Chronic exposure to glucocorticoids shapes gene expression and modulates innate and adaptive activation pathways in macrophages with distinct changes in leukocyte attraction

Martijn D B van de Garde, Fernando O Martinez, Barbro N Melgert, Machteld N Hylkema, René E Jonkers, Jörg Hamann

Onderzoeksoutput: ArticleAcademicpeer review

59 Citaten (Scopus)

Samenvatting

Glucocorticoids (GCs) have been used for more than 50 y as immunosuppressive drugs, yet their efficacy in macrophage-dominated disorders, such as chronic obstructive pulmonary disease, is debated. Little is known how long-term GC treatment affects macrophage responses in inflammatory conditions. In this study, we compared the transcriptome of human macrophages, matured in the presence or absence of fluticasone propionate (FP), and their ability to initiate or sustain classical activation, mimicked using acute LPS and chronic IFN-γ stimulation, respectively. We identified macrophage gene expression networks, modulated by FP long-term exposure, and specific patterns of IFN-γ- and LPS-induced genes that were resistant, inhibited, or exacerbated by FP. Results suggest that long-term treatment with GCs weakens adaptive immune signature components of IFN-γ and LPS gene profiles by downmodulating MHC class II and costimulatory molecules, but strengthens innate signature components by maintaining and increasing expression of chemokines involved in phagocyte attraction. In a mouse model of chronic obstructive pulmonary disease, GC treatment induced higher chemokine levels, and this correlated with enhanced recruitment of leukocytes. Thus, GCs do not generally suppress macrophage effector functions, but they cause a shift in the innate-adaptive balance of the immune response, with distinct changes in the chemokine-chemokine receptor network.

Originele taal-2English
Pagina's (van-tot)1196-1208
Aantal pagina's13
TijdschriftJournal of Immunology
Volume192
Nummer van het tijdschrift3
DOI's
StatusPublished - 1-feb-2014

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