IFNβ/TNFa synergism induces a non-canonical STAT2/IRF9-dependent pathway triggering a novel DUOX2 NADPH Oxidase-mediated airway antiviral response  

作　　者：Karin Fink Lvdie Martin Esperance Mukawera St&any Chartier Xavier De Deken Emmanuelle Brochiero Francoise Mi Nathalie Grandvaux 

机构地区：[1]Centre de Recherche du CHUM (CRCHUM), Montreal QuObec, Canada H2X 1P1 [2]Department of Biochemistry, Faculty of Medicine, Universit de Montrkal, Qukbec, Canada H3T 1J4 [3]Institut de Recherche Interdisciplinaire en Biologic Humaine et MolOculaire, UniversitO Libre de Bruxelles, Campus Erasme, 1070 Brussels, Belgium [4]Department of Medicine, Faculty of Medi- cine, UniversitO de Montrkal, MontrOal, Quebec, Canada H3T 1J4

出　　处：《Cell Research》2013年第5期673-690,共18页细胞研究（英文版）

摘　　要：Airway epithelial cells are key initial innate immune responders in the fight against respiratory viruses, primarily via the secretion of antiviral and proinflammatory cytokines that act in an autocrine/paracrine fashion to trigger the establishment of an antiviral state. It is currently thought that the early antiviral state in airway epithelial cells primarily relies on IFNecretion and the subsequent activation of the interferon-stimulated gene factor 3 （ISGF3） transcription factor complex, composed of STAT1, STAT2 and IRF9, which regulates the expression of a panoply of interferon-stimulated genes encoding proteins with antiviral activities. However, the specific pathways engaged by the synergistic action of different cytokines during viral infections, and the resulting physiological outcomes are still ill-defined. Here, we unveil a novel delayed antiviral response in the airways, which is initiated by the synergistic autocrine/paracrine action of IFN[I and TNFa, and signals through a non-canonical STAT2- and IRF9-dependent, but STATl-independent cascade. This pathway ultimately leads to the late induction of the DUOX2 NADPH oxidase expression. Importantly, our study uncovers that the development of the antiviral state relies on DUOX2-dependent H202 production. Key antiviral pathways are often targeted by evasion strategies evolved by various pathogenic viruses. In this regard, the importance of the novel DUOX2-dependent antiviral pathway is further underlined by the observation that the human respiratory syncytial virus is able to subvert DUOX2 induction.

关 键 词：ANTIVIRAL cell signaling innate immunity inflammation NADPH oxidase INTERFERON 

分 类 号：S858.236.4[农业科学—临床兽医学] S432.23[农业科学—兽医学]