Posttranscriptional regulation of IL-23 expression by IFN-gamma through tristetraprolin.

ABSTRACT: IL-23 plays an essential role in maintenance of IL-17-producing Th17 cells that are involved in the pathogenesis of several autoimmune diseases. Regulation of Th17 cells is tightly controlled by multiple factors such as IL-27 and IFN-?. However, the detailed mechanisms responsible for IFN-?-mediated Th17 cell inhibition are still largely unknown. In this study, we demonstrate that IFN-? differentially regulates IL-12 and IL-23 production in both dendritic cells and macrophages. IFN-? suppresses IL-23 expression by selectively targeting p19 mRNA stability through its 3'-untranslated region (3'UTR). Furthermore, IFN-? enhances LPS-induced tristetraprolin (TTP) mRNA expression and protein production. Overexpression of TTP suppresses IL-23 p19 mRNA expression and p19 3'UTR-dependent luciferase activity. Additionally, deletion of TTP completely abolishes IFN-?-mediated p19 mRNA degradation. We further demonstrate that IFN-? suppresses LPS-induced p38 phosphorylation, and blockade of p38 MAPK signaling pathway with SB203580 inhibits IFN-?- and LPS-induced p19 mRNA expression, whereas overexpression of p38 increases p19 mRNA expression via reducing TTP binding to the p19 3'UTR. Finally, inhibition of p38 phosphorylation by IFN-? leads to TTP dephosphorylation that could result in stronger binding of the TTP to the adenosine/uridine-rich elements in the p19 3'UTR and p19 mRNA degradation. In summary, our results reveal a direct link among TTP, IFN-?, and IL-23, indicating that IFN-?-mediated Th17 cell suppression might act through TTP by increasing p19 mRNA degradation and therefore IL-23 inhibition.

SUBMITTER: Qian X 

PROVIDER: S-EPMC3914637 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature