title: c-FLIP maintains tissue homeostasis by preventing apoptosis and programmed necrosis.
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.
authors.affiliation: Department of Immunology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Xuehua
authors.initials: X
authors.lastname: Piao
authors.forename: Sachiko
authors.initials: S
authors.lastname: Komazawa-Sakon
authors.forename: Takashi
authors.initials: T
authors.lastname: Nishina
authors.forename: Masato
authors.initials: M
authors.lastname: Koike
authors.forename: Jiang-Hu
authors.initials: JH
authors.lastname: Piao
authors.forename: Hanno
authors.initials: H
authors.lastname: Ehlken
authors.forename: Hidetake
authors.initials: H
authors.lastname: Kurihara
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Hara
authors.forename: Nico
authors.initials: N
authors.lastname: Van Rooijen
authors.forename: Günther
authors.initials: G
authors.lastname: Schütz
authors.forename: Masaki
authors.initials: M
authors.lastname: Ohmuraya
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchiyama
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.forename: You-Wen
authors.initials: YW
authors.lastname: He
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Nakano
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism*; D053181:Caspase 8; D003092:Colitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053222:Fas Ligand Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006505:Hepatitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006706:Homeostasis; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009336:Necrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity / Q000187:drug effects / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506387:Cflar protein, mouse; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D053221:TNF-Related Apoptosis-Inducing Ligand; C506236:Tnfrsf1a protein, mouse; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C505526:Casp8 protein, mouse; D053181:Caspase 8