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

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.

Expression of Raf kinase inhibitor protein is downregulated in response to Newcastle disease virus infection to promote viral replication

“…Earlier findings showed NDV infection induced phosphorylation of IkBa, a crucial player in the activation of the IkBa/NF-kB signalling axis, and ERK1/2, a kinase for the activation of Raf/MEK/ERK signalling (Ng et al, 2013;Paulmann et al, 2014). To get insight into the pathway of RKIP-related inhibition of virus replication, we set out to confirm whether NDV infection-induced phosphorylation of IkBa and ERK1/2 also applied under the conditions used here.…”

IL10, TGF Beta1, and IFN Gamma Modulate Intracellular Signaling Pathways and Cytokine Production to Control Toxoplasma gondii Infection in BeWo Trophoblast Cells1

“…Mesenchymal stem cells from rat bone marrow down-modulated the maturation of murine dendritic cells when IL10 triggered the JAK1/STAT3 signaling pathway [44]. Furthermore, IL10 and STAT3 are involved in the increased susceptibility to infections caused by Leishmania amazonensis, Leishmania donovani, the Newcastle disease virus, and Listeria monocytogenes [45][46][47][48]. According to our present data, IL10 also promoted higher infectivity during T. gondii infection in murine dendritic cells [49], and increased IL10 levels were associated with the high susceptibility to reinfection with different recombinant T. gondii strains in BALB/c mice [50].…”

Regulator Versus Effector Paradigm: Interleukin-10 as Indicator of the Switching Response

“…The IL-10 is shown as crucial factor inhibiting the harmful effect of innate proinflammatory immune response only in a T helper (Th) 1-dominated milieu, but not if the balance is shifted toward a Th2 response [70]. Notably, studies on DCs have demonstrated that Th2 induction and modulation of migrating lymph DCs responses are controlled more strongly by the pathogen encountered than the DC subsets [58,65,73,74]. Similarly to DCs, effector CD8+ T cell response is inhibited during H5N1 viral infection by IL-10 producing CD8+ Treg cells [75,76].…”

“…Similarly to DCs, effector CD8+ T cell response is inhibited during H5N1 viral infection by IL-10 producing CD8+ Treg cells [75,76]. The induced manipulation toward the Th2 profile assures increased surviving possibility for different infective agents, such as viruses, chlamydias, and parasites [65, 67-69, 73,74,[77][78][79]. The early IL-10 production by T cell, B cell, and monocyte/macrophage (but not on NK and DC) activation can lead to chronicity of lymphocytic choriomeningitis and B hepatitis virus infections, and the IL-10-mediated early T cell Similarly to viral infections, parasite-induced IL-10 production by various immune cells is associated with impaired resistance to protozoan and nematodes [80,81,86,87].…”

“…The IL-10 shifts (activates or suppresses) innate and adaptive immunity of central and peripheral immune system in an immediate and effective way from the view-point of organism, tumor, or infective agent [57, 81,89,135,160,162,163]. Thus, induction of IL-10 mRNA by DCs has been observed only 3 h after infection with Newcastle disease virus [74]. The IL-10 also stimulated macrophage phenotype switch between days 1 and 4 of post-injury, demonstrating a central role in regulating the switch of immune cells [164].…”