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J Immunol. 2012 Jun 15;188(12):5887-97. doi: 10.4049/jimmunol.1102941. Epub 2012 May 14.

Protein kinase C-θ promotes Th17 differentiation via upregulation of Stat3.

Author information

1
Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.

Abstract

Although protein kinase C-θ (PKC-θ)-deficient mice are resistant to the induction of Th17-dependent experimental autoimmune encephalomyelitis, the function of PKC-θ in Th17 differentiation remains unknown. In this article, we show that purified, naive CD4 PKC-θ(-/-) T cells were defective in Th17 differentiation, whereas Th1 and Th2 differentiation appeared normal. Activation of PKC-θ with PMA promoted Th17 differentiation in wild type (WT) but not PKC-θ(-/-) T cells. Furthermore, PKC-θ(-/-) T cells had notably lower levels of Stat3, a transcription factor required for Th17 differentiation, and PMA markedly stimulated the expression of Stat3 in WT but not PKC-θ(-/-) T cells. In contrast, activation of Stat4 and Stat6, which are critical for Th1 and Th2 differentiation, was normal in PKC-θ(-/-) T cells. Forced expression of Stat3 significantly increased Th17 differentiation in PKC-θ(-/-) T cells, suggesting that reduced Stat3 levels were responsible for impaired Th17 differentiation, and that Stat3 lies downstream of PKC-θ. Constitutively active PKC-θ, or WT PKC-θ activated by either PMA or TCR cross-linking, stimulated expression of a luciferase reporter gene driven by the Stat3 promoter. PKC-θ-mediated activation of the Stat3 promoter was inhibited by dominant-negative AP-1 and IκB kinase-β, but stimulated by WT AP-1 and IκB kinase-β, suggesting that PKC-θ stimulates Stat3 transcription via the AP-1 and NF-κB pathways. Lastly, conditions favoring Th17 differentiation induced the highest activation level of PKC-θ. Altogether, the data indicate that PKC-θ integrates the signals from TCR signaling and Th17 priming cytokines to upregulate Stat3 via NF-κB and AP-1, resulting in the stimulation of Th17 differentiation.

PMID:
22586032
PMCID:
PMC3484892
DOI:
10.4049/jimmunol.1102941
[Indexed for MEDLINE]
Free PMC Article

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