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 α (PKCα) as a signaling intermediate specific to the Th17 cell subset in the activation of TGFβRI. We have shown that PKCα physically interacts and functionally cooperates with TGFβRI to promote robust SMAD2-3 activation. Furthermore, PKCα-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.
|Titolo:||The kinase PKCα selectively upregulates interleukin-17A during Th17 cell immune responses|
|Parole Chiave:||Animals ; Encephalomyelitis, Autoimmune, Experimental ; Gene Expression Regulation ; Interleukin-17 ; Mice ; Mice, Knockout ; Myelin-Oligodendrocyte Glycoprotein ; Peptide Fragments ; Protein Kinase C-alpha ; Receptors, Transforming Growth Factor beta ; Signal Transduction ; Smad Proteins ; Substrate Specificity ; Th17 Cells|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||24-gen-2013|
|Digital Object Identifier (DOI):||10.1016/j.immuni.2012.09.021|
|Appare nelle tipologie:||01 - Articolo su periodico|