title: Corticosteroids inhibit the production of inflammatory mediators in immature monocyte-derived DC and induce the development of tolerogenic DC3.
abstract: Corticosteroids (CS) are potent immunosuppressive agents that are known to affect T cell-mediated inflammation by the inhibition of proliferation and cytokine production, as well as the immunostimulatory function of monocytes and macrophages. Not much is known of the effect of corticosteroids on dendritic cells (DC), the professional T cell stimulatory antigen-presenting cells. We report that the endogenous CS hydrocortisone and the synthetic CS clobetasol-17-propionate strongly inhibited the production of the inflammatory mediators interleukin (IL)-12 p70, tumor necrosis factor alpha (TNF-alpha), and IL-6 by lipopolysaccharide (LPS)-stimulated monocyte-derived immature DC (iDC) in vitro. In contrast, the stimulatory capacity, antigen uptake, and the expression of costimulatory molecules were not affected. In accordance with the decreased production of IL-12 p70, CS-treated iDC induced less production of the inflammatory Th1 cytokine interferon-y and enhanced levels of the Th2 cytokines IL-10 and IL-5 in staphylococcal enterotoxin B-stimulated CD4+ Th cells. Furthermore, CS inhibited the maturation of iDC as assessed by the lack of expression of CD83 as well as by the prevention of the loss of antigen uptake capacities. These type 3 DC (DC3) matured in the presence of CS produce less IL-12 p70 and have a decreased T cell stimulatory capacity. Moreover, uncommitted T cells that encounter the CS-induced DC3 develop into Th2-biased cells, which may additionally decrease the Th1-mediated tissue damage but, on the other hand, Th2 cytokines may promote undesirable elevation of IgE and eosinophilia. These findings indicate that suppression of T cell-mediated inflammation by CS not only relies on direct effects on T cells, but also on various effects on DC, their professional antigen-presenting cells.
authors.affiliation: Academic Medical Centre, University of Amsterdam, Department of Cell Biology and Histology, The Netherlands.
authors.forename: E C
authors.initials: EC
authors.lastname: de Jong
authors.forename: P L
authors.initials: PL
authors.lastname: Vieira
authors.forename: P
authors.initials: P
authors.lastname: Kalinski
authors.forename: M L
authors.initials: ML
authors.lastname: Kapsenberg
mesh_terms: D002454:Cell Differentiation; D002990:Clobetasol / Q000031:analogs & derivatives* / Q000494:pharmacology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D007108:Immune Tolerance; D018664:Interleukin-12 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D005938:Glucocorticoids; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D002990:Clobetasol; D006854:Hydrocortisone