title: 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-γ. However, the detailed mechanisms responsible for IFN-γ-mediated Th17 cell inhibition are still largely unknown. In this study, we demonstrate that IFN-γ differentially regulates IL-12 and IL-23 production in both dendritic cells and macrophages. IFN-γ suppresses IL-23 expression by selectively targeting p19 mRNA stability through its 3'-untranslated region (3'UTR). Furthermore, IFN-γ 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-γ-mediated p19 mRNA degradation. We further demonstrate that IFN-γ suppresses LPS-induced p38 phosphorylation, and blockade of p38 MAPK signaling pathway with SB203580 inhibits IFN-γ- 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-γ 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-γ, and IL-23, indicating that IFN-γ-mediated Th17 cell suppression might act through TTP by increasing p19 mRNA degradation and therefore IL-23 inhibition.
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, Saint Louis University School of Medicine, St Louis, MO 63104, USA.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Qian
authors.forename: Huan
authors.initials: H
authors.lastname: Ning
authors.forename: Jidong
authors.initials: J
authors.lastname: Zhang
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hoft
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Stumpo
authors.forename: Perry J
authors.initials: PJ
authors.lastname: Blackshear
authors.forename: Jianguo
authors.initials: J
authors.lastname: Liu
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002460:Cell Line; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007371:Interferon-gamma / Q000494:pharmacology*; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D053765:Interleukin-12 Subunit p35 / Q000235:genetics / Q000378:metabolism; D053759:Interleukin-23 / Q000235:genetics* / Q000378:metabolism; D053760:Interleukin-23 Subunit p19 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010766:Phosphorylation / Q000187:drug effects; D020871:RNA Stability / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects; D051816:Tristetraprolin / Q000235:genetics* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D053765:Interleukin-12 Subunit p35; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D008070:Lipopolysaccharides; D051816:Tristetraprolin; D018664:Interleukin-12; D007371:Interferon-gamma; D048051:p38 Mitogen-Activated Protein Kinases