The kinase PKC? selectively upregulates interleukin-17A during Th17 cell immune responses.

ABSTRACT: Transforming growth-factor ? (TGF?) 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? receptor (TGF?R) signaling has been implicated in Th17-cell-mediated autoimmune pathogenesis. Nevertheless, the full molecular mechanisms involved in the activation of the TGF?R pathway in driving IL-17A expression remain unknown. Here, we identified protein kinase C ? (PKC?) as a signaling intermediate specific to the Th17 cell subset in the activation of TGF?RI. We have shown that PKC? physically interacts and functionally cooperates with TGF?RI to promote robust SMAD2-3 activation. Furthermore, PKC?-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.

SUBMITTER: Meisel M 

PROVIDER: S-EPMC3556779 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature