title: IFN-γ primes macrophage activation by increasing phosphatase and tensin homolog via downregulation of miR-3473b.
abstract: The classical activation of macrophages, one of major innate effector cells, requires IFN-γ pretreatment (priming) and subsequent TLR stimuli (triggering). The priming effect of IFN-γ can promote macrophages to secrete higher level of proinflammatory cytokines but lower level of the anti-inflammatory cytokines, enhancing microbicidal and tumoricidal activity of macrophages. However, the underlying molecular mechanisms for IFN-γ-priming effect on macrophage activation remain to be fully understood. microRNAs (miRNAs) are now emerging as important regulators in immune response, including signaling transduction in immune cell function. In this study, we explored the effect of IFN-γ on miRNA expression profiling in macrophages and tried to identify the definite miRNA involved in the priming effect of IFN-γ. We discovered that miR-3473b, which was significantly downregulated after IFN-γ priming, could attenuate the priming effect of IFN-γ. miR-3473b promoted Akt/glycogen synthase kinase 3 signaling and IL-10 production through directly targeting phosphatase and tensin homolog (PTEN) to suppress activation of macrophages and inflammatory response. Our data indicate that IFN-γ beefs up macrophage innate response and cytotoxicity by downregulating miR-3473b to release PTEN from suppression, and then the increase of PTEN contributes to the full activation of IFN-γ-primed macrophages. Our results provide mechanistic insight to priming effect of IFN-γ on macrophage classical activation by identifying an IFN-γ/miR-3473b/PTEN regulatory loop in the regulation of macrophage function.
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China; Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; and.
authors.forename: Cong
authors.initials: C
authors.lastname: Wu
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China;
authors.forename: Yiquan
authors.initials: Y
authors.lastname: Xue
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China;
authors.forename: Pin
authors.initials: P
authors.lastname: Wang
authors.affiliation: National Key Laboratory of Medical Molecular Biology, Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China.
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China;
authors.forename: Qiuyan
authors.initials: Q
authors.lastname: Liu
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China;
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; and.
authors.forename: Junfang
authors.initials: J
authors.lastname: Xu
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China; Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; and National Key Laboratory of Medical Molecular Biology, Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China caoxt@immunol.org.
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology*; D016753:Interleukin-10 / Q000096:biosynthesis; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009369:Neoplasms / Q000276:immunology; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000276:immunology*; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology; D034622:RNA Interference; D034741:RNA, Small Interfering
chemical_list: D016207:Cytokines; C000593133:MIRN3473 microRNA, mouse; D035683:MicroRNAs; D034741:RNA, Small Interfering; D016753:Interleukin-10; D007371:Interferon-gamma; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse