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From the Institutes of Clinical Medicine and ¶Basic Medical Sciences,
Departments of Microbiology and Immunology and Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan,
the ||Department of Nursing, Chung Hwa University of Medical Technology, Tainan 717, Taiwan, and
the **Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University, Tainan 701, Taiwan
Abstract:
Autophagy is regulated for IFN--mediated antimicrobial efficacy;however, its molecular effects for IFN- signaling are largelyunknown. Here, we show that autophagy facilitates IFN--activatedJak2-STAT1. IFN- induces autophagy in wild-type but not in autophagyprotein 5 (Atg5–/–)-deficient mouse embryonic fibroblasts(MEFs), and, autophagy-dependently, IFN- induces IFN regulatoryfactor 1 and cellular inflammatory responses. Pharmacologicallyinhibiting autophagy using 3-methyladenine, a known inhibitorof class III phosphatidylinositol 3-kinase, confirms these effects.Either Atg5–/– or Atg7–/– MEFs are,independent of changes in IFN- receptor expression, resistantto IFN--activated Jak2-STAT1, which suggests that autophagyis important for IFN- signal transduction. Lentivirus-basedshort hairpin RNA for Atg5 knockdown confirmed the importanceof autophagy for IFN--activated STAT1. Without autophagy, reactiveoxygen species increase and cause SHP2 (Src homology-2 domain-containingphosphatase 2)-regulated STAT1 inactivation. Inhibiting SHP2reversed both cellular inflammation and the IFN--induced activationof STAT1 in Atg5–/– MEFs. Our study provides evidencethat there is a link between autophagy and both IFN- signalingand cellular inflammation and that autophagy, because it inhibitsthe expression of reactive oxygen species and SHP2, is pivotalfor Jak2-STAT1 activation.
Key Words: Autophagy • Inflammation • Interferon • Jak Kinase • Phosphatase • Reactive Oxygen Species (ROS) • Signal Transduction • STAT Transcription Factor
Received for publication April 13, 2010.
Revision received June 21, 2010.
1 To whom correspondence should be addressed: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. Tel.: 886-6-235-3535 (ext. 4240); Fax: 886-6-275-8781; E-mail: cflin{at}mail.ncku.edu.tw.
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