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PKC-alpha controls MYD88-dependent TLR/IL-1R signaling and cytokine production in mouse and human dendritic cells.
- Source :
-
European journal of immunology [Eur J Immunol] 2010 Feb; Vol. 40 (2), pp. 505-15. - Publication Year :
- 2010
-
Abstract
- 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, Gö6976 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-kappaB- and AP-1-driven promoter activities in TLR2-expressing human embryonic kidney 293 T cells. Dominant negative PKC-alpha inhibited NF-kappaB 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 IkappaB kinase-alpha/beta phosphorylations and IkappaBalpha 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.
- Subjects :
- Adaptor Proteins, Vesicular Transport genetics
Adaptor Proteins, Vesicular Transport metabolism
Animals
Carbazoles pharmacology
Cell Line
Cells, Cultured
Dendritic Cells cytology
Enzyme Inhibitors pharmacology
Humans
Immunoblotting
Intracellular Signaling Peptides and Proteins metabolism
Membrane Proteins metabolism
Mice
Mice, Inbred C57BL
Mice, Inbred Strains
Mice, Knockout
Mitogen-Activated Protein Kinases metabolism
Myeloid Differentiation Factor 88 genetics
Myristoylated Alanine-Rich C Kinase Substrate
NF-kappa B metabolism
Phosphorylation
Protein Kinase C antagonists & inhibitors
Receptors, Interleukin-1 genetics
Reverse Transcriptase Polymerase Chain Reaction
Toll-Like Receptors genetics
Transcription Factor AP-1 metabolism
Cytokines metabolism
Dendritic Cells metabolism
Myeloid Differentiation Factor 88 metabolism
Protein Kinase C metabolism
Receptors, Interleukin-1 metabolism
Toll-Like Receptors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1521-4141
- Volume :
- 40
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- European journal of immunology
- Publication Type :
- Academic Journal
- Accession number :
- 19950169
- Full Text :
- https://doi.org/10.1002/eji.200939391