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FLIPping Multiple Death Signals Off

The gene c-Flip, which encodes the antiapoptotic protein c-FLIP, is expressed in response to nuclear factor κB (NF-κB) activation. NF-κB–mediated protection of the intestine and liver from proapoptotic signaling is important for tissue maintenance (homeostasis). Avoiding the embryonic lethality caused by complete knockout of c-Flip in mice, Piao et al. selectively deleted c-Flip in intestinal epithelial cells (IECs) or hepatocytes. Whereas c-FLIP–deficient IECs exhibited tumor necrosis factor (TNF)–dependent apoptosis and programmed necrosis, a cell death process morphologically and mechanistically distinct from that of apoptosis, leading to perinatal death of the mice, c-FLIP–deficient hepatocytes exhibited apoptosis and programmed necrosis, and mice died in a TNF-independent manner. Induced loss of c-FLIP in hepatocytes in adult mice led to lethal hepatitis, which was prevented by blocking multiple proinflammatory factors that trigger apoptosis. Together, these data show that c-FLIP blocks both apoptosis and programmed necrosis to maintain tissue homeostasis and suggest that targeting both cell death pathways may be effective in treating certain viral infections in which c-FLIP abundance is reduced.

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 κB (NF-κB) 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-κB–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.

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Supplementary Material

Summary

Fig. S1. Histological analysis of the small intestine and colon.
Fig. S2. c-FlipF/F;Villin-Cre;Tnfr1+/− mice do not develop colitis.
Fig. S3. ConA-induced hepatitis is exacerbated in c-FlipF/F;Alb-Cre mice.
Fig. S4. Degradation of RIPK1 protein correlates with selective induction of apoptosis in the liver.
Fig. S5. c-FLIP in hepatocytes, but not hematopoietic cells, plays a crucial role in the protection of hepatocytes from cell death.
Fig. S6. Administration of clodronate liposomes and anti-ASGM1 antibody depletes Kupffer cells and NK cells, respectively.
Fig. S7. Clodronate liposomes inhibit poly I:C–induced depletion of c-FLIP protein in the livers of c-FlipF/F;Mx1-Cre mice through suppression of Ifnb1 expression.
Table S1. Elimination of Tnfr1 partially rescues the perinatal lethality of c-FlipF/F;Villin-Cre mice.
Table S2. Genotyping of c-FlipF/F;Alfp-Cre mice that were generated by crossing c-FlipF/+;Alfp-Cre mice with c-FlipF/F mice.
Table S3. Elimination of Tnfr1 does not rescue the perinatal lethality of c-FlipF/F;Alfp-Cre mice.

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Published In

Science Signaling
Volume 5 | Issue 255
December 2012

Submission history

Received: 30 August 2012
Accepted: 30 November 2012

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Acknowledgments

We thank S. Yamaoka, S. Takaki, K. Nakauchi, and K. Takeda for helpful discussion. We also thank Y. Tanno and the members of the Laboratory of Molecular and Biochemical Research, Research Support Center, Juntendo University Graduate School of Medicine, for technical support. Funding: This work was supported in part by a Grant-in-Aid (S1201013) from a MEXT (Ministry of Education, Culture, Sports, Science and Technology)–Supported Program for the Strategic Research Foundation at Private Universities, 2012 to 2017, and Scientific Research (B) (24390100) and Challenging Exploratory Research (23659404) from the Japan Society for the Promotion of Science (JSPS), Scientific Research on Innovative Areas (23117717) from MEXT, Japan, a research grant of the Astellas Foundation for Research on Metabolic Disorders, and the Takeda Science Foundation. Author contributions: X.P., S.K.-S., T.N., M.K., J.-H.P., H.E., H.K., M.H., and Y.U. planned and performed the experiments; N.V.R., G.S., M.O., H.Y., K.O., and Y.-W.H. provided critical reagents; and H.N. designed the project and wrote the manuscript. Competing interests: The authors declare that they have no competing interests.

Authors

Affiliations

Xuehua Piao
Department of Immunology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Atopy Research Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Sachiko Komazawa-Sakon
Department of Immunology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Takashi Nishina
Department of Immunology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Atopy Research Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Masato Koike
Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Jiang-Hu Piao
Department of Immunology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Department of Immunology, School of Basic Medical Science, Ningxia Medical College, 1160 Shengli Street, Xingqing-Qu, Yinchuan 750004, China.
Hanno Ehlken
University Medical Center Hamburg-Eppendorf, I. Department of Internal Medicine, Martin Str. 52, Hamburg 20246, Germany.
Hidetake Kurihara
Department of Anatomy, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Mutsuko Hara
Atopy Research Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Nico Van Rooijen
Department of Molecular Cell Biology, Faculty of Medicine, Vrije Universiteit, Amsterdam 1081 BT, Netherlands.
Günther Schütz
Department of Molecular Biology of the Cell I, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
Masaki Ohmuraya
Center for Animal Resources and Development, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan.
Yasuo Uchiyama
Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Hideo Yagita
Department of Immunology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Ko Okumura
Department of Immunology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Atopy Research Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
You-Wen He
Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
Hiroyasu Nakano* [email protected]
Department of Immunology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
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.

Notes

*
To whom correspondence should be addressed. E-mail: [email protected]

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