title: MiR-34a inhibits lipopolysaccharide-induced inflammatory response through targeting Notch1 in murine macrophages.
abstract: Inflammatory responses are complex events occurring when the host immune system fights against invading pathogens, which are double-edged swords requiring appropriate control. MicroRNAs (miRNAs), emerging as a new layer of gene-regulation mechanism, have been reported to have crucial effects on inflammation. In the current study, we identified miR-34a, previously known for its potent tumor suppressive role, to be a novel inflammation regulator. We found that the expression of miR-34a was downregulated in macrophages after lipopolysaccharide (LPS) stimulation. MiR-34a mimics decreased, while the inhibition of miR-34a increased, the expression of inflammatory cytokines tumor necrosis factor-<alpha> (TNF-<alpha>) and interleukin-6 (IL-6) in LPS treated RAW264.7 cells. Bioinformatics predictions revealed a potential binding site of miR-34a in 3' untranslated region (UTR) of Notch1 and it was further confirmed by luciferase assay. Moreover, both the mRNA and protein level of Notch1 were downregulated by miR-34a in RAW264.7. Subsequently, knockdown of Notch1 with either genetic or pharmacological inhibition exhibited similar effects as miR-34a mimics on LPS-induced macrophage inflammatory response. Furthermore, the NF-κB activation induced by LPS was also significantly suppressed by miR-34a. These results together identify, for the first time, miR-34a as a negative regulator in LPS-induced inflammation at least partially by targeting Notch1. Besides extending the knowledge of miR-34a from tumor suppressor to inflammation regulator, this study also provides an implication that compounds which can enhance miR-34a expression or miR-34a itself may hold a promise in anti-inflammatory drugs development.
authors.affiliation: Department of Immunology, Shanghai Medical College, Key Laboratory of Molecular Medicine of Ministry of Education, Fudan University, Shanghai, People's Republic of China.
authors.forename: Pei
authors.initials: P
authors.lastname: Jiang
authors.forename: Ronghua
authors.initials: R
authors.lastname: Liu
authors.forename: Yijie
authors.initials: Y
authors.lastname: Zheng
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Liu
authors.forename: Lijun
authors.initials: L
authors.lastname: Chang
authors.forename: Shudao
authors.initials: S
authors.lastname: Xiong
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Chu
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D005786:Gene Expression Regulation; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D009690:Nucleic Acid Conformation; D034622:RNA Interference; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D020413:3' Untranslated Regions; D016207:Cytokines; D008070:Lipopolysaccharides; C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D016328:NF-kappa B; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1