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Protein kinase C alpha is involved in interferon regulatory factor 3 activation and type I interferon-beta synthesis

Journal:
Journal of Biological Chemistry


Issue Date:
2007


Abstract(summary):

Protein kinase C ( PKC) isoforms are critically involved in the regulation of innate immune responses. Herein, we investigated the role of conventional PKC alpha in the regulation of IFN-beta gene expression mediated by the Toll-like receptor 3 ( TLR3) signaling pathway. Inhibition of conventional PKC ( cPKC) activity in monocyte-derived dendritic cells or TLR3-expressing cells by an isoform-specific inhibitor, Go "6976, selectively inhibited IFN-beta synthesis induced by double-stranded RNA polyinosine-polycytidylic acid. Furthermore, reporter gene assays confirmed that PKC alpha regulates IFN-beta promoter activity, since overexpression of dominant negative PKC alpha but not PKC beta(I) repressed interferon regulatory factor 3 ( IRF-3)-dependent but not NF-kappa B-mediated promoter activity upon TLR3 engagement in HEK 293 cells. Dominant negative PKC alpha inhibited IRF-3 transcriptional activity mediated by overexpression of TIR domain-containing adapter inducing IFN-beta and Tank-binding kinase-1. Additional biochemical analysis demonstrated that Go "6976-treated dendritic cells exhibited IRF-3 phosphorylation, dimerization, nuclear translocation, and DNA binding activity analogous to their control counterparts in response to polyinosine-polycytidylic acid. In contrast, co-immunoprecipitation experiments revealed that TLR3-induced cPKC activity is essential for mediating the interaction of IRF-3 but not p65/RelA with the coactivator CREB-binding protein. Furthermore, PKC alpha knockdown with specific small interfering RNA inhibited IFN-beta expression and down-regulated IRF-3-dependent promoter activity, establishing PKC alpha as a component of TLR3 signaling that regulates IFN-beta gene expression by targeting IRF-3-CREB-binding protein interaction. Finally, we analyzed the involvement of cPKCs in other signaling pathways leading to IFN-beta synthesis. These experiments revealed that cPKCs play a role in the synthesis of IFN-beta induced via both TLR-dependent and -independent pathways.


Page:
15022---15032


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