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

Apoptosis : an International Journal on Programmed Cell Death
Y WangT R Billiar

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 alpha plus actinomycin D (TNFalpha/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 TNFalpha/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 TNFalpha/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 TNFalpha/ActD-induced apoptosis in hepatocytes and that this occurs in association ...Continue Reading

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Citations

Jun 11, 2008·Apoptosis : an International Journal on Programmed Cell Death·Xiaoying ZhangTimothy R Billiar
Oct 17, 2008·Bulletin of Experimental Biology and Medicine·S A KozyrevV V Sherstnev
Aug 21, 2013·Journal of Molecular Neuroscience : MN·Shabnam Zeighamy AlamdaryFariba Khodagholi
May 29, 2012·Biochemical and Biophysical Research Communications·Rajesh BhattacharjeeTimothy R Billiar
Mar 30, 2007·Journal of Oral Pathology & Medicine : Official Publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology·Andreas KaratsaidisKarl Schenck
Feb 1, 2012·Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society·Haofeng JiJerzy W Kupiec-Weglinski
Dec 21, 2010·Journal of Oral Pathology & Medicine : Official Publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology·Robert I Henkin, Irina Velicu
Dec 22, 2014·Pharmacology & Therapeutics·Roland SeifertHeike Bähre

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