title: TGF-beta and vitamin D3 utilize distinct pathways to suppress IL-12 production and modulate rapid differentiation of human monocytes into CD83+ dendritic cells.
abstract: We previously demonstrated that agents known to signal infection or inflammation can rapidly and directly drive differentiation of human CD14+ monocytes into CD83+ dendritic cells (DCs) when introduced to cells under serum-free conditions. In this study, we evaluated the effects of TGF-beta and vitamin D3 (VitD3) on the proportion and function of monocytes that adopt DC characteristics. TGF-beta significantly decreased the proportion of cells that rapidly adopted stable DC characteristics in response to LPS, but had little or no effect on calcium ionophore-induced differentiation. In contrast, VitD3 showed no such pathway specificity and dramatically suppressed differentiation of monocytes into DCs in response to these agents. Both TGF-beta and VitD3 altered cytokine and chemokine production in LPS-treated monocytes, inhibited IL-12 and IL-10 secretion, and decreased the functional capacity of DCs. Despite the similar effects of TGF-beta and VitD3, there are significant differences in the signaling pathways used by these agents, as evidenced by their distinct effects on LPS- and calcium ionophore-induced DC differentiation, on LPS-induced secretion of IL-10, and on two members of the NF-kappaB family of transcription factors, RelB and cRel. These studies identify TGF-beta and VitD3 as potent regulatory factors that use distinct pathways to suppress both the differentiation of DCs as well as their capacity to secrete the Th1-polarizing cytokine IL-12. Because these agents are present in serum and negatively affect DC differentiation at physiological concentrations, our findings are likely to have significance regarding the in vivo role of TGF-beta and VitD3 in determining the type of immune responses.
authors.affiliation: Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Lyudmila A
authors.initials: LA
authors.lastname: Lyakh
authors.forename: Michael
authors.initials: M
authors.lastname: Sanford
authors.forename: Sebel
authors.initials: S
authors.lastname: Chekol
authors.forename: Howard A
authors.initials: HA
authors.lastname: Young
authors.forename: Anita B
authors.initials: AB
authors.lastname: Roberts
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000502:physiology*; D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis*; D007155:Immunologic Factors / Q000502:physiology*; D016130:Immunophenotyping; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007959:Lymphocyte Culture Test, Mixed; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D015398:Signal Transduction / Q000276:immunology*; D051785:Smad Proteins; D051193:Toll-Like Receptors; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000097802:CD83 Antigen
chemical_list: D015703:Antigens, CD; D002762:Cholecalciferol; D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins; D007136:Immunoglobulins; D007155:Immunologic Factors; D018664:Interleukin-12; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D051785:Smad Proteins; D051193:Toll-Like Receptors; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases; D000097802:CD83 Antigen