title: Loss of autophagy enhances MIF/macrophage migration inhibitory factor release by macrophages.
abstract: MIF (macrophage migration inhibitory factor [glycosylation-inhibiting factor]) is a pro-inflammatory cytokine expressed in multiple cells types, including macrophages. MIF plays a pathogenic role in a number of inflammatory diseases and has been linked to tumor progression in some cancers. Previous work has demonstrated that loss of autophagy in macrophages enhances secretion of IL1 family cytokines. Here, we demonstrate that loss of autophagy, by pharmacological inhibition or siRNA silencing of Atg5, enhances MIF secretion by monocytes and macrophages. We further demonstrate that this is dependent on mitochondrial reactive oxygen species (ROS). Induction of autophagy with MTOR inhibitors had no effect on MIF secretion, but amino acid starvation increased secretion. This was unaffected by Atg5 siRNA but was again dependent on mitochondrial ROS. Our data demonstrate that autophagic regulation of mitochondrial ROS plays a pivotal role in the regulation of inflammatory cytokine secretion in macrophages, with potential implications for the pathogenesis of inflammatory diseases and cancers.
authors.affiliation: a Lupus Research Group, Center for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Faculty of Medicine, Nursing and Health Sciences, Monash University , Clayton , Victoria , Australia.
authors.forename: Jacinta P W
authors.initials: JP
authors.lastname: Lee
authors.affiliation: a Lupus Research Group, Center for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Faculty of Medicine, Nursing and Health Sciences, Monash University , Clayton , Victoria , Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Foote
authors.affiliation: a Lupus Research Group, Center for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Faculty of Medicine, Nursing and Health Sciences, Monash University , Clayton , Victoria , Australia.
authors.forename: Huapeng
authors.initials: H
authors.lastname: Fan
authors.affiliation: b Immune Regulation Research Group, Department of Biochemistry and Immunology, Trinity College , Dublin , Ireland.
authors.forename: Celia
authors.initials: C
authors.lastname: Peral de Castro
authors.affiliation: a Lupus Research Group, Center for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Faculty of Medicine, Nursing and Health Sciences, Monash University , Clayton , Victoria , Australia.
authors.forename: Tali
authors.initials: T
authors.lastname: Lang
authors.affiliation: a Lupus Research Group, Center for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Faculty of Medicine, Nursing and Health Sciences, Monash University , Clayton , Victoria , Australia.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Jones
authors.affiliation: a Lupus Research Group, Center for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Faculty of Medicine, Nursing and Health Sciences, Monash University , Clayton , Victoria , Australia.
authors.forename: Nichita
authors.initials: N
authors.lastname: Gavrilescu
authors.affiliation: b Immune Regulation Research Group, Department of Biochemistry and Immunology, Trinity College , Dublin , Ireland.
authors.forename: Kingston H G
authors.initials: KH
authors.lastname: Mills
authors.affiliation: a Lupus Research Group, Center for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Faculty of Medicine, Nursing and Health Sciences, Monash University , Clayton , Victoria , Australia.
authors.forename: Michelle
authors.initials: M
authors.lastname: Leech
authors.affiliation: a Lupus Research Group, Center for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Faculty of Medicine, Nursing and Health Sciences, Monash University , Clayton , Victoria , Australia.
authors.forename: Eric F
authors.initials: EF
authors.lastname: Morand
authors.affiliation: a Lupus Research Group, Center for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Faculty of Medicine, Nursing and Health Sciences, Monash University , Clayton , Victoria , Australia.
authors.forename: James
authors.initials: J
authors.lastname: Harris
mesh_terms: D000596:Amino Acids / Q000172:deficiency; D000818:Animals; D001343:Autophagy; D006801:Humans; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D000067996:RAW 264.7 Cells; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000596:Amino Acids; D008263:Macrophage Migration-Inhibitory Factors; D017382:Reactive Oxygen Species
keywords: LPS; autophagosome; cytokines; inflammation; macrophage; reactive oxygen species; starvation