Cyclic Nucleotides Suppress Tumor Necrosis Factor α-Mediated Apoptosis by Inhibiting Caspase Activation and Cytochrome cRelease in Primary Hepatocytes via a Mechanism Independent of Akt Activation
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Discussion
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Implication
In vitro study demonstrates cyclic nucleotides inhibit TNF-alpha-induced apoptosis in primary hepatocytes independent of Akt, suggesting multiple coexisting survival pathways.
Key Points
- To elucidate the intracellular mechanisms through which cyclic nucleotides (cAMP and cGMP) prevent TNF-alpha-induced apoptosis in primary hepatocytes.
- Treated cultured primary hepatocytes with TNF-alpha and actinomycin D alongside cAMP analogs, cGMP analogs, or the adenylyl cyclase activator forskolin.
- Assessed caspase activation, mitochondrial cytochrome c release, and Akt phosphorylation in the presence of PI3K inhibitors (LY294002 and wortmannin) and a PKA inhibitor (KT5720).
- cAMP, cGMP analogs, and forskolin suppressed TNF-alpha-induced apoptosis, caspase cleavage, and mitochondrial cytochrome c release in a dose-dependent manner.
- Inhibition of cyclic nucleotide-induced Akt activation via PI3K inhibitors did not reduce cell survival.
- The PKA inhibitor KT5720 completely blocked cGMP-mediated survival and partially attenuated cAMP-mediated protection.
Cite This Study
Li et al. (2000) studied this question.