The Kinase PKC¦Á Selectively Upregulates Interleukin-17A during Th17 Cell Immune Responses

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• 作者：Marlies Meisel¹ ; Natascha Hermann-Kleiter¹ ; Reinhard Hinterleitner¹ ; Thomas Gruber¹ ; Katarzyna Wachowicz¹ ; Christa Pfeifhofer-Obermair¹ ; Friedrich Fresser¹ ; Michael Leitges² ; Cristiana Soldani³ ; Antonella Viola³ ; Sandra Kaminski¹ ; Gottfried Baier¹ ; ^{gottfried.baier@i-med.ac.at}
• 刊名：Immunity
• 出版年：2013
• 出版时间：24 January, 2013
• 年：2013
• 卷：38
• 期：1
• 页码：41-52
• 全文大小：1495 K

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Summary

Transforming growth-factor ¦Â (TGF¦Â) 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 TGF¦Â receptor (TGF¦ÂR) signaling has been implicated in Th17-cell-mediated autoimmune pathogenesis. Nevertheless, the full molecular mechanisms involved in the activation of the TGF¦ÂR pathway in driving IL-17A expression remain unknown. Here, we identified protein kinase C ¦Á (PKC¦Á) as a signaling intermediate specific to the Th17 cell subset in the?activation of TGF¦ÂRI. We have shown that PKC¦Á physically interacts and functionally cooperates with TGF¦ÂRI to promote robust SMAD2-3 activation.?Furthermore, PKC¦Á-deficient (Prkca^?/?) cells demonstrated a defect in SMAD-dependent IL-2 suppression, as well as decreased STAT3 DNA binding within the Il17a promoter. 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.