PKC-alpha controls MYD88-dependent TLR/IL-1R signaling and cytokine production in mouse and human dendritic cells.
Eur J Immunol
; 40(2): 505-15, 2010 Feb.
Article
em En
| MEDLINE
| ID: mdl-19950169
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Células Dendríticas
/
Proteína Quinase C
/
Citocinas
/
Receptores de Interleucina-1
/
Receptores Toll-Like
/
Fator 88 de Diferenciação Mieloide
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Eur J Immunol
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
Bélgica