cell infiltration, eosinophilia, and IL-5 and IL-13 expression in the lung in a STAT6-independent manner. The augmented STAT6-independent allergic inflammation correlated with enhanced primary immune responses to allergic sensitization and elevated production of multiple inflammatory chemokines (CCL11, CCL17, CCL22, and CXCL12) in the lung after allergen challenge. We also showed that the PGI2 analogue cicaprost inhibited CD4 T cell proliferation and IL-5 and IL-13 expression in vitro, and IP deficiency diminished the stimulatory effect of indomethacin on STAT6-independent IL-5 and IL-13 responses in vivo. The inhibitory effects of PGI2 and the IP signaling pathway on CD4 T cell activation, inflammatory chemokine production, and allergic sensitization and airway inflammation suggest that PGI2 and its analogue iloprost, both Food and Drug Administration-approved drugs, may be useful in treating allergic diseases and asthma. In addition, inhibiting PGI2 signaling by drugs that either block PGI2 production or restrain IP signaling may augment STAT6-independent pathways of allergic inflammation.
过敏性气道疾病是与2型免疫反应增强以及炎症部位白细胞介素-5（IL-5）和白细胞介素-13产生相关的免疫紊乱。我们之前报道过，吲哚美辛对环氧合酶（COX）的抑制以一种不依赖信号转导及转录激活因子6（STAT6）的方式加剧了过敏性气道炎症。然而，负责抑制吲哚美辛介导的不依赖STAT6的过敏性炎症的关键COX产物尚不清楚。在本研究中，我们使用卵清蛋白（OVA）诱导的过敏性气道炎症小鼠模型，确定前列环素（PGI2）受体（IP）信号传导对于吲哚美辛诱导的、不依赖STAT6的促过敏作用至关重要。我们证明，IP缺陷以不依赖STAT6的方式增加了肺部炎症细胞浸润、嗜酸性粒细胞增多以及IL-5和IL-13的表达。不依赖STAT6的过敏性炎症加剧与对过敏性致敏的初级免疫反应增强以及变应原激发后肺部多种炎症趋化因子（CCL11、CCL17、CCL22和CXCL12）产生增加相关。我们还表明，PGI2类似物西卡前列素在体外抑制CD4 T细胞增殖以及IL-5和IL-13的表达，而IP缺陷减弱了吲哚美辛对体内不依赖STAT6的IL-5和IL-13反应的刺激作用。PGI2及其IP信号通路对CD4 T细胞活化、炎症趋化因子产生以及过敏性致敏和气道炎症的抑制作用表明，PGI2及其类似物伊洛前列素（二者均为美国食品药品监督管理局批准的药物）可能对治疗过敏性疾病和哮喘有用。此外，通过阻断PGI2产生或抑制IP信号传导的药物抑制PGI2信号传导可能会增强不依赖STAT6的过敏性炎症途径。
