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Sci. Signal., 18 December 2012
Vol. 5, Issue 255, p. ra93
[DOI: 10.1126/scisignal.2003558]

RESEARCH ARTICLES

c-FLIP Maintains Tissue Homeostasis by Preventing Apoptosis and Programmed Necrosis

Xuehua Piao1,2, Sachiko Komazawa-Sakon1, Takashi Nishina1,2, Masato Koike3, Jiang-Hu Piao1,4, Hanno Ehlken5, Hidetake Kurihara6, Mutsuko Hara2, Nico Van Rooijen7, Günther Schütz8, Masaki Ohmuraya9, Yasuo Uchiyama3, Hideo Yagita1, Ko Okumura1,2, You-Wen He10, and Hiroyasu Nakano1,11*

1 Department of Immunology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
2 Atopy Research Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
3 Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
4 Department of Immunology, School of Basic Medical Science, Ningxia Medical College, 1160 Shengli Street, Xingqing-Qu, Yinchuan 750004, China.
5 University Medical Center Hamburg-Eppendorf, I. Department of Internal Medicine, Martin Str. 52, Hamburg 20246, Germany.
6 Department of Anatomy, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
7 Department of Molecular Cell Biology, Faculty of Medicine, Vrije Universiteit, Amsterdam 1081 BT, Netherlands.
8 Department of Molecular Biology of the Cell I, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
9 Center for Animal Resources and Development, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan.
10 Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
11 Laboratory of Molecular and Biochemical Research, Biomedical Research Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.

Abstract: As a catalytically inactive homolog of caspase-8, a proapoptotic initiator caspase, c-FLIP blocks apoptosis by binding to and inhibiting caspase-8. The transcription factor nuclear factor {kappa}B (NF-{kappa}B) plays a pivotal role in maintaining the homeostasis of the intestine and the liver by preventing death receptor–induced apoptosis, and c-FLIP plays a role in the NF-{kappa}B–dependent protection of cells from death receptor signaling. Because c-Flip–deficient mice die in utero, we generated conditional c-Flip–deficient mice to investigate the contribution of c-FLIP to homeostasis of the intestine and the liver at developmental and postnatal stages. Intestinal epithelial cell (IEC)– or hepatocyte-specific deletion of c-Flip resulted in perinatal lethality as a result of the enhanced apoptosis and programmed necrosis of the IECs and the hepatocytes. Deficiency in the gene encoding tumor necrosis factor–α (TNF-α) receptor 1 (Tnfr1) partially rescued perinatal lethality and the development of colitis in IEC-specific c-Flip–deficient mice but did not rescue perinatal lethality in hepatocyte-specific c-Flip–deficient mice. Moreover, adult mice with interferon (IFN)–inducible deficiency in c-Flip died from hepatitis soon after depletion of c-FLIP. Pretreatment of IFN-inducible c-Flip–deficient mice with a mixture of neutralizing antibodies against TNF-α, Fas ligand (FasL), and TNF-related apoptosis-inducing ligand (TRAIL) prevented hepatitis. Together, these results suggest that c-FLIP controls the homeostasis of IECs and hepatocytes by preventing cell death induced by TNF-α, FasL, and TRAIL.

* To whom correspondence should be addressed. E-mail: hnakano{at}juntendo.ac.jp

Citation: X. Piao, S. Komazawa-Sakon, T. Nishina, M. Koike, J.-H. Piao, H. Ehlken, H. Kurihara, M. Hara, N. Van Rooijen, G. Schütz, M. Ohmuraya, Y. Uchiyama, H. Yagita, K. Okumura, Y.-W. He, H. Nakano, c-FLIP Maintains Tissue Homeostasis by Preventing Apoptosis and Programmed Necrosis. Sci. Signal. 5, ra93 (2012).

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