Viral Infection Increases Glucocorticoid-Induced Interleukin-10 Production through ERK-Mediated Phosphorylation of the Glucocorticoid Receptor in Dendritic Cells: Potential Clinical Implications

Sinnie Sin Man Ng,George N Pavlakis,Keiko Ozato,Tomoshige Kino,Andrew Li

doi:10.1371/journal.pone.0063587

Sinnie Sin Man Ng, George N Pavlakis + Show 3 more

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https://doi.org/10.1371/journal.pone.0063587

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Journal: PloS one	Publication Date: May 8, 2013
Citations: 69	License type: CC0 1.0

Affiliation: National Institutes of Health

Abstract

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.

Highlights

Glucocorticoids (GCs), end products of the hypothalamicpituitary-adrenal (HPA) axis, play a central role in the body’s adaptive response to changes in external and internal environment, called ‘‘stressors’’ [1]
We focused on dendritic cells (DCs), central components of the immune response against pathogen infection, and found that viral infection potently enhanced GC-induced expression of IL-10 and other glucocorticoid-responsive genes by phosphorylating glucocorticoid receptor (GR) through activation of extracellular signal-regulated kinase (ERK)
To study the effect of GC treatment and viral infection on DCmediated immune response, we first pre-treated FMS-like tyrosine kinase 3 ligand (FLT3L)-induced bone marrow-derived DCs with DEX, infected with Newcastle disease virus (NDV), and quantitatively measured mRNA expression of 89 genes whose products play important roles in the Toll-like receptors (TLRs) signaling pathways and anti-pathogen response promoted by these cells

Summary

Introduction

Glucocorticoids (GCs), end products of the hypothalamicpituitary-adrenal (HPA) axis, play a central role in the body’s adaptive response to changes in external and internal environment, called ‘‘stressors’’ [1]. Infection of pathogens, such as of viruses and bacteria, is one of such external stressors, potently activating the HPA axis and inducing subsequent secretion of GCs from the adrenal cortex. Pathogens stimulate central part of thisregulatory system (e.g., brain hypothalamus and pituitary corticotrophs) directly with their structural and genetic components, and indirectly with cytokines and inflammatory mediators secreted from activated immune cells and infected tissues [2]. Actions of the GR are under strict regulation by other signaling pathways with various modes of actions, including phosphorylation of its N-terminal domain by several serine/ threonine kinases [8]

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