3 years ago

Cholera toxin enhances IL-17A production in both CD4+ and CD8+ cells via a cAMP/PKA-mediated IL-17A promoter activation

Shanshan Lee, Hsing-Chuan Tsa, Reen Wu, Sharlene Velichko
Cholera toxin (CT) is a bacterial component that increases intracellular cAMP levels in host cells and suppresses T cell activation. Recently, CT was reported to induce Th17-skewing dendritic cells and activate IL-17A production in CD4+ T cells via a cAMP-dependent pathway. However, the underlying mechanism by which cAMP regulates IL-17A production in T cells is not completely defined. In this study, we took advantage of a small molecule PKA inhibitor (H89) and different cAMP analogs: a PKA-specific activator (N6-Benzoyl-adenosine-cAMP), a EPAC-specific activator (Rp-8-Chlorophenylthio-2′-O-methyl cAMP), and a PKA inhibitor (Rp-8-Bromo-cAMP), to elucidate the signaling cascade of cAMP in IL-17A regulation in T cells. We found that CT induces IL-17A production and IL-17A promoter activity in activated CD4+ T cells via a cAMP/PKA pathway. Moreover, this regulation was via CREB-meidated transcriptional activation by utilizing the transfection of IL-17A promoter-luciferase reporter construct and CREB siRNA in Jurkat cells. Also, we also showed that CREB binded to the CRE motif located at -183 of the IL-17A promoter in vitro. Most interestingly, not only in CD4+ T cells, CT also enhanced cAMP/PKA dependent IL-17A production and CREB phosphorylation in CD8+ T cells. In conclusion, our data suggest that CT induces an IL-17A-dominated immune microenvironment via cAMP/PKA/CREB signaling pathway. Our study also highlights the potentials of CT and cAMP in modulating Th17 responses in vivo. This article is protected by copyright. All rights reserved.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/imm.12900

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