title: Exposure of myeloid dendritic cells to exogenous or endogenous IL-10 during maturation determines their longevity.
abstract: Dendritic cells (DC) are essential for the initiation of primary adaptive immune responses, and their functionality is strongly down-modulated by IL-10. Both innate and adaptive immune signals trigger the up-regulation of antiapoptotic Bcl-2 family members to facilitate the survival of DCs after maturation. However, whether IL-10 alters the expression of apoptotic-related genes in maturing DCs has not been determined. In this study, we demonstrate that spontaneous apoptosis rapidly occurred in myeloid DCs exposed to exogenous IL-10 upon maturation. Microarray analysis indicates that IL-10 suppressed the induction of three antiapoptotic genes, bcl-2, bcl-x, and bfl-1, which was coincident with the increased sensitivity of mature DCs to spontaneous apoptosis. IL-10 markedly inhibited the accumulation of steady state Bcl-2 message and protein in myeloid DCs activated through TLRs or TNFR family members, whereas exogenous IL-10 affected Bcl-x(L) expression in a moderate manner. In contrast, bcl-2 expression of plasmacytoid DCs was less sensitive to the effects of IL-10. We further show that autocrine IL-10 significantly limited the longevity of myeloid DCs and altered the expression kinetics of Bcl-2 but not Bcl-x(L) in maturing DCs. We conclude that the degree of IL-10 exposure and/or the level of endogenous IL-10 production upon myeloid DC maturation play a critical role in determining DC longevity. This regulatory mechanism of IL-10 is associated with the dynamic control of antiapoptotic Bcl-2 proteins.
authors.affiliation: Center for Comparative Medicine, University of California-Davis, County Road 98 and Hutchison Drive, Davis, CA 95616, USA. wlchang@ucdavis.edu
authors.forename: W L William
authors.initials: WL
authors.lastname: Chang
authors.forename: Nicole
authors.initials: N
authors.lastname: Baumgarth
authors.forename: Meghan K
authors.initials: MK
authors.lastname: Eberhardt
authors.forename: C Y Daniel
authors.initials: CY
authors.lastname: Lee
authors.forename: Colin A
authors.initials: CA
authors.lastname: Baron
authors.forename: Jeff P
authors.initials: JP
authors.lastname: Gregg
authors.forename: Peter A
authors.initials: PA
authors.lastname: Barry
mesh_terms: D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D039521:CD11c Antigen / Q000032:analysis; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology*; D008213:Lymphocyte Activation; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D019253:Proto-Oncogene Proteins c-bcl-2; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D051020:bcl-X Protein / Q000032:analysis / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D039521:CD11c Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D016753:Interleukin-10