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

Publication ,  Journal Article
Piao, X; Komazawa-Sakon, S; Nishina, T; Koike, M; Piao, J-H; Ehlken, H; Kurihara, H; Hara, M; Van Rooijen, N; Schütz, G; Ohmuraya, M; He, Y-W ...
Published in: Sci Signal
December 18, 2012

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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Published In

Sci Signal

DOI

EISSN

1937-9145

Publication Date

December 18, 2012

Volume

5

Issue

255

Start / End Page

ra93

Location

United States

Related Subject Headings

  • Tumor Necrosis Factor-alpha
  • TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor, Type I
  • Protein Binding
  • Organ Specificity
  • Necrosis
  • NF-kappa B
  • Mice, Mutant Strains
  • Mice
  • Liver
 

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Piao, X., Komazawa-Sakon, S., Nishina, T., Koike, M., Piao, J.-H., Ehlken, H., … Nakano, H. (2012). c-FLIP maintains tissue homeostasis by preventing apoptosis and programmed necrosis. Sci Signal, 5(255), ra93. https://doi.org/10.1126/scisignal.2003558
Piao, Xuehua, Sachiko Komazawa-Sakon, Takashi Nishina, Masato Koike, Jiang-Hu Piao, Hanno Ehlken, Hidetake Kurihara, et al. “c-FLIP maintains tissue homeostasis by preventing apoptosis and programmed necrosis.Sci Signal 5, no. 255 (December 18, 2012): ra93. https://doi.org/10.1126/scisignal.2003558.
Piao X, Komazawa-Sakon S, Nishina T, Koike M, Piao J-H, Ehlken H, et al. c-FLIP maintains tissue homeostasis by preventing apoptosis and programmed necrosis. Sci Signal. 2012 Dec 18;5(255):ra93.
Piao, Xuehua, et al. “c-FLIP maintains tissue homeostasis by preventing apoptosis and programmed necrosis.Sci Signal, vol. 5, no. 255, Dec. 2012, p. ra93. Pubmed, doi:10.1126/scisignal.2003558.
Piao X, Komazawa-Sakon S, Nishina T, Koike M, Piao J-H, Ehlken H, Kurihara H, Hara M, Van Rooijen N, Schütz G, Ohmuraya M, Uchiyama Y, Yagita H, Okumura K, He Y-W, Nakano H. c-FLIP maintains tissue homeostasis by preventing apoptosis and programmed necrosis. Sci Signal. 2012 Dec 18;5(255):ra93.

Published In

Sci Signal

DOI

EISSN

1937-9145

Publication Date

December 18, 2012

Volume

5

Issue

255

Start / End Page

ra93

Location

United States

Related Subject Headings

  • Tumor Necrosis Factor-alpha
  • TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor, Type I
  • Protein Binding
  • Organ Specificity
  • Necrosis
  • NF-kappa B
  • Mice, Mutant Strains
  • Mice
  • Liver