Differential signaling of cmvIL‐10 through common variants of the IL‐10 receptor 1

Abstract

Human IL‐10 (hIL‐10) signaling is mediated by receptors consisting of two subunits, IL‐10 receptor 1 (IL‐10R1) and IL‐10 receptor 2. Two common variants of the IL‐10R1 (Ser 138 Gly (single‐nucleotide polymorphism 3, SNP3) and Gly 330 Arg (SNP4)) are associated with diverse disease phenotypes. Viral homologs to hIL‐10, such as cmvIL‐10, utilize the same IL‐10 receptor complex as part of viral immune evasion strategies. For the present study we hypothesized that IL‐10R1 variants alter the ability of viral IL‐10 to utilize the IL‐10R1 signaling pathway. HeLa cell clones expressing different IL‐10R1 haplotypes (WT or any variant) were incubated with hIL‐10 or cmvIL‐10. In cells expressing IL‐10R1‐WT, cmvIL‐10 (both non‐glycosylated‐ and HeLa‐expressed) resulted in equal or slightly stronger STAT3 phosphorylation compared with hIL‐10. In clones expressing IL‐10R1‐SNP3, IL‐10R1‐SNP4 or IL‐10R1‐SNP3+4, the cmvIL‐10 showed significantly less STAT3 phosphorylation, especially when HeLa‐expressed cytokines were used. Time course experiments demonstrated a slower kinetic of cmvIL‐10 STAT3 activation through the variant IL‐10R1. Similarly, IL‐10R1 variants decreased the cmvIL‐10‐induced SOCS3 and signaling lymphocytic activation molecule mRNA expression. These data suggest that the IL‐10R1 variants differentially reduce the signaling activity of cmvIL‐10 and thereby may affect CMV's ability to escape from the host's immune surveillance.

Koi Herpesvirus Encodes and Expresses a Functional Interleukin-10

“…This, and their very different locations in the viral genomes (3,56), suggests that alloherpesvirus IL-10s may have arisen from independent gene capture events and that each has undergone rapid divergent evolution since capture from the host genome. Similar patterns of divergence from host IL-10 sequences have been observed among certain mammalian herpesvirus and poxvirus IL-10 orthologs (49), and this appears to have been driven by functional adaptations that modify their interaction with the host IL-10 receptor, resulting in altered signaling profiles (15,60). There is abundant evidence for a very dynamic genetic interaction between large DNA viruses and their hosts in evolutionary time scales through processes that can result in both the capture and loss of genes (20,24,49).…”

IL-10R1 (Ser138Gly) functional polymorphism is associated with acute myocardial infarction in Tunisian patients

“…Amongst these, SNP3 (rs3135932, c.536A/G, p.S138G) is of particular importance since it maps to exon 4 encoding IL-10R1 receptor domain (7) and has been associated with various diseases (e.g. schizophrenia, progression of fibrosis in chronic hepatitis C...) (8)(9)(10).…”

Regulation of Interleukin-10 Receptor Ubiquitination and Stability by Beta-TrCP-Containing Ubiquitin E3 Ligase

“…C-terminally Flag-tagged IL-10R1 plasmid used throughout in the present study was generated via sub-cloning of hIL-10R1 coding sequence from pIRESpuro3-IL-10R1 (a kind gift from Dr. C Gasche, University of Vienna, Austria [70]) into the pcDNA vector. The Flag-tagged mIL-10R1 was prepared from MIGR1-mIL-10R1 vector (a generous gift from Dr. D Yu, University of Pennsylvania), and also sub-cloned into pcDNA.…”