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

Hsing Chuan Tsai, Sharlene Velichko, Shanshan Lee, Reen Wu

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

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 T helper type 17-skewing dendritic cells and activate interleukin-17A (IL-17A) production in CD4+ T cells through 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 protein kinase A (PKA) inhibitor (H89) and different cAMP analogues: a PKA-specific activator (N6-benzoyl-adenosine-cAMP), an exchange protein activated by cAMP-specific activator (Rp-8-chlorophenylthio-2'-O-methyl cAMP), and a PKA inhibitor (Rp-8-bromo-cAMP), to elucidate the signalling cascade of cAMP in IL-17A regulation in T cells. We found that CT induced IL-17A production and IL-17A promoter activity in activated CD4+ T cells through a cAMP/PKA pathway. Moreover, this regulation was via cAMP-response element binding protein (CREB) -mediated transcriptional activation by using the transfection of an IL-17A promoter-luciferase reporter construct and CREB small interfering RNA in Jurkat cells. Also, we showed that CREB bound 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 through the cAMP/PKA/CREB signalling pathway. Our study also highlights the potentials of CT and cAMP in modulating T helper type 17 responses in vivo.

Original languageEnglish (US)
JournalImmunology
DOIs
StateAccepted/In press - Jan 1 2018

Keywords

  • CAMP
  • CAMP-response element binding protein
  • Cholera toxin
  • Interleukin-17A-expressing CD8 T cells
  • Protein kinase A
  • T helper type 17 cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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