Posttranscriptional Regulation of IL-23 Expression by IFN-gamma through Tristetraprolin

作者：Qian Xuesong; Ning Huan; Zhang Jidong; Hoft Daniel F; Stumpo Deborah J; Blackshear Perry J; Liu Jianguo^*

来源：The Journal of Immunology, 2011, 186(11): 6454-6464.

DOI：10.4049/jimmunol.1002672

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-gamma. However, the detailed mechanisms responsible for IFN-gamma-mediated Th17 cell inhibition are still largely unknown. In this study, we demonstrate that IFN-gamma differentially regulates IL-12 and IL-23 production in both dendritic cells and macrophages. IFN-gamma suppresses IL-23 expression by selectively targeting p19 mRNA stability through its 3'-untranslated region (3'UTR). Furthermore, IFN-gamma 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-gamma-mediated p19 mRNA degradation. We further demonstrate that IFN-gamma suppresses LPS-induced p38 phosphorylation, and blockade of p38 MAPK signaling pathway with SB203580 inhibits IFN-gamma- and LPS-induced p19 mRNA expression, whereas over-expression of p38 increases p19 mRNA expression via reducing TTP binding to the p19 3'UTR. Finally, inhibition of p38 phosphorylation by IFN-gamma 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-gamma, and IL-23, indicating that IFN-gamma-mediated Th17 cell suppression might act through TTP by increasing p19 mRNA degradation and therefore IL-23 inhibition. The Journal of Immunology, 2011, 186: 6454-6464.

• 出版日期2011-6-1