The hypothalamic-pituitary-adrenal axis plays a central role in the adaptive response to stress including infection of pathogens through glucocorticoids. Physical and/or mental stress alter susceptibility to viral infection possibly by affecting this regulatory system, thus we explored potential cellular targets and mechanisms that underlie this phenomenon in key immune components dendritic cells (DCs). Dexamethasone (DEX) treatment and subsequent Newcastle disease virus (NDV) infection most significantly and cooperatively stimulated mRNA expression of the interleukin (IL)-10 in murine bone marrow-derived DCs among 89 genes involved in the Toll-like receptor signaling pathways. NDV increased DEX-induced IL-10 mRNA and protein expression by 7- and 3-fold, respectively, which was observed from 3 hours after infection. Conventional DCs (cDCs), but not plasmacytoid DCs (pDCs) were major sources of IL-10 in bone marrow-derived DCs treated with DEX and/or infected with NDV. Murine cytomegalovirus and DEX increased serum IL-10 cooperatively in female mice. Pre-treatment of DCs with the extracellular signal-regulated kinase (ERK) inhibitor U0126 abolished cooperative induction of IL-10 by DEX and NDV. Further, ERK overexpression increased IL-10 promoter activity stimulated by wild-type human GR but not by its mutant defective in serine 203, whereas ERK knockdown abolished NDV/DEX cooperation on IL-10 mRNA and phosphorylation of the mouse GR at serine 213. NDV also increased DEX-induced mRNA expression of three known glucocorticoid-responsive genes unrelated to the Toll-like receptor signaling pathways in DCs. These results indicate that virus and glucocorticoids cooperatively increase production of anti-inflammatory cytokine IL-10 by potentiating the transcriptional activity of GR in DCs, through which virus appears to facilitate its own propagation in infected hosts. The results may further underlie in part known exacerbation of IL-10/T helper-2-related allergic disorders by stress and viral infection.
Glucocorticoids (GC) are end-products of the HPA axis, which play central roles in stress response, including pathogen infection, and are widely used as therapeutic agents for inflammatory diseases. It is known that stressed condition altered the susceptibility to viral infection. Since it is not known how GC influence the function of DCs upon viral infection, we infected murine DC with Newcastle disease virus (NDV) in the presence of glucocorticoid receptor (GR) ligand dexamethasone (Dex), and examined mRNA expression of 84 genes, which play various roles in the TLR signaling cascade. We found that NDV infection potently induced mRNA expression of 24 genes. Among them, 7 genes (interferon (IFN)-γ, interleukin (IL)-6, IL-10, lymphotoxin A, C-type lectin domain family 4, nuclear factor of κ light chain gene enhancer in B cell inhibitor β and prostaglandin-endoperoxidase synthase 2) were further up- or down-regulated by Dex pre-treatment. Particularly on IL-10, Dex synergistically up-regulated NDV-induced mRNA by 7-fold. The Dex effect was mediated by GR, as inhibitor RU 486 abolished the effect. In contrast to IFN-γ and IL-6, which are Th1 cytokines and response at early time point (6 h), kinetics of IL-10 mRNA showed the highest synergistic effect of NDV and Dex at a later time point (24 h). ELISA results showed consistent results with mRNA expression. Taken together, our study indicates that GC modulate host immunity, altering TLR-related gene expression in DCs.
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