부산대학교 도서관

Summary: 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. [ABSTRACT FROM AUTHOR]