IL-10-deficient mice exhibit spontaneous enterocolitis and other symptoms akin to Crohn’s disease, indicating that IL-10 might regulate normal physiology in the gut. However, clinical trials with IL-10 in Crohn’s disease were disappointing, although some patients showed healing of intestinal mucosa. This study searched for genetic polymorphisms within the IL-10 pathway. We decided to screen for mutations of the IL-10R1 cDNA in healthy volunteers and Crohn’s disease patients and identified two novel variants: a serine 138-to-glycine (S138G) and a glycine 330-to-arginine (G330R) substitution. The allelic frequency in a European cohort was relatively high (16% for the S138G and 33% for the G330R), and S138G was in strong linkage disequilibrium with G330R. A similar allele frequency was found in a group of Crohn’s patients. In IL-10R1 G330R-expressing monocytes, the inhibitory effect of IL-10 on TNF-α production was diminished, indicating that this variant may be a loss-of-function allele. No such difference was observed between haplotypes 4 (G330R only) and 7 (S138G and G330R). In addition, these IL-10R1 variants had no influence on the IL-10R1 expression density. Structural analysis of the S138G variant revealed that the substitution of S138G may interfere with binding of IL-10 to IL-10R1.
Genetic predisposition is a risk factor for the development of inflammatory bowel diseases (IBDs). Disruption of the interleukin (IL)-10 pathway in mice causes intestinal inflammation similar to human IBD. Two common non-synonymous IL-10R1 variants, S138G and G330R, were cloned and expressed in HeLa and Ba/F3. A reduction in IL-10-induced STAT1 and STAT3 activation was seen for IL-10R1-S138G (but not IL-10R1-G330R) by phosphospecific western blotting in both cell types. When analyzing 52 world populations for the presence of IL-10R1 variants, a strong dissimilarity was found between major geographical regions. In addition, when 182 IBD-parent trios were genotyped for both variants, a reduced transmission of haplotype -7 (carrying the S138G variant allele) to offspring with ulcerative colitis (UC) was observed. This UC-protective effect of S138G was confirmed in a Hungarian cohort (n ¼ 185, allele frequency 11.6 versus 17.5%; P ¼ 0.017) but not in an independent Belgian cohort (n ¼ 666, allele frequency 15.9 versus 15.5%; P ¼ 0.8). In conclusion, the IL-10R1 S138G variant is a loss-offunction allele for IL-10-induced STAT1 and STAT3 activation but does not protect from UC susceptibility.
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.
Several lines of evidence have confirmed the importance of Nod2 mutations for disease susceptibility in Crohn's disease. For tracing Nod2 evolution, exons 4a, 4e, 8, and 12 mutations were screened in a collection of 1,064 DNA samples from 52 worldwide populations. The overall allele frequency was 7.5% for single nucleotide polymorphism (SNP)5, 0.2% for SNP8, 0.3% for SNP12, and 0.4% for SNP13. Nod2 mutations are mainly Caucasian alleles with strong distribution dissimilarity between single populations and major geographical regions. This regional diversity of Nod2 mutations within Europe points to the regional existence of selection pressure (possibly through dairy-associated bacterial infections within Neolithic cattle farming populations). The SNP5 gradient between Africa and the Middle East and its absence in Asian and Native American populations indicate that the evolution of this variant occurred in the Middle East. As mutations in exons 4e, 8, and 12 were only found in association with SNP5, this variant may have allowed selection pressure to arise.
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