The Kinase PKCα Selectively Upregulates Interleukin-17A during Th17 Cell Immune Responses

Abstract

SummaryTransforming 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.

MicroRNA-21 promotes Th17 differentiation and mediates experimental autoimmune encephalomyelitis

“…In fact, IL-2 has been shown to promote clonal expansion and effector development of T cells in vivo and has been the growth-supporting cytokine in classical T cell clone-transferred EAE studies (63)(64)(65). Within Th17 cells, downregulation of IL-2 expression by TGF-β occurs by a SMAD-mediated inhibition of gene transcription (20)(21)(22)(23). We found that during Th17 differentiation, miR-21 plays a significant role in the downregulation of IL-2 expression and that the antibody against IL-2 abrogated the observed defect in Th17 differentiation induced by Mir21 -/-T cells.…”

“…TGF-β signals are transduced through activation of the SMAD proteins SMAD-2 and SMAD-3 (18), and enhanced generation of Th17 cells is associated with increased TGF-β-induced SMAD-2/3 activation (19)(20)(21). In addition, TGF-β signaling has been shown to downregulate IL-2 expression and abrogate IL-2-mediated suppression of Th17 differentiation (20)(21)(22)(23). However, the role that microRNAs (miRNAs) play in the activation of TGF-βR signaling in driving Th17 cell development and, consequently, Th17-mediated autoimmunity remains unknown.…”

Phytocomponent 4-hydroxy-3-methoxycinnamaldehyde ablates T-cell activation by targeting protein kinase C-θ and its downstream pathways

“…The absence of PKCα has been reported to selectively inhibit the effector function of Th17 cells at the transcriptional level of IL-17A. Additionally, PKCα has been identified as a critical member of TGFβRI signalling pathway [23]. Thus, isoforms of PKC in T cells are important therapeutic targets for autoimmune pathologies and transplantation [24].…”

Protein kinase C: a regulator of cytoskeleton remodelling and T-cell migration

“…Baier and colleagues [15] showed that the expression of PKCα was up-regulated in murine CD4 + T-cells differentiated into the effector Th17 lineage in vitro. Baier and colleagues [15] showed that the expression of PKCα was up-regulated in murine CD4 + T-cells differentiated into the effector Th17 lineage in vitro.…”