c-FLIP maintains tissue homeostasis by preventing apoptosis and programmed necrosis

• Published in: Science signaling Vol. 5; no. 255; p. ra93
• Main Authors: Piao, Xuehua, Komazawa-Sakon, Sachiko, Nishina, Takashi, Koike, Masato, Piao, Jiang-Hu, Ehlken, Hanno, Kurihara, Hidetake, Hara, Mutsuko, Van Rooijen, Nico, Schütz, Günther, Ohmuraya, Masaki, Uchiyama, Yasuo, Yagita, Hideo, Okumura, Ko, He, You-Wen, Nakano, Hiroyasu
• Format: Journal Article
• Language: English
• Published: United States 18.12.2012
• Subjects: Animals; Antibodies, Neutralizing - pharmacology; Apoptosis; CASP8 and FADD-Like Apoptosis Regulating Protein - genetics; CASP8 and FADD-Like Apoptosis Regulating Protein - metabolism; Caspase 8; Colitis - genetics; Colitis - metabolism; Colitis - pathology; Fas Ligand Protein - antagonists & inhibitors; Fas Ligand Protein - genetics; Fas Ligand Protein - metabolism; Hepatitis - genetics; Hepatitis - metabolism; Hepatitis - pathology; Hepatocytes - metabolism; Hepatocytes - pathology; Homeostasis; Intestines - metabolism; Intestines - pathology; Liver - metabolism; Liver - pathology; Mice; Mice, Mutant Strains; Necrosis - genetics; Necrosis - metabolism; Necrosis - pathology; NF-kappa B - genetics; NF-kappa B - metabolism; Organ Specificity - drug effects; Organ Specificity - genetics; Protein Binding - drug effects; Protein Binding - genetics; Receptors, Tumor Necrosis Factor, Type I - genetics; Receptors, Tumor Necrosis Factor, Type I - metabolism; TNF-Related Apoptosis-Inducing Ligand - genetics; TNF-Related Apoptosis-Inducing Ligand - metabolism; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1937-9145
• DOI: 10.1126/scisignal.2003558

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.