title: Tristetraprolin regulates interleukin-6 expression through p38 MAPK-dependent affinity changes with mRNA 3' untranslated region.
abstract: Tristetraprolin (TTP) is a well-characterized, zinc finger-containing, RNA-binding protein. TTP targets tumor necrosis factor α for degradation via the 3' untranslated region (3'UTR). Although AU-rich elements (AREs) in the 3'UTR of interleukin-6 (IL-6) mRNA dictate mRNA degradation, the role of TTP in the post-transcriptional regulation of IL-6 gene expression is unclear. Here we used TTP-deficient mice to test the hypothesis that IL-6 expression is influenced by TTP. Genetic and siRNA-mediated knockdown of TTP resulted in increased IL-6 production and overexpression of TTP had the reverse effect. IL-6 and tumor necrosis factor α production were elevated after injection of IL-1β in TTP-deficient mice. Further, embryonic fibroblasts from these mice (mouse embryonic fibroblasts) exhibited greater IL-6 mRNA expression and longer half-life than wild-type mouse embryonic fibroblasts. Overexpression of TTP reduced IL-6 3'UTR luciferase reporter activity in an ARE-dependent manner. Proximal and distal regions of the 3'UTR acted synergistically to produce the full repression of TTP. Mutation-based luciferase assays show that ARE2, ARE3, and ARE4 are required for TTP-mediated repression. The constitutively activated p38-MK2 pathway abrogated TTP-mediated repression of IL-6 3'UTR reporter activity. RNA immunoprecipitation assay indicated that the deficiency of p38α resulted in the increased affinity of TTP to IL-6 mRNA. Taken together, we propose that TTP downregulates IL-6 gene expression at the post-transcriptional level by targeting ARE elements in the 3'UTR region.
authors: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.
authors: Wenpu
authors: W
authors: Zhao
authors: Min
authors: M
authors: Liu
authors: Nisha J
authors: NJ
authors: D'Silva
authors: Keith L
authors: KL
authors: Kirkwood
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D019076:Transgenes / Q000235:genetics; D051816:Tristetraprolin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D015850:Interleukin-6; D034741:RNA, Small Interfering; D051816:Tristetraprolin; D048051:p38 Mitogen-Activated Protein Kinases