Abstract
Epstein Barr virus (EBV) is a gamma herpes virus associated with certain malignancies and autoimmune diseases. EBV maintains latency in B cells with occasional reactivation, in part by overcoming the host immune response with viral homologs of several human proteins. EBV interleukin 10 (vIL-10), a lytic phase protein, is a homolog of human IL-10 (hIL-10). The effect of vIL-10 on human monocytes, which are one of the first immune cells to respond to infection, is not known. To understand the role of vIL-10, monocytes from peripheral blood mononuclear cells were stimulated with hIL-10 or vIL-10. Human IL-10 stimulated STAT3 phosphorylation, which is required for suppression of inflammatory responses. However, vIL-10 induced significantly lower phosphorylation of STAT3 compared to hIL-10, and was less efficient in downregulating inflammatory genes. vIL-10 significantly reduced the expression of scavenger receptor CD163 on monocytes, suggesting inhibition of M2 polarization. Furthermore, uptake of apoptotic cells was reduced in vIL-10-stimulated monocytes compared to hIL-10-stimulated monocytes. A neutralizing antibody to IL-10R1 inhibited STAT3 phosphorylation induced by either hIL-10 or vIL-10, suggesting that vIL-10 signals through IL-10R1. Interestingly, vIL-10 suppressed hIL-10-induced STAT3 phosphorylation and inhibited upregulation of suppressors of inflammatory response by hIL-10. We further show that vIL-10 levels were significantly higher in plasma samples from systemic lupus erythematosus (SLE) patients compared to matched unaffected controls. vIL-10 levels did not correlate with hIL-10 levels, but were associated with levels of IgA antibodies to EBV viral capsid antigen, which is an indirect measure of viral reactivation. We propose that the suppression of hIL-10- induced anti-inflammatory genes by vIL-10, together with an increase in inflammatory gene expression, may overcome the anti-inflammatory effects of hIL-10 and exacerbate autoimmune responses in systemic autoimmune diseases.
Highlights
Epstein Barr virus (EBV) is a highly prevalent gamma herpes virus with over 90% of the adult population being previously exposed to the virus
In this study we examined whether vIL-10 has similar inhibitory effects on monocytes as human interleukin 10 (hIL-10) and whether vIL-10 is associated with systemic lupus erythematosus (SLE)
We confirmed our data using western blot analyses of whole cell lysates from monocytes stimulated with hIL-10 or vIL-10 for phosphorylated STAT3 (pSTAT3) and total STAT3
Summary
Epstein Barr virus (EBV) is a highly prevalent gamma herpes virus with over 90% of the adult population being previously exposed to the virus. EBV encodes homologs of cellular cytokines that allow the virus to escape or curtail host anti-viral responses and to establish latency. One such protein is viral interleukin 10 (vIL10), a homolog of human interleukin 10 (hIL-10). VIL-10, a late lytic phase protein encoded by the BCRF-1 gene, shares ∼80% homology with hIL-10 [7,8,9]. HIL-10 is the founding member of the class II cytokine family, which includes IL-19, IL-20, IL-22, IL-24, and IL-26 [10]. IL-10 is a unique class II cytokine because it potently inhibits the production of pro-inflammatory cytokines such as IFNγ, TNFα, IL-1β, and IL-6, prevents dendritic cell (DC) maturation and inhibits the expression of MHC and co-stimulatory molecules on myeloid cells. IL-10 is a unique class II cytokine because it potently inhibits the production of pro-inflammatory cytokines such as IFNγ, TNFα, IL-1β, and IL-6, prevents dendritic cell (DC) maturation and inhibits the expression of MHC and co-stimulatory molecules on myeloid cells. hIL-10 is a potent growth and differentiation factor for B-cells, mast cells and thymocytes
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