title: Upregulation of KSRP by miR-27b provides IFN-γ-induced post-transcriptional regulation of CX3CL1 in liver epithelial cells.
abstract: Aberrant cellular responses to pro-inflammatory cytokines, such as IFN-γ, are pathogenic features in many chronic inflammatory diseases. A variety of feedback regulatory pathways have evolved to prevent an inappropriate cellular reaction to these pro-inflammatory cytokines. CX3CL1 is a unique chemokine and plays an important role in chronic liver diseases. We report here that IFN-γ stimulation induces a transient CX3CL1 production in liver epithelial cells (i.e., hepatocytes and biliary epithelial cells). This transient CX3CL1 production is accompanied with a destabilization of CX3CL1 mRNA associated with the induction of the KH-type splicing regulatory protein (KSRP). IFN-γ treatment of liver epithelial cells decreases expression level of miR-27b, a miRNA that targets the 3' untranslated region of KSRP mRNA resulting in translational suppression. Induction of KSRP following IFN-γ stimulation depends on the downregulation of miR-27b. Functional manipulation of KSRP or miR-27b caused reciprocal alterations in CX3CL1 mRNA stability in liver epithelial cells. Moreover, transfection of miR-27b precursor influences CX3CL1-associated chemotaxis effects of biliary epithelial cells to Jurkat T cells. These findings suggest that miR-27b-mediated post-transcriptional suppression controls the expression of KSRP in liver epithelial cells, and upregulation of KSRP destabilizes CX3CL1 mRNA, providing fine-tuning of cellular inflammatory reactions in response to IFN-γ stimulation.
authors.affiliation: School of Basic Medical Sciences, Wuhan University, Hubei 430071, China.
authors.forename: Zijie
authors.initials: Z
authors.lastname: Xia
authors.affiliation: School of Basic Medical Sciences, Wuhan University, Hubei 430071, China.
authors.forename: Yajing
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Institute of Hematology, Union Hospital, Tongji Medical School, Huazhong University of Science and Technology, Wuhan, Hubei 430000, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Li
authors.affiliation: School of Basic Medical Sciences, Wuhan University, Hubei 430071, China.
authors.forename: Tiebo
authors.initials: T
authors.lastname: Mao
authors.affiliation: Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, NE 68178, USA.
authors.forename: Xian-Ming
authors.initials: XM
authors.lastname: Chen
authors.affiliation: School of Basic Medical Sciences, Wuhan University, Hubei 430071, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhou
mesh_terms: D000818:Animals; D054428:Chemokine CX3CL1 / Q000235:genetics* / Q000378:metabolism; D002633:Chemotaxis / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism* / Q000494:pharmacology; D008099:Liver / Q000166:cytology* / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D020871:RNA Stability / Q000187:drug effects; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C515538:CX3CL1 protein, human; D054428:Chemokine CX3CL1; C105789:KHSRP protein, human; C531388:MIRN27 microRNA, human; D035683:MicroRNAs; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D007371:Interferon-gamma