Posttranscriptional gene regulation of IL-17 by the RNA-binding protein HuR required for initiation of autoimmune neuroinflammation
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[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Posttranscriptional gene regulation is a critical mechanism of controlling the gene expression. The RNA binding-proteins (RBPs) mediate RNA splicing, localization, stabilization, and translation. Human antigen R (HuR/also known as HuA) is a member of the Hu family of RBPs which also include HuB, HuC, and HuD. HuR is homologous to the Drosophila embryonic lethal abnormal vision (Elav) family. HuR is ubiquitously expressed in all tissues, while HuB, HuC and HuD are expressed primarily in neuronal system. HuR has been shown to play a critical role in cancer and chronic inflammatory diseases such as asthma and colitis. In many diseases, HuR positively regulates the stability of target mRNAs via binding the adenylate-uridylate-rich elements (AREs) present in the 3' untranslated region (UTR). Many inflammatory cytokine mRNAs including TNF-[alpha], IL-4 and IL-13 are direct HuR target. The role of HuR in inflammatory diseases, however, needs to be studied. Interleukin-17 (IL-17), an important inflammatory cytokine, is produced by activated T helper-17 (Th17) cells and other immune cells. IL-17-producing Th17 cells are major contributors to chronic inflammatory and autoimmune diseases, such as multiple sclerosis (MS), rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Although the transcriptional regulation of Th17 cells is well understood, the posttranscriptional regulation of IL-17 gene expression by HuR remains to be elucidated. To better understand if HuR regulates IL-17 gene expression and plays a pathogenic role in IL-17-mediated autoimmune neuroinflammation, we performed in vitro experiments including cell culture, real time PCR, western blot, flow cytometry, and biotin pull-down assay. For in vivo studies, we generated OX40-cre HuRf/f conditional knockout (KO) mice, in which HuR gene was specifically deleted in activated T cells. We used the KO and HuRf/f (control) mice to induce experimental autoimmune encephalomyelitis (EAE), a mouse model for human MS. The results showed that the production of IL
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