The Kinase PKC[alpha] Selectively Upregulates Interleukin-17A during Th17 Cell Immune Responses

Transforming growth-factor β (TGFβ) has been implicated in T helper 17 (Th17) cell biology and in triggering expression of interleukin-17A (IL-17A), which is a key Th17 cell cytokine. Deregulated TGFβ receptor (TGFβR) signaling has been implicated in Th17-cell-mediated autoimmune pathogenesis. Never...

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Published in:Immunity (Cambridge, Mass.) Mass.), 2013-01, Vol.38 (1), p.41
Main Authors: Meisel, Marlies, Hermann-Kleiter, Natascha, Hinterleitner, Reinhard, Gruber, Thomas, Wachowicz, Katarzyna, Pfeifhofer-Obermair, Christa, Fresser, Friedrich, Leitges, Michael, Soldani, Cristiana, Viola, Antonella, Kaminski, Sandra, Baier, Gottfried
Format: Article
Language:English
Subjects:
Cytokines
Immune system
Kinases
Pathogenesis
Phosphorylation
Proteins
Regulation
Transcription factors
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Summary:Transforming growth-factor β (TGFβ) has been implicated in T helper 17 (Th17) cell biology and in triggering expression of interleukin-17A (IL-17A), which is a key Th17 cell cytokine. Deregulated TGFβ receptor (TGFβR) signaling has been implicated in Th17-cell-mediated autoimmune pathogenesis. Nevertheless, the full molecular mechanisms involved in the activation of the TGFβR pathway in driving IL-17A expression remain unknown. Here, we identified protein kinase C [alpha] (PKC[alpha]) as a signaling intermediate specific to the Th17 cell subset in the activation of TGFβRI. We have shown that PKC[alpha] physically interacts and functionally cooperates with TGFβRI to promote robust SMAD2-3 activation. Furthermore, PKC[alpha]-deficient (Prkca-/-) cells demonstrated a defect in SMAD-dependent IL-2 suppression, as well as decreased STAT3 DNA binding within theIl17apromoter. Consistently,Prkca-/-cells failed to mount appropriate IL-17A, but not IL-17F, responses in vitro and were resistant to induction of Th17-cell-dependent experimental autoimmune encephalomyelitis in vivo.
ISSN:1074-7613
1097-4180
DOI:10.1016/j.immuni.2012.09.021