PMID- 29244194 OWN - NLM STAT- MEDLINE DCOM- 20190122 LR - 20201209 IS - 1521-4141 (Electronic) IS - 0014-2980 (Linking) VI - 48 IP - 4 DP - 2018 Apr TI - Arid5a stabilizes OX40 mRNA in murine CD4(+) T cells by recognizing a stem-loop structure in its 3'UTR. PG - 593-604 LID - 10.1002/eji.201747109 [doi] AB - AT-rich interactive domain-containing protein 5a (Arid5a) is an RNA-binding protein (RBP) required for autoimmunity via stabilization of interleukin-6 (Il6) and signal transducer and activator of transcription 3 (STAT3) mRNAs. However, the roles of Arid5a in Th17 cells and its association with autoimmunity remain unknown. Here, we show that the levels of Arid5a and OX40 are correlated in CD4(+) T cells under Th17 conditions in an IL-6-dependent manner. Lack of Arid5a in T cells reduced OX40 expression levels and repressed IL-17 production in response to OX40 ligation. Arid5a stabilized OX40 mRNA by recognizing the alternative decay element (ADE)-like stem-loop (SL) in the 3' untranslated region (3'UTR). Interestingly, Arid5a impaired the RNA-destabilizing functions of Regnase-1 and Roquin-1 on OX40 ADE-like SL. In EAE, Arid5a-deficient mice exhibited resistance to EAE, with reduced OX40 expression in CD4(+) T cells, and the number of CD4(+) CD45(+) T cells was decreased in CNS. Furthermore, ameliorated EAE was induced by adoptive transfer of Arid5a(-/-) encephalitogenic CD4(+) T cells expressing less OX40 mRNA and producing less IL-17. In conclusion, our findings indicate that the Arid5a/OX40 axis in CD4(+) T cells may have important implications in pathogenesis of autoimmune diseases such as EAE. CI - (c) 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. FAU - Hanieh, Hamza AU - Hanieh H AD - Physiology Laboratory, Biological Sciences Department, King Faisal University, 31982, Hofuf, Saudi Arabia. AD - Laboratory of Immune Regulation, World Premier International-Immunology Frontier Research Center, Osaka University, Osaka, 565-0871, Japan. FAU - Masuda, Kazuya AU - Masuda K AD - Laboratory of Immune Regulation, World Premier International-Immunology Frontier Research Center, Osaka University, Osaka, 565-0871, Japan. AD - Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of Pennsylvania, School of Medicine, Philadelphia, PA, 19104, USA. FAU - Metwally, Hozaifa AU - Metwally H AD - Laboratory of Immune Regulation, World Premier International-Immunology Frontier Research Center, Osaka University, Osaka, 565-0871, Japan. FAU - Chalise, Jaya P AU - Chalise JP AD - Laboratory of Immune Regulation, World Premier International-Immunology Frontier Research Center, Osaka University, Osaka, 565-0871, Japan. FAU - Mohamed, Maged AU - Mohamed M AD - Pharmaceutical Sciences Department, King Faisal University, 31982, Hofuf, Saudi Arabia. AD - Pharmacognosy Department, Zagazig University, Zagazig, 44519, Egypt. FAU - Nyati, Kishan K AU - Nyati KK AD - Laboratory of Immune Regulation, World Premier International-Immunology Frontier Research Center, Osaka University, Osaka, 565-0871, Japan. FAU - Standley, Daron M AU - Standley DM AD - Laboratory of System Immunology, World Premier International-Immunology Frontier Research Center, Osaka University, Osaka, 565-0871, Japan. FAU - Li, Songling AU - Li S AD - Laboratory of System Immunology, World Premier International-Immunology Frontier Research Center, Osaka University, Osaka, 565-0871, Japan. FAU - Higa, Mitsuru AU - Higa M AD - Laboratory of Immune Regulation, World Premier International-Immunology Frontier Research Center, Osaka University, Osaka, 565-0871, Japan. FAU - Zaman, Mohammad M AU - Zaman MM AD - Laboratory of Immune Regulation, World Premier International-Immunology Frontier Research Center, Osaka University, Osaka, 565-0871, Japan. FAU - Kishimoto, Tadamitsu AU - Kishimoto T AUID- ORCID: 0000-0002-7862-154X AD - Laboratory of Immune Regulation, World Premier International-Immunology Frontier Research Center, Osaka University, Osaka, 565-0871, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180205 PL - Germany TA - Eur J Immunol JT - European journal of immunology JID - 1273201 RN - 0 (Arid5a protein, mouse) RN - 0 (DNA-Binding Proteins) RN - 0 (Il17a protein, mouse) RN - 0 (Interleukin-17) RN - 0 (Interleukin-6) RN - 0 (Membrane Glycoproteins) RN - 0 (OX40 Ligand) RN - 0 (RNA, Messenger) RN - 0 (RNA, Small Interfering) RN - 0 (RNA-Binding Proteins) RN - 0 (STAT3 Transcription Factor) RN - 0 (Stat3 protein, mouse) RN - 0 (Tnfsf4 protein, mouse) RN - 0 (Transcription Factors) RN - 0 (Tumor Necrosis Factors) RN - 0 (interleukin-6, mouse) RN - EC 2.3.2.27 (Rc3h1 protein, mouse) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) RN - EC 3.1.- (Ribonucleases) RN - EC 3.1.- (Zc3h12a protein, mouse) SB - IM MH - Adoptive Transfer MH - Animals MH - Autoimmunity/genetics/*immunology MH - Cell Line MH - DNA-Binding Proteins/*metabolism MH - Encephalomyelitis, Autoimmune, Experimental/immunology/pathology MH - HEK293 Cells MH - Humans MH - Interleukin-17/biosynthesis MH - Interleukin-6/immunology MH - Inverted Repeat Sequences/genetics MH - Membrane Glycoproteins/*genetics MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - OX40 Ligand MH - RNA Interference MH - RNA, Messenger/genetics MH - RNA, Small Interfering/genetics MH - RNA-Binding Proteins/metabolism MH - Ribonucleases/genetics MH - STAT3 Transcription Factor/genetics/*immunology MH - Th17 Cells/*immunology MH - Transcription Factors/*metabolism MH - Tumor Necrosis Factors/*genetics MH - Ubiquitin-Protein Ligases/genetics OTO - NOTNLM OT - Arid5a OT - EAE OT - IL-17 OT - IL-6 OT - OX40 OT - Th17 EDAT- 2017/12/16 06:00 MHDA- 2019/01/23 06:00 CRDT- 2017/12/16 06:00 PHST- 2017/04/30 00:00 [received] PHST- 2017/10/26 00:00 [revised] PHST- 2017/12/06 00:00 [accepted] PHST- 2017/12/16 06:00 [pubmed] PHST- 2019/01/23 06:00 [medline] PHST- 2017/12/16 06:00 [entrez] AID - 10.1002/eji.201747109 [doi] PST - ppublish SO - Eur J Immunol. 2018 Apr;48(4):593-604. doi: 10.1002/eji.201747109. Epub 2018 Feb 5.