Viruses and Glucocorticoids – Interleukin-10 Production
A study published in the May 2013 issue of PLoS One may indicate a novel, unrecognized interaction between viruses and the glucocorticoid (GC)-signaling system that results in the induction of interleukin (IL)-10 production by dendritic cells (DCs).
In this report, Sinnie Ng and colleagues from the National Institutes of Child Health and Human Development, and the National Cancer Institute, National Institutes of Health (NIH), US, evaluated the cooperative effect of GCs and NDV in mouse bone marrow-derived DCs on the expression of 89 genes whose products play important roles in the TLR signaling pathways. Among the genes differentially regulated by DEX and/or NDV, we focused on IL-10, as mRNA expression of this gene showed the most significant change. In addition, DCs are the major immune cells that secrete this cytokine.
The investigators targeted DCs, professional antigen presenting cells that activate T cells and other immune components. Dendritic cells act as sentinels of the immune system, capturing and processing pathogens and presenting their antigens to T cells. Little is known, however, about how GCs regulate the immune response, conducted by DCs, in particular during viral infection.
By using real time PCR and other techniques, the authors found that IL-10 mRNA abundance and IL-10 secretion were strongly upregulated in DCs when they were pretreated with GCs before viral infection. Thus, Newcastle disease virus (NDV) infection enhanced DEX pre-treatment-induced IL-10 mRNA expression and protein production in DCs. 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 (MCMV) and DEX cooperatively enhanced production of IL-10 in mice. NDV activated ERK1/2, phosphorylated human GR at serine 203 (213 in mice) and ultimately increased the transcriptional activity of GR, not only on the IL-10 gene but also on other TLR-unrelated glucocorticoid-responsive genes.
The authors further screened the signaling pathway responsible for this action, and found that extracellular signal-regulated kinase (ERK) inhibitors abolished the cooperation between GCs and viral infection in DCs. This study indicates that viruses and GCs cooperatively increase IL-10 production by potentiating the transcriptional activity of GC receptors in DCs, through which viruses appear to facilitate their own propagation in infected hosts.
It is known that IL-10, a major anti-inflammatory cytokine, has potent immunosuppressive actions. Upon viral infection, circulating levels of IL-10 increase after ∼24 hours to 20 days in mice to facilitate resolution of inflammation promoted by pro-inflammatory cytokines, which are secreted into circulation immediately (∼3–6 hours) after infection
The authors found that cooperation between DEX and NDV on the IL-10 production started as early as 3 hours after the viral infection in DCs. Thus, it is quite possible that some viruses distort normal regulation of IL-10 secretion in these cells through cooperation with GCs, and increase their propagation in host tissues.
Of note, Epstein-Barr virus and the varicella-zoster virus, encode IL-10-like molecules, which share immunosuppressive properties of host IL-10, while persistent infection or the reactivation of Mycobacterium tuberculosis infection is also associated with excessive production of IL-10.
The authors discuss that their results revealing the cooperation of DEX and virus on IL-10 production may in part explain the previous observation that mental/physical stress increases susceptibility to viral infection and tendency to exacerbate/prolong its disease course.
In conclusion, the investigators described a novel cooperation between viral infectionand GCs on the expression of glucocorticoid-responsive genes in DCs through phosphorylation of GR by ERK.
Thus, this study may provide some further insights into mechanisms driving stress-induced increased susceptibility to viral infection as documented by previous research. Furthermore, as the link between viral infections, psychological stress and asthma exacerbations is well-known, the study helps explain this connection as increased IL-10 production and resulting activation of T helper (Th)2-driven humoral immunity play important roles in asthma development.