Critical role of protein kinase C epsilon for lipopolysaccharide-induced IL-12 synthesis in monocyte-derived dendritic cells.
In the present study we have investigated the potential involvement of protein kinase C (PKC) in the maturation of human dendritic cells (DC) by bacterial lipopolysaccharide (LPS). LPS stimulation of DC derived from human monocytes resulted in PKC phosphorylation. Inhibition of PKC activation using bisindolylmaleimide (Bis), a pan-PKC inhibitor, was associated with a dose-dependent decrease of LPS-induced IL-12 production. In contrast, up-regulation of MHC class II, CD80 and CD86 was not altered. Consistent with the diminished IL-12 synthesis, DC stimulated with LPS in presence of Bis were deficient in the induction of IFN-gamma production by allogeneic CD4+ T cells. Furthermore, we found that PKC inhibition impaired LPS-induced I kappa B-alpha degradation and subsequent nuclear factor (NF)-kappa B activation in DC. LPS resulted in the phosphorylation of conventional alpha/beta and novel epsilon PKC isoforms in DC. Inhibition of LPS-induced PKC activity using pseudosubstrate peptides specific for PKC isoforms established that PKC epsilon but not PKC alpha/beta was involved in the production of IL-12 and TNF-alpha. Overall, these data provide evidence that PKC inhibition impairs LPS signaling in DC and identify PKC epsilon as a potential target for the inhibition of Toll-like receptor-4-mediated, IL-12-dependent Th1 type responses.
Aksoy
Ezra
E
Laboratory of Experimental Immunology, Université Libre de Bruxelles, Brussels, Belgium.
Amraoui
Zoulikha
Z
Goriely
Stanislas
S
Goldman
Michel
M
Willems
Fabienne
F
D003713:Dendritic Cells / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D018664:Interleukin-12 / Q000096:biosynthesis*; D007527:Isoenzymes / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009000:Monocytes / Q000166:cytology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D011493:Protein Kinase C / Q000502:physiology*; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D051744:Protein Kinase C-epsilon; D018417:Th1 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D020672:I-kappa B Proteins; D007527:Isoenzymes; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D018664:Interleukin-12; C496628:PRKCA protein, human; C497255:PRKCE protein, human; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D051744:Protein Kinase C-epsilon