Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

J. Biol. Chem. 285 (37): 28715-28722

© 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Autophagy Facilitates IFN-{gamma}-induced Jak2-STAT1 Activation and Cellular Inflammation*Formula

Yu-Ping Chang{ddagger}§, Cheng-Chieh Tsai{ddagger}||, Wei-Ching Huang{ddagger}, Chi-Yun Wang{ddagger}, Chia-Ling Chen§, Yee-Shin Lin§**, Jui-In Kai{ddagger}, Chia-Yuan Hsieh{ddagger}, Yi-Lin Cheng{ddagger}{ddagger}{ddagger}, Pui-Ching Choi{ddagger}, Shun-Hua Chen§, Shih-Ping Chang§, Hsiao-Sheng Liu§, , and Chiou-Feng Lin{ddagger}§1

From the Institutes of {ddagger}Clinical Medicine and
Basic Medical Sciences,
Departments of §Microbiology and Immunology and
{ddagger}{ddagger}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 Back to Top

Abstract: Autophagy is regulated for IFN-{gamma}-mediated antimicrobial efficacy; however, its molecular effects for IFN-{gamma} signaling are largely unknown. Here, we show that autophagy facilitates IFN-{gamma}-activated Jak2-STAT1. IFN-{gamma} induces autophagy in wild-type but not in autophagy protein 5 (Atg5–/–)-deficient mouse embryonic fibroblasts (MEFs), and, autophagy-dependently, IFN-{gamma} induces IFN regulatory factor 1 and cellular inflammatory responses. Pharmacologically inhibiting autophagy using 3-methyladenine, a known inhibitor of class III phosphatidylinositol 3-kinase, confirms these effects. Either Atg5–/– or Atg7–/– MEFs are, independent of changes in IFN-{gamma} receptor expression, resistant to IFN-{gamma}-activated Jak2-STAT1, which suggests that autophagy is important for IFN-{gamma} signal transduction. Lentivirus-based short hairpin RNA for Atg5 knockdown confirmed the importance of autophagy for IFN-{gamma}-activated STAT1. Without autophagy, reactive oxygen species increase and cause SHP2 (Src homology-2 domain-containing phosphatase 2)-regulated STAT1 inactivation. Inhibiting SHP2 reversed both cellular inflammation and the IFN-{gamma}-induced activation of STAT1 in Atg5–/– MEFs. Our study provides evidence that there is a link between autophagy and both IFN-{gamma} signaling and cellular inflammation and that autophagy, because it inhibits the expression of reactive oxygen species and SHP2, is pivotal for 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}

Autophagy facilitates cytokine-induced ICAM-1 expression.
C.-Y. Wang, T.-H. Chiang, C.-L. Chen, P.-C. Tseng, S.-Y. Chien, Y.-J. Chuang, T.-T. Yang, C.-Y. Hsieh, P.-C. Choi, and C.-F. Lin (2014)
Innate Immunity 20, 200-213
   Abstract »    Full Text »    PDF »
Interferon-{gamma} Signaling Inhibition Ameliorates Angiotensin II-Induced Cardiac Damage.
L. Marko, H. Kvakan, J.-K. Park, F. Qadri, B. Spallek, K. J. Binger, E. P. Bowman, M. Kleinewietfeld, V. Fokuhl, R. Dechend, et al. (2012)
Hypertension 60, 1430-1436
   Abstract »    Full Text »    PDF »
A Unique Hybrid Renal Mononuclear Phagocyte Activation Phenotype in Murine Systemic Lupus Erythematosus Nephritis.
R. Bethunaickan, C. C. Berthier, M. Ramanujam, R. Sahu, W. Zhang, Y. Sun, E. P. Bottinger, L. Ivashkiv, M. Kretzler, and A. Davidson (2011)
J. Immunol. 186, 4994-5003
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882