| First Author | Kwon MJ | Year | 2012 |
| Journal | J Immunol | Volume | 188 |
| Issue | 12 | Pages | 5887-97 |
| PubMed ID | 22586032 | Mgi Jnum | J:188872 |
| Mgi Id | MGI:5442479 | Doi | 10.4049/jimmunol.1102941 |
| Citation | Kwon MJ, et al. (2012) Protein kinase C-theta promotes Th17 differentiation via upregulation of Stat3. J Immunol 188(12):5887-97 |
| abstractText | Although protein kinase C-theta (PKC-theta)-deficient mice are resistant to the induction of Th17-dependent experimental autoimmune encephalomyelitis, the function of PKC-theta in Th17 differentiation remains unknown. In this article, we show that purified, naive CD4 PKC-theta(-/-) T cells were defective in Th17 differentiation, whereas Th1 and Th2 differentiation appeared normal. Activation of PKC-theta with PMA promoted Th17 differentiation in wild type (WT) but not PKC-theta(-/-) T cells. Furthermore, PKC-theta(-/-) 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-theta(-/-) T cells. In contrast, activation of Stat4 and Stat6, which are critical for Th1 and Th2 differentiation, was normal in PKC-theta(-/-) T cells. Forced expression of Stat3 significantly increased Th17 differentiation in PKC-theta(-/-) T cells, suggesting that reduced Stat3 levels were responsible for impaired Th17 differentiation, and that Stat3 lies downstream of PKC-theta. Constitutively active PKC-theta, or WT PKC-theta activated by either PMA or TCR cross-linking, stimulated expression of a luciferase reporter gene driven by the Stat3 promoter. PKC-theta-mediated activation of the Stat3 promoter was inhibited by dominant-negative AP-1 and IkappaB kinase-beta, but stimulated by WT AP-1 and IkappaB kinase-beta, suggesting that PKC-theta stimulates Stat3 transcription via the AP-1 and NF-kappaB pathways. Lastly, conditions favoring Th17 differentiation induced the highest activation level of PKC-theta. Altogether, the data indicate that PKC-theta integrates the signals from TCR signaling and Th17 priming cytokines to upregulate Stat3 via NF-kappaB and AP-1, resulting in the stimulation of Th17 differentiation. |
