• Ya-Ching Hsieh, Yen-Hsu Chen, Hsiao-Ching Jao, Hseng-Kuang Hsu, Li-Ju Huang, and Chin Hsu.
• Department of Physiology, Kaohsiung Medical University, Kaohsiung, 807 Taiwan.
• Shock. 2005 Oct 1;24(4):357-63.

AbstractPrevious studies have shown that a decrease in protein kinase C (PKC) alpha levels contributes to hepatic failure and/or apoptosis during sepsis, and suppression of PKCalpha plays a critical role in triggering caspase-dependent apoptosis, which can modulate expression of Bcl-xL. However, the underlying molecular mechanism remains uncertain. In the present study, we examined whether a decrease in the nuclear PKCalpha levels causes hepatic apoptosis via modulation of cAMP-response element-binding protein (CREB) or nuclear factor-kappaB (NFkappaB), the crucial factors regulating the expression of prosurvival Bcl-xL. For polymicrobial sepsis induction, a cecal ligation and puncture model was used; at 9 or 18 h after CLP, experiments were terminated, referring as early or late sepsis, respectively. Additionally, PKCalpha was suppressed by stable transfection of antisense PKCalpha plasmid into a Clone-9 rat hepatic epithelial cell. The results showed that the nuclear PKCalpha was significantly decreased in the liver during sepsis, which was accompanied by decreases in phospho-CREB content, DNA-binding activity of CREB, and Bcl-xL expression. Likewise, the binding activity of NFkappaB increased significantly, which was associated with a decrease in cytosolic inhibitory-kappaBalpha content. The in vitro suppression of PKCalpha also resulted in decreases in the phospho-CREB content and DNA-binding activity, which were accompanied by down-regulation of Bcl-xL and apoptosis, but no significant alteration in NFkappaB-binding activity. The in vivo and in vitro results suggest that the suppression of PKCalpha results in a decreased CREB phosphorylation and subsequent down-regulation of Bcl-xL, which may contribute to the hepatic apoptosis during sepsis.

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