RRC ID 11870
Author Johnson J, Molle C, Aksoy E, Goldman M, Goriely S, Willems F.
Title A conventional protein kinase C inhibitor targeting IRF-3-dependent genes differentially regulates IL-12 family members.
Journal Mol. Immunol.
Abstract Protein kinase C (PKC) isoforms play a critical role in the regulation of innate immune responses. We have previously demonstrated that conventional PKC (cPKC) α is involved in interferon regulatory factor 3 (IRF-3) activation and IFN-β synthesis. Herein, we investigated the role of cPKCs in the regulation of IL-12 family members expression mediated by the Toll-like receptor 3 (TLR3) and TLR4. First, inhibition of cPKCs activity in human DCs by a cPKC-specific inhibitor, Gö6976 downregulated the expression of IL-12p70 and IL-27p28 but not IL-12/IL-23p40, IL-23, IL-27EBI3 induced by LPS or poly(I:C). Furthermore, reporter gene assays in RAW 264.7 macrophages showed that cPKCs regulate IL-12p35 and IL-27p28 promoter activities since Gö6976 repressed LPS and poly(I:C)-mediated transcriptional activities of IL-12p35 and IL-27p28. In contrast, no effect was observed with IL-12/IL-23p40 and IL-23p19 reporter constructs. These results prompted us to study the role of IRF-3 on IL-23 expression. Bone marrow-derived DC (BMDCs) from IRF-3(-/-) mice produced comparable levels of IL-23 induced by both LPS and poly(I:C) as compared to wild type BMDCs, indicating that IRF-3 is not involved in IL-23 production. Finally, BMDCs from PKCα(-/-) mice displayed a reduced synthesis of IL-27 induced by poly(I:C). Collectively, these data identify cPKCs as critical components that control IRF-3-dependent IL-12p35 and IL-27p28 gene expression downstream of TLR3 and TLR4.
Volume 48(12-13)
Pages 1484-93
Published 2011-7
DOI 10.1016/j.molimm.2011.04.006
PII S0161-5890(11)00130-1
PMID 21550664
MeSH Animals Carbazoles / pharmacology Dendritic Cells / drug effects Dendritic Cells / immunology Dendritic Cells / metabolism Gene Expression Regulation Interferon Regulatory Factor-3 / metabolism* Interleukin-12 / biosynthesis Interleukin-12 / genetics* Interleukin-12 / metabolism Interleukin-17 / biosynthesis Interleukin-17 / genetics Interleukin-23 / biosynthesis Interleukin-23 / genetics Interleukins / genetics Interleukins / metabolism Lipopolysaccharides / immunology Mice Mice, Transgenic Poly I-C / immunology Polymerase Chain Reaction Protein Kinase C / antagonists & inhibitors* Protein Kinase C / metabolism* Toll-Like Receptor 3 / metabolism Toll-Like Receptor 4 / metabolism Transcription, Genetic / drug effects
IF 3.188
Times Cited 4
Mice IRF-3 knockout mice C57BL/6J