Journal
SCIENCE SIGNALING
Volume 5, Issue 255, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.2003558
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Funding
- MEXT (Ministry of Education, Culture, Sports, Science and Technology)-Supported Program for the Strategic Research Foundation at Private Universities [S1201013, 24390100]
- Japan Society for the Promotion of Science (JSPS), Scientific Research on Innovative Areas from MEXT, Japan [23659404, 23117717]
- Astellas Foundation for Research on Metabolic Disorders
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [23659404, 23390041, 23790238, 24591214, 24390100, 23390260, 23659102] Funding Source: KAKEN
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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-alpha (TNF-alpha) 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-alpha, 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-alpha, FasL, and TRAIL.
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