Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 40, Issue 2, Pages 505-515Publisher
WILEY
DOI: 10.1002/eji.200939391
Keywords
MyD88; PKC; TLR
Categories
Funding
- Fonds National de la Recherche Scientifique (Belgium)
- Interuniversity Attraction Pole of the Belgian Federal Science Policy
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Conventional PKC (cPKC)-alpha regulates TRIF-dependent IFN response factor 3 (IRF3)-mediated gene transcription, but its role in MyD88-dependent TLR signaling remains unknown. Herein, we demonstrate that PKC-alpha is induced by several MyD88-dependent TLR/IL-1R ligands and regulates cytokine expression in human and murine DC. First, inhibition of cPKC activity in human DC by cPKC-specific inhibitors, Go6976 or HBDDe, downregulated. the production of classical inflammatory/immunomodulatory cytokines induced by TLR2, TLR5 or IL-1R but not by TLR3 stimulation. Similarly, dominant negative PKC-alpha repressed Pam(3)CSK(4) induced NF-kappa B- and AP-1-driven promoter activities in TLR2-expressing human embryonic kidney 293 T cells. Dominant negative PKC-a inhibited NF-kappa B reporter activity mediated by overexpression of MyD88 but not TRIF. Unexpectedly, BM-derived DC from PKC-alpha(-/-) mice exhibited decreased TNF-alpha and IL-12p40 production induced by both MyD88- and TRIF-dependent ligands. Furthermore, PKC-alpha is coupled to TLR2 signaling proximal to MyD88 since MAPK and I kappa B kinase-alpha/beta phosphorylations and I kappa B alpha degradation were inhibited in PKC-alpha(-/-) BM-derived DC. Finally, co-immunoprecipitation assays revealed that PKC-alpha physically interacts with Pam(3)CSK(4) activated TLR2 in WT but not in MyD88(-/-) DC. Collectively this study identifies a species-specific role of PKC-alpha as a key component that controls MyD88-dependent cytokine gene expression in human and mouse but differentially regulates production of TRIF-dependent cytokines.
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