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.


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


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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References and Notes

Degterev A., Yuan J., Expansion and evolution of cell death programmes. Nat. Rev. Mol. Cell Biol. 9, 378–390 (2008).
Skaug B., Jiang X., Chen Z. J., The role of ubiquitin in NF-κB regulatory pathways. Annu. Rev. Biochem. 78, 769–796 (2009).
Vallabhapurapu S., Karin M., Regulation and function of NF-κB transcription factors in the immune system. Annu. Rev. Immunol. 27, 693–733 (2009).
Greten F. R., Eckmann L., Greten T. F., Park J. M., Li Z. W., Egan L. J., Kagnoff M. F., Karin M., IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118, 285–296 (2004).
Maeda S., Kamata H., Luo J. L., Leffert H., Karin M., IKKβ couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121, 977–990 (2005).
Luedde T., Beraza N., Kotsikoris V., van Loo G., Nenci A., De Vos R., Roskams T., Trautwein C., Pasparakis M., Deletion of NEMO/IKKγ in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell 11, 119–132 (2007).
Nenci A., Becker C., Wullaert A., Gareus R., van Loo G., Danese S., Huth M., Nikolaev A., Neufert C., Madison B., Gumucio D., Neurath M. F., Pasparakis M., Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446, 557–561 (2007).
Papa S., Bubici C., Zazzeroni F., Pham C. G., Kuntzen C., Knabb J. R., Dean K., Franzoso G., The NF-κB-mediated control of the JNK cascade in the antagonism of programmed cell death in health and disease. Cell Death Differ. 13, 712–729 (2006).
Nakano H., Nakajima A., Sakon-Komazawa S., Piao J. H., Xue X., Okumura K., Reactive oxygen species mediate crosstalk between NF-κB and JNK. Cell Death Differ. 13, 730–737 (2006).
Micheau O., Lens S., Gaide O., Alevizopoulos K., Tschopp J., NF-κB signals induce the expression of c-FLIP. Mol. Cell. Biol. 21, 5299–5305 (2001).
Chang L., Kamata H., Solinas G., Luo J. L., Maeda S., Venuprasad K., Liu Y. C., Karin M., The E3 ubiquitin ligase Itch couples JNK activation to TNFα-induced cell death by inducing c-FLIPL turnover. Cell 124, 601–613 (2006).
Nakajima A., Komazawa-Sakon S., Takekawa M., Sasazuki T., Yeh W. C., Yagita H., Okumura K., Nakano H., An antiapoptotic protein, c-FLIPL, directly binds to MKK7 and inhibits the JNK pathway. EMBO J. 25, 5549–5559 (2006).
Vandenabeele P., Galluzzi L., Vanden Berghe T., Kroemer G., Molecular mechanisms of necroptosis: An ordered cellular explosion. Nat. Rev. Mol. Cell Biol. 11, 700–714 (2010).
Weinlich R., Dillon C. P., Green D. R., Ripped to death. Trends Cell Biol. 21, 630–637 (2011).
Zhang D. W., Shao J., Lin J., Zhang N., Lu B. J., Lin S. C., Dong M. Q., Han J., RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325, 332–336 (2009).
Cho Y. S., Challa S., Moquin D., Genga R., Ray T. D., Guildford M., Chan F. K., Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137, 1112–1123 (2009).
He S., Wang L., Miao L., Wang T., Du F., Zhao L., Wang X., Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-α. Cell 137, 1100–1111 (2009).
Degterev A., Hitomi J., Germscheid M., Ch’en I. L., Korkina O., Teng X., Abbott D., Cuny G. D., Yuan C., Wagner G., Hedrick S. M., Gerber S. A., Lugovskoy A., Yuan J., Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat. Chem. Biol. 4, 313–321 (2008).
Zhang J., Cado D., Chen A., Kabra N. H., Winoto A., Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1. Nature 392, 296–300 (1998).
Varfolomeev E. E., Schuchmann M., Luria V., Chiannilkulchai N., Beckmann J. S., Mett I. L., Rebrikov D., Brodianski V. M., Kemper O. C., Kollet O., Lapidot T., Soffer D., Sobe T., Avraham K. B., Goncharov T., Holtmann H., Lonai P., Wallach D., Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. Immunity 9, 267–276 (1998).
Yeh W. C., Pompa J. L., McCurrach M. E., Shu H. B., Elia A. J., Shahinian A., Ng M., Wakeham A., Khoo W., Mitchell K., El-Deiry W. S., Lowe S. W., Goeddel D. V., Mak T. W., FADD: Essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science 279, 1954–1958 (1998).
Yeh W. C., Itie A., Elia A. J., Ng M., Shu H. B., Wakeham A., Mirtsos C., Suzuki N., Bonnard M., Goeddel D. V., Mak T. W., Requirement for Casper (c-FLIP) in regulation of death receptor–induced apoptosis and embryonic development. Immunity 12, 633–642 (2000).
Pfeffer K., Matsuyama T., Kündig T. M., Wakeham A., Kishihara K., Shahinian A., Wiegmann K., Ohashi P. S., Krönke M., Mak T. W., Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell 73, 457–467 (1993).
Adachi M., Suematsu S., Kondo T., Ogasawara J., Tanaka T., Yoshida N., Nagata S., Targeted mutation in the Fas gene causes hyperplasia in peripheral lymphoid organs and liver. Nat. Genet. 11, 294–300 (1995).
Kaiser W. J., Upton J. W., Long A. B., Livingston-Rosanoff D., Daley-Bauer L. P., Hakem R., Caspary T., Mocarski E. S., RIP3 mediates the embryonic lethality of caspase-8-deficient mice. Nature 471, 368–372 (2011).
Zhang H., Zhou X., McQuade T., Li J., Chan F. K., Zhang J., Functional complementation between FADD and RIP1 in embryos and lymphocytes. Nature 471, 373–376 (2011).
Degterev A., Huang Z., Boyce M., Li Y., Jagtap P., Mizushima N., Cuny G. D., Mitchison T. J., Moskowitz M. A., Yuan J., Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat. Chem. Biol. 1, 112–119 (2005).
Oberst A., Dillon C. P., Weinlich R., McCormick L. L., Fitzgerald P., Pop C., Hakem R., Salvesen G. S., Green D. R., Catalytic activity of the caspase-8–FLIPL complex inhibits RIPK3-dependent necrosis. Nature 471, 363–367 (2011).
Dillon C. P., Oberst A., Weinlich R., Janke L. J., Kang T. B., Ben-Moshe T., Mak T. W., Wallach D., Green D. R., Survival function of the FADD-CASPASE-8-cFLIPL complex. Cell Rep. 1, 401–407 (2012).
Zhang N., Hopkins K., He Y. W., The long isoform of cellular FLIP is essential for T lymphocyte proliferation through an NF-κB-independent pathway. J. Immunol. 180, 5506–5511 (2008).
Zhang N., He Y. W., An essential role for c-FLIP in the efficient development of mature T lymphocytes. J. Exp. Med. 202, 395–404 (2005).
Schattenberg J. M., Zimmermann T., Wörns M., Sprinzl M. F., Kreft A., Kohl T., Nagel M., Siebler J., Bergkamen H. S., He Y. W., Galle P. R., Schuchmann M., Ablation of c-FLIP in hepatocytes enhances death-receptor mediated apoptosis and toxic liver injury in vivo. J. Hepatol. 55, 1272–1280 (2011).
Madison B. B., Dunbar L., Qiao X. T., Braunstein K., Braunstein E., Gumucio D. L., cis Elements of the villin gene control expression in restricted domains of the vertical (crypt) and horizontal (duodenum, cecum) axes of the intestine. J. Biol. Chem. 277, 33275–33283 (2002).
Kellendonk C., Opherk C., Anlag K., Schütz G., Tronche F., Hepatocyte-specific expression of Cre recombinase. Genesis 26, 151–153 (2000).
Kühn R., Schwenk F., Aguet M., Rajewsky K., Inducible gene targeting in mice. Science 269, 1427–1429 (1995).
Guicciardi M. E., Gores G. J., Apoptosis as a mechanism for liver disease progression. Semin. Liver Dis. 30, 402–410 (2010).
Beraza N., Malato Y., Sander L. E., Al-Masaoudi M., Freimuth J., Riethmacher D., Gores G. J., Roskams T., Liedtke C., Trautwein C., Hepatocyte-specific NEMO deletion promotes NK/NKT cell– and TRAIL-dependent liver damage. J. Exp. Med. 206, 1727–1737 (2009).
Canbay A., Feldstein A. E., Higuchi H., Werneburg N., Grambihler A., Bronk S. F., Gores G. J., Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression. Hepatology 38, 1188–1198 (2003).
Welz P. S., Wullaert A., Vlantis K., Kondylis V., Fernández-Majada V., Ermolaeva M., Kirsch P., Sterner-Kock A., van Loo G., Pasparakis M., FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation. Nature 477, 330–334 (2011).
Gunther C., Martini E., Wittkopf N., Amann K., Weigmann B., Neumann H., Waldner M. J., Hedrick S. M., Tenzer S., Neurath M. F., Becker C., Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis. Nature 477, 335–339 (2011).
Kajino-Sakamoto R., Inagaki M., Lippert E., Akira S., Robine S., Matsumoto K., Jobin C., Ninomiya-Tsuji J., Enterocyte-derived TAK1 signaling prevents epithelium apoptosis and the development of ileitis and colitis. J. Immunol. 181, 1143–1152 (2008).
Nakajima A., Kojima Y., Nakayama M., Yagita H., Okumura K., Nakano H., Downregulation of c-FLIP promotes caspase-dependent JNK activation and reactive oxygen species accumulation in tumor cells. Oncogene 27, 76–84 (2008).
Nell S., Suerbaum S., Josenhans C., The impact of the microbiota on the pathogenesis of IBD: Lessons from mouse infection models. Nat. Rev. Microbiol. 8, 564–577 (2010).
Xavier R. J., Podolsky D. K., Unravelling the pathogenesis of inflammatory bowel disease. Nature 448, 427–434 (2007).
Bettermann K., Vucur M., Haybaeck J., Koppe C., Janssen J., Heymann F., Weber A., Weiskirchen R., Liedtke C., Gassler N., Müller M., de Vos R., Wolf M. J., Boege Y., Seleznik G. M., Zeller N., Erny D., Fuchs T., Zoller S., Cairo S., Buendia M. A., Prinz M., Akira S., Tacke F., Heikenwalder M., Trautwein C., Luedde T., TAK1 suppresses a NEMO-dependent but NF-κB-independent pathway to liver cancer. Cancer Cell 17, 481–496 (2010).
Maeda S., Chang L., Li Z. W., Luo J. L., Leffert H., Karin M., IKKβ is required for prevention of apoptosis mediated by cell-bound but not by circulating TNFα. Immunity 19, 725–737 (2003).
Geisler F., Algül H., Paxian S., Schmid R. M., Genetic inactivation of RelA/p65 sensitizes adult mouse hepatocytes to TNF-induced apoptosis in vivo and in vitro. Gastroenterology 132, 2489–2503 (2007).
Stefanescu R., Bassett D., Modarresi R., Santiago F., Fakruddin M., Laurence J., Synergistic interactions between interferon-γ and TRAIL modulate c-FLIP in endothelial cells, mediating their lineage-specific sensitivity to thrombotic thrombocytopenic purpura plasma–associated apoptosis. Blood 112, 340–349 (2008).
Stefanidou M., Ramos I., Mas Casullo V., Trepanier J. B., Rosenbaum S., Fernandez-Sesma A., Herold B. C., HSV-2 prevents dendritic cell maturation, induces apoptosis and triggers release of pro-inflammatory cytokines: Potential links to HSV-HIV synergy. J. Virol. 10.1128/JVI.01302-12 (2012).
Maedler K., Fontana A., Ris F., Sergeev P., Toso C., Oberholzer J., Lehmann R., Bachmann F., Tasinato A., Spinas G. A., Halban P. A., Donath M. Y., FLIP switches Fas-mediated glucose signaling in human pancreatic β cells from apoptosis to cell replication. Proc. Natl. Acad. Sci. U.S.A. 99, 8236–8241 (2002).
Nishina T., Komazawa-Sakon S., Yanaka S., Piao X., Zheng D. M., Piao J. H., Kojima Y., Yamashina S., Sano E., Putoczki T., Doi T., Ueno T., Ezaki J., Ushio H., Ernst M., Tsumoto K., Okumura K., Nakano H., Interleukin-11 links oxidative stress and compensatory proliferation. Sci. Signal. 5, ra5 (2012).
Sato K., Hida S., Takayanagi H., Yokochi T., Kayagaki N., Takeda K., Yagita H., Okumura K., Tanaka N., Taniguchi T., Ogasawara K., Antiviral response by natural killer cells through TRAIL gene induction by IFN-α/β. Eur. J. Immunol. 31, 3138–3146 (2001).


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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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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.



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.


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

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