title: The kinase PKCα selectively upregulates interleukin-17A during Th17 cell immune responses.
abstract: 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.
authors.affiliation: Department for Pharmacology and Genetics, Division of Translational Cell Genetics, Medical University of Innsbruck, Innsbruck 6020, Austria.
authors.forename: Marlies
authors.initials: M
authors.lastname: Meisel
authors.forename: Natascha
authors.initials: N
authors.lastname: Hermann-Kleiter
authors.forename: Reinhard
authors.initials: R
authors.lastname: Hinterleitner
authors.forename: Thomas
authors.initials: T
authors.lastname: Gruber
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Wachowicz
authors.forename: Christa
authors.initials: C
authors.lastname: Pfeifhofer-Obermair
authors.forename: Friedrich
authors.initials: F
authors.lastname: Fresser
authors.forename: Michael
authors.initials: M
authors.lastname: Leitges
authors.forename: Cristiana
authors.initials: C
authors.lastname: Soldani
authors.forename: Antonella
authors.initials: A
authors.lastname: Viola
authors.forename: Sandra
authors.initials: S
authors.lastname: Kaminski
authors.forename: Gottfried
authors.initials: G
authors.lastname: Baier
mesh_terms: D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000009:adverse effects; D010446:Peptide Fragments / Q000009:adverse effects; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D013379:Substrate Specificity; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism*
chemical_list: D020381:Interleukin-17; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; C445081:myelin oligodendrocyte glycoprotein (35-55); D051571:Protein Kinase C-alpha