| First Author | Qian X | Year | 2011 |
| Journal | J Immunol | Volume | 186 |
| Issue | 11 | Pages | 6454-64 |
| PubMed ID | 21515794 | Mgi Jnum | J:173201 |
| Mgi Id | MGI:5013533 | Doi | 10.4049/jimmunol.1002672 |
| Citation | Qian X, et al. (2011) Posttranscriptional Regulation of IL-23 Expression by IFN-{gamma} through Tristetraprolin. J Immunol 186(11):6454-64 |
| abstractText | 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 overexpression 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. |
