title: Downregulated expression of microRNA-124 in pediatric intestinal failure patients modulates macrophages activation by inhibiting STAT3 and AChE.
abstract: Intestinal inflammation plays a critical role in the pathogenesis of intestinal failure (IF). The macrophages are essential to maintain the intestinal homeostasis. However, the underlying mechanisms of intestinal macrophages activation remain poorly understood. Since microRNAs (miRNAs) have pivotal roles in regulation of immune responses, here we aimed to investigate the role of miR-124 in the activation of intestinal macrophages. In this study, we showed that the intestinal macrophages increased in pediatric IF patients and resulted in the induction of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). The miRNA fluorescence in situ hybridization analysis showed that the expression of miR-124 significantly reduced in intestinal macrophages in IF patients. Overexpression of miR-124 was sufficient to inhibit intestinal macrophages activation by attenuating production of IL-6 and TNF-α. Further studies showed that miR-124 could directly target the 3'-untranslated region of both signal transducer and activator of transcription 3 (STAT3) and acetylcholinesterase (AChE) mRNAs, and suppress their protein expressions. The AChE potentially negates the cholinergic anti-inflammatory signal by hydrolyzing the acetylcholine. We here showed that intestinal macrophages increasingly expressed the AChE and STAT3 in IF patients when compared with controls. The inhibitors against to STAT3 and AChE significantly suppressed the lipopolysaccharides-induced IL-6 and TNF-α production in macrophages. Taken together, these findings highlight an important role for miR-124 in the regulation of intestinal macrophages activation, and suggest a potential application of miR-124 in pediatric IF treatment regarding as suppressing intestinal inflammation.
authors.affiliation: Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.|Shanghai Institute for Pediatric Research, Shanghai, China.|Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
authors.forename: Yong-Tao
authors.initials: YT
authors.lastname: Xiao
authors.affiliation: Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.|Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.|Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.|Shanghai Institute for Pediatric Research, Shanghai, China.|Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cai
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D002648:Child; D016264:Dextran Sulfate; D015536:Down-Regulation / Q000235:genetics*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D007410:Intestinal Diseases / Q000235:genetics* / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology; D008262:Macrophage Activation / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D000067996:RAW 264.7 Cells; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D015850:Interleukin-6; C509207:MIRN124 microRNA, human; D035683:MicroRNAs; D050796:STAT3 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D016264:Dextran Sulfate; D000110:Acetylcholinesterase