Novel Variants of the IL-10 Receptor 1 Affect Inhibition of Monocyte TNF-α Production

Gasché, Christoph; Grundtner, P; Zwirn, P; Reinisch, Walter; Shaw, Sarah H.; Zdanov, Alexander; Śarmā, Ushā; Williams, Lynn M.; Foxwell, Brian M. J.; Gangl, Alfred

doi:10.4049/jimmunol.170.11.5578

Cited by 58 publications

(70 citation statements)

References 39 publications

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“…37 Specifically, monocytes from homozygous mutant individuals were not capable to completely downregulate LPSinduced TNF-alpha production upon high doses of IL-10. Also, the ID50 (the IL-10 concentration that caused a 50% reduction of LPS-induced TNF-alpha production) was significantly higher in monocytes from homozygous mutant individuals.…”

Section: Discussionmentioning

confidence: 99%

“…Exclusion criteria were alcohol abuse (weekly ethanol consumption of more than 50 g for males Genotyping of IL-10R1 variants Two allele-specific polymerase chain reaction (PCRs) were used for detection of IL-10R1 SNP3 and SNP4 in genomic DNA as described. 37 The PCR products of the SNP3 reaction are 464-bp (control PQ-138), 337-bp (wildtype AQ-138) and 183-bp (variant PB-138). The PCR products of the SNP4 reaction are at 515-bp (control PQ-330), 318-bp (wild-type AQ-330) and 248-bp (variant PB-330).…”

Section: Patientsmentioning

confidence: 99%

“…30,31 Interaction of IL-10 with the IL-10R complex stabilizes dimerization of both IL-10R subunits, activates phosphorylation of the receptor-associated Janus tyrosine kinases, Jak1 and Tyk2 32,33 and induces mainly STAT3-mediated signal transduction. [34][35][36] Our group recently identified two novel SNP of the IL-10R1, 37 one of which (G330R, SNP4) affects IL-10-mediated inhibition of TNFa production in human monocytes. 37 The other SNP, S138G (SNP3), is genetically linked to SNP4.…”

Section: Introductionmentioning

confidence: 99%

“…[34][35][36] Our group recently identified two novel SNP of the IL-10R1, 37 one of which (G330R, SNP4) affects IL-10-mediated inhibition of TNFa production in human monocytes. 37 The other SNP, S138G (SNP3), is genetically linked to SNP4. Modeling of the extra cellular receptor domain of the IL-10/ IL-10R1 SNP3 complex revealed that this serine to glycine exchange may produce certain conformational rearrangements of this receptor domain.…”

Section: Introductionmentioning

confidence: 99%

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Bi-allelic presence of the interleukin-10 receptor 1 G330R allele is associated with cirrhosis in chronic HCV-1 infection

et al. 2005

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Immune response to viral infection is an important determinant of liver injury in chronic hepatitis C (CHC). Experimental and clinical data suggest a protective role of interleukin-10 (IL-10) in hepatic fibrogenesis. The significance of two SNPs of the interleukin-10 receptor 1 (IL-10R1), S138G (SNP3) and G330R (SNP4) was investigated on (i) susceptibility to CHC, (ii) progression of hepatic fibrosis and (iii) response to interferon/ribavirin therapy. DNA and liver biopsies were obtained from 212 patients with HCV (hepatitis C virus)-genotype-1 infection. The allele frequencies were 0.17 for SNP3 and 0.33 for SNP4, both of which were indifferent from healthy controls (0.17 and 0.32, respectively). Stage 1 liver fibrosis was found in 22 cases (10.4%), stage 2 in 108 (50.9%), stage 3 in 27 (12.8%), and stage 4 (cirrhosis) in 55 (25.9%). An association was found between the SNP4 allele and the presence of cirrhosis (P ¼ 0.01). Homozygous SNP4 individual variants segregated within the cirrhosis group (P ¼ 0.03). We found neither an association with SNP3 nor with the necroinflammatory disease activity (as measured by ALT levels) nor with the response to antiviral therapy. Our work implies that IL-10R1 SNP4 is a recessively inherited risk factor for hepatic cirrhosis in HCV genotype-1 infection.

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Section: Discussionmentioning

confidence: 99%

Section: Patientsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Bi-allelic presence of the interleukin-10 receptor 1 G330R allele is associated with cirrhosis in chronic HCV-1 infection

et al. 2005

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“…These variants were not associated with CD but affected IL-10-dependent inhibition of tumor necrosis factor-a production in monocytes. 25 The aim of this study was to investigate the effect of these variants on IL-10 signal transduction, the distribution in various populations and their significance for UC susceptibility.…”

Section: Introductionmentioning

confidence: 99%

The IL-10R1 S138G loss-of-function allele and ulcerative colitis

et al. 2008

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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.

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Homozygosity of the interleukin‐10 receptor 1 G330R allele is associated with schizophrenia

Schosser

Aschauer

Wildenauer

et al. 2006

American J of Med Genetics Pt B

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Infections of unknown origin and an altered immune response have been hypothesized to play a role in the pathogenesis of schizophrenia. We have previously identified two single nucleotide polymorphisms (SNPs) of the IL-10 receptor 1 (IL-10R1) causing a substitution of glycine 330 to arginine (G330R) and of serine 138 to glycine (S138G). A possible association between these IL-10R1 variants and schizophrenia has been investigated in the present study. DNA of 101 unrelated Austrian patients with a DSM-III-R (Diagnostic and Statistical Manual of Mental Disorders) consensus diagnosis of schizophrenia (n = 70) or schizoaffective disorder (n = 31) and DNA of 121 German schizophrenic patients (DSM-III-R) was analyzed for the presence of S138G and G330R by allele-specific multiplex PCRs. Data from patients were compared with 250 unrelated, psychiatric healthy controls. No difference in allele frequency was detected between patients and controls (G330R: 34.0% vs. 30.0%, P = 0.208; S138G: 19.7% vs. 16.6%, P = 0.235; by Fisher's exact test). However, there was a significant difference in genotype distribution (wt/wt, wt/mut, mut/mut) for G330R between patients (46.8%, 38.3%, 14.9%) and controls (47.6%, 44.8%, 7.6%; Fisher's test P = 0.032). No such difference was seen for S138G. Our results suggest that homozygosity of the IL-10R1 G330R allele is associated with schizophrenia and may contribute to the expression of disease phenotype in susceptible individuals.

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Novel Variants of the IL-10 Receptor 1 Affect Inhibition of Monocyte TNF-α Production

Cited by 58 publications

References 39 publications

Bi-allelic presence of the interleukin-10 receptor 1 G330R allele is associated with cirrhosis in chronic HCV-1 infection

Bi-allelic presence of the interleukin-10 receptor 1 G330R allele is associated with cirrhosis in chronic HCV-1 infection

The IL-10R1 S138G loss-of-function allele and ulcerative colitis

Homozygosity of the interleukin‐10 receptor 1 G330R allele is associated with schizophrenia

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