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, Andrew Li, George N. Pavlakis, Keiko Ozato, Tomoshige Kino

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish
Article numbere63587
JournalPLoS One
Volume8
Issue number5
DOIs
Publication statusPublished - 10 May 2013
Externally publishedYes

Fingerprint

Phosphorylation
Extracellular Signal-Regulated MAP Kinases
Glucocorticoid Receptors
Virus Diseases
dendritic cells
interleukin-10
glucocorticoids
mitogen-activated protein kinase
Interleukin-10
Dendritic Cells
Glucocorticoids
Viruses
Newcastle disease virus
phosphorylation
dexamethasone
Dexamethasone
infection
Messenger RNA
Toll-Like Receptors
mice

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Viral Infection Increases Glucocorticoid-Induced Interleukin-10 Production through ERK-Mediated Phosphorylation of the Glucocorticoid Receptor in Dendritic Cells : Potential Clinical Implications. / Ng, Sinnie Sin Man; Li, Andrew; Pavlakis, George N.; Ozato, Keiko; Kino, Tomoshige.

In: PLoS One, Vol. 8, No. 5, e63587, 10.05.2013.

Research output: Contribution to journalArticle

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