Cyclic AMP and Cyclic GMP suppress TNFα-induced hepatocyte apoptosis by inhibiting FADD up-regulation via a protein kinase A-dependent pathway

Y. Wang, Peter K.M. Kim, X. Peng, P. Loughran, Y. Vodovotz, B. Zhang, T. R. Billiar*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Cyclic AMP (cAMP) and cyclic GMP (cGMP) suppress apoptosis in many cell types, including hepatocytes. We have previously shown that membrane-permeable cAMP and cGMP analogs attenuate tumor necrosis factor α plus actinomycin D (TNFα/ActD)-induced apoptosis in hepatocytes at a step upstream of caspase activation and cytochrome c release. Recently we have also shown that FADD levels increase 10 folds in response to TNFα/ActD. Therefore we hypothesized that cAMP and cGMP would inhibit FADD upregulation. We show here that cyclic nucleotide analogs dibutyryl cAMP (db-cAMP) and 8-bromo-cGMP (Br-cGMP) inhibit cell death and the cleavages of multiple caspases including caspase-10, -9, -8, -3, and -2, as well as suppress FADD protein up-regulation in TNFα/ActD-induced apoptosis. The inhibitory effects of cAMP were seen at lower concentrations than cGMP. Both cAMP and cGMP prevented FADD overexpression and cell death in hepatocytes transfected with the FADD gene. A protein kinase A (PKA) inhibitor, KT 5720, reversed the inhibition of FADD protein levels induced by cAMP or cGMP. In conclusion, our findings indicate that cAMP and cGMP prevent TNFα/ActD-induced apoptosis in hepatocytes and that this occurs in association with a near complete inhibition of the upregulation of FADD via a PKA-dependent mechanism.

Original languageEnglish
Pages (from-to)441-451
Number of pages11
JournalApoptosis
Volume11
Issue number3
DOIs
StatePublished - Mar 2006
Externally publishedYes

Keywords

  • Cyclic AMP
  • Cyclic GMP
  • FADD
  • Hepatocytes
  • PKA

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