title: Rapid lipopolysaccharide-induced differentiation of CD14(+) monocytes into CD83(+) dendritic cells is modulated under serum-free conditions by exogenously added IFN-gamma and endogenously produced IL-10.
abstract: We showed previously that about half of purified CD14(+) peripheral blood monocytes cultured under serum-free conditions and treated with GM-CSF and bacterial LPS rapidly (2 - 4 day) differentiate into CD83(+) dendritic cells (DC). The remaining cells retain the CD14(+)/CD83(-) monocyte/macrophage phenotype. In order to identify factors that influence whether monocytes differentiate into DC or remain on the monocyte/macrophage developmental pathway, we evaluated the effects of exogenously added IFN-gamma and endogenously produced IL-10 on the proportion and function of CD14(+) monocytes that adopt DC characteristics in response to LPS. IFN-gamma priming dramatically increased the proportion of monocytes that adopted stable DC characteristics in response to LPS, improved their T cell allosensitizing capacity, and enhanced levels of secreted IL-12 heterodimer. IFN-gamma priming also suppressed the production of IL-10, a cytokine known to have inhibitory effects on DC differentiation. When monocytes were treated with LPS plus IL-10-neutralizing antibodies, dramatically enhanced DC differentiation, IL-12 secretion, and T cell allosensitizing capacity were observed, mimicking in many respects the effects of IFN-gamma priming. IFN-gamma primed cells still displayed appreciable sensitivity to exogenously added IL-10, suggesting that attenuated IL-10 secretion is partially responsible for the enhancing effects of IFN-gamma. These studies therefore identify IFN-gamma as a DC differentiation co-factor for CD14(+) monocytes, and IL-10 as an autocrine/paracrine inhibitor of DC differentiation, linking these agents for the first time as mutually opposed regulators that govern whether CD14(+) cells differentiate into DC upon contact with LPS or remain on the monocyte/macrophage developmental pathway.
authors.affiliation: Regulation of Cell Growth Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, USA. dendritic_cell@hotmail.com
authors.forename: G K
authors.initials: GK
authors.lastname: Koski
authors.forename: L A
authors.initials: LA
authors.lastname: Lyakh
authors.forename: N R
authors.initials: NR
authors.lastname: Rice
mesh_terms: D000938:Antigen-Presenting Cells / Q000502:physiology; D015703:Antigens, CD; D002454:Cell Differentiation / Q000187:drug effects; D016895:Culture Media, Serum-Free; D003713:Dendritic Cells / Q000187:drug effects* / Q000502:physiology; D004357:Drug Synergism; D006801:Humans; D007136:Immunoglobulins / Q000032:analysis*; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000494:pharmacology*; D016753:Interleukin-10 / Q000502:physiology*; D018950:Lipopolysaccharide Receptors / Q000032:analysis*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D007959:Lymphocyte Culture Test, Mixed; D008562:Membrane Glycoproteins / Q000032:analysis*; D009000:Monocytes / Q000187:drug effects* / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D051841:Transcription Factor RelB; D014157:Transcription Factors / Q000096:biosynthesis; D000097802:CD83 Antigen
chemical_list: D015703:Antigens, CD; D016895:Culture Media, Serum-Free; D007136:Immunoglobulins; D007371:Interferon-gamma; D016753:Interleukin-10; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D051841:Transcription Factor RelB; D014157:Transcription Factors; D000097802:CD83 Antigen; C497593:RELB protein, human