PKCδ Mediates NF-κB Inflammatory Response and Downregulates SIRT1 Expression in Liver Fibrosis

The precise mechanism of hepatic cirrhosis remains largely unclear. In particular, a potential regulatory mechanism by which protein kinase C-delta (PKC delta ) affects profibrogenic gene expression involved in hepatic cirrhosis has never been explored. In the present study, we investigated whether PKC delta activation is involved in liver inflammatory fibrosis in both lipopolysaccharide (LPS)-treated RAW 264.7 and CCl4-treated mice. PKC delta was strongly activated by LPS or CCl4 treatment and consequently stimulated nuclear factor (NF)-kappa B inflammatory response. Interestingly, the activation of PKC delta negatively regulated sirtuin-1 (SIRT1) expression, whereas PKC delta suppression by PKC delta peptide inhibitor V1-1 or siRNA dramatically increased SIRT1 expression. Furthermore, we showed that the negative regulation of PKC delta leads to a decrease in SIRT1 expression. To our knowledge, these results are the first demonstration of the involvement of PKC delta in modulating NF-kappa B through SIRT1 signaling in fibrosis in mice, suggesting a novel role of PKC delta in inflammatory fibrosis. The level of NF-kappa B p65 in the nucleus was also negatively regulated by SIRT1 activity. We showed that the inhibition of PKC delta promoted SIRT1 expression and decreased p65 levels in the nucleus through deacetylation. Moreover, the inactivation of PKC delta with V1-1 dramatically suppressed the inflammatory fibrosis, indicating that PKC delta represents a promising target for treating fibrotic diseases like hepatic cirrhosis.