title: Autophagy regulates IL-23 secretion and innate T cell responses through effects on IL-1 secretion.
abstract: Autophagy controls IL-1β secretion by regulating inflammasome activation and by targeting pro-IL-1β for degradation. In this article, we show that inhibition of autophagy, either with the PI3K inhibitors 3-methyladenine, wortmannin, and LY294002 or with small interfering RNA against autophagy proteins augmented the secretion of IL-23 by human and mouse macrophages and dendritic cells in response to specific TLR agonists. This process occurred at the transcriptional level and was dependent on reactive oxygen species and IL-1R signaling; it was abrogated with an IL-1R antagonist or with IL-1-neutralizing Abs, whereas treatment with either rIL-1α or IL-1β induced IL-23 secretion. Dendritic cells treated with LPS and 3-methyladenine secreted enhanced levels of both IL-1β and IL-23, and supernatants from these cells stimulated the innate secretion of IL-17, IFN-γ, and IL-22 by γδ T cells. These data demonstrate that autophagy has a potentially pivotal role to play in the induction and regulation of inflammatory responses by innate immune cells, largely driven by IL-1 and its consequential effects on IL-23 secretion.
authors.affiliation: Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin 2, Ireland.
authors.forename: Celia
authors.initials: C
authors.lastname: Peral de Castro
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Jones
authors.forename: Clíona
authors.initials: C
authors.lastname: Ní Cheallaigh
authors.forename: Claire A
authors.initials: CA
authors.lastname: Hearnden
authors.forename: Laura
authors.initials: L
authors.lastname: Williams
authors.forename: Jan
authors.initials: J
authors.lastname: Winter
authors.forename: Ed C
authors.initials: EC
authors.lastname: Lavelle
authors.forename: Kingston H G
authors.initials: KH
authors.lastname: Mills
authors.forename: James
authors.initials: J
authors.lastname: Harris
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000276:immunology*; D002460:Cell Line; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D005260:Female; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D053582:Interleukin-1alpha / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D053759:Interleukin-23 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
chemical_list: C508585:IL1B protein, human; D018836:Inflammation Mediators; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D053759:Interleukin-23; C025946:3-methyladenine; D000225:Adenine