title: IL-10 restricts dendritic cell (DC) growth at the monocyte-to-monocyte-derived DC interface by disrupting anti-apoptotic and cytoprotective autophagic molecular machinery.
abstract: An evolving premise is that cytoprotective autophagy responses are essential to monocyte-macrophage differentiation. Whether autophagy functions similarly during the monocyte-to-dendritic cell (DC) transition is unclear. IL-10, which induces apoptosis in maturing human DCs, has been shown to inhibit starvation-induced autophagy in murine macrophage cell lines. Based on the strict requirement that Bcl-2-mediated anti-apoptotic processes are implemented during the monocyte-to-DC transition, we hypothesized that cytoprotective autophagy responses also operate at the monocyte-DC interface and that IL-10 inhibits both anti-apoptotic and cytoprotective autophagy responses at this critical juncture. In support of our premise, we show that levels of anti-apoptotic Bcl-2 and autophagy-associated LC3 and Beclin-1 proteins are coincidentally upregulated during the monocyte-to-DC transition. Autophagy was substantiated by increased autophagosome visualization after bafilomycin treatment. Moreover, the autophagy inhibitor 3-MA restricted DC differentiation by prompting apoptosis. IL-10 implemented apoptosis that was coincidentally associated with reduced levels of Bcl-2 and widespread disruption of the autophagic flux. During peak apoptosis, IL-10 produced the death of newly committed DCs. However, cells surviving the IL-10 apoptotic schedule were highly phagocytic macrophage-like cells displaying reduced capacity to stimulate allogeneic naïve T cells in a mixed leukocyte reaction, increased levels of LC3, and mature autophagosomes. Thus, IL-10's negative control of DC-driven adaptive immunity at the monocyte-DC interface includes disruption of coordinately regulated molecular networks involved in pro-survival autophagy and anti-apoptotic responses.
authors.affiliation: Biology Department, Farmingdale State College, State University of New York, Farmingdale, NY, 11735, USA.
authors.forename: Carla
authors.initials: C
authors.lastname: Martin
authors.affiliation: Molecular Genetics and Microbiology and Department of Medicine, State University of New York at Stony Brook, Stony Brook, NY, 11794, USA.
authors.forename: Mel Pilar
authors.initials: MP
authors.lastname: Espaillat
authors.affiliation: Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA. Fsantiago1@nshs.edu.
authors.forename: Frances
authors.initials: F
authors.lastname: Santiago-Schwarz
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy; D000071186:Beclin-1; D002450:Cell Communication; D002454:Cell Differentiation; D002478:Cells, Cultured; D019610:Cytoprotection; D003713:Dendritic Cells / Q000276:immunology*; D005786:Gene Expression Regulation; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009000:Monocytes / Q000276:immunology*; D010588:Phagosomes / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016753:Interleukin-10
keywords: Apoptosis; Dendritic cells; Interleukin 10; Macroautophagy; Monocyte–macrophages