Dataset Information

IL-28B Genetic Variants Determine the Extent of Monocyte-Induced Activation of NK Cells in Hepatitis C.

ABSTRACT:

Background

Immuno-genetic studies suggest a functional link between NK cells and ?-IFNs. We recently showed that NK cells are negative for the IFN-? receptor IFN-?R1 and do not respond to IFN-?, suggesting a rather indirect association between IL-28B genotype and NK cell activity.

Methods

A total of 75 HCV(+) patients and 67 healthy controls were enrolled into this study. IL-28B (rs12979860) and IFNL-4 (rs368234815) genotypes were determined by rtPCR. Total PBMC, monocytes, and NK cells were stimulated with IL-29, the TLR-7/8 agonist R848, or a combination of both. NK cell IFN-? response was analysed by FACS. IL-12 and IL-18 secretion of monocytes was studied by ELISA. In blocking experiments anti-IL-12/anti-IL-18 were used.

Results

Following stimulation of total PBMCs with R848 we found NK cell IFN- ? responses to vary with the IL-28B genotype, with carriers of a T/T genotype displaying the lowest frequency of IFN-?(+)NK cells. When isolated NK cells were studied no such associations were observed, indicating an indirect association between IL-28B genotype and NK cell activity. Accordingly, we found R848-stimulated monocytes of patients with a T/T genotype to be significantly less effective in triggering NK cell IFN- ? production than monocytes from carriers of a non-T/T genotype. In line with these findings we observed monocytes from T/T patients to secrete significantly lower concentrations of IL-12 than monocytes from non-T/T individuals.

Conclusions

Our data indicate that monocytes from carriers of an IL-28B T/T genotype display a reduced ability to stimulate NK cell activity and, thus, provide a link between IL-28B genotype and NK functions.

SUBMITTER: Kramer B

PROVIDER: S-EPMC5008784 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Publications

IL-28B Genetic Variants Determine the Extent of Monocyte-Induced Activation of NK Cells in Hepatitis C.

Krämer Benjamin B Finnemann Claudia C Sastre Beatriz B Lutz Philipp P Glässner Andreas A Wolter Franziska F Goeser Felix F Kokordelis Pavlos P Kaczmarek Dominik D Nischalke Hans-Dieter HD Strassburg Christian P CP Spengler Ulrich U Nattermann Jacob J

PloS one 20160901 9

<h4>Background</h4>Immuno-genetic studies suggest a functional link between NK cells and λ-IFNs. We recently showed that NK cells are negative for the IFN-λ receptor IFN-λR1 and do not respond to IFN-λ, suggesting a rather indirect association between IL-28B genotype and NK cell activity.<h4>Methods</h4>A total of 75 HCV(+) patients and 67 healthy controls were enrolled into this study. IL-28B (rs12979860) and IFNL-4 (rs368234815) genotypes were determined by rtPCR. Total PBMC, monocytes, and NK ...[more]

PMID: 27583440

Similar Datasets

Project description:Reports of the role of host interleukin 28B (IL-28B) genetic variants in liver disease severity in patients with chronic hepatitis C (CHC) have obtained conflicting results. The impact of IL-28B in Asian patients with different viral genotypes remains elusive.We try to elucidate the effect of IL-28B genetic variants in a large Asian cohort with different viral genotypes.The association between the IL-28B rs8099917 genotype and liver fibrosis was investigated in 1288 patients with biopsy-proven CHC.Patients with hepatitis C virus genotype 1 (HCV-1) infection comprised 59.4% of the population. The remaining 40.6% (518 patients) did not have HCV-1 infection. Of the 1084 patients with the IL-28 genotype, 85.6% (928 patients) had the TT genotype. Univariate analysis revealed that, compared to patients without advanced liver fibrosis, patients with advanced liver fibrosis (Metavir fibrosis score 3-4) had an older age, a lower platelet count, a higher ?-fetoprotein level, a higher alanine aminotransferase level, a higher incidence of diabetes, and a higher frequency of rs8099917 non-TT genotype carriage.Logistic regression analysis revealed that factors significantly associated with advanced liver fibrosis included age (odds ratio [OR]/95% confidence interval [CI]: 1.023/1.009-1.037, P?=?.001), diabetes (OR/CI: 1.736/1.187-2.539, P?=?.004), ?-fetoprotein (OR/CI: 1.007/1.002-1.012, P?=?.009), platelet count (OR/CI: 0.991/0.988-0.993, P?<?.001), and carriage of the rs8099917 non-TT genotype (OR/CI: 0.585/0.400-0.856, P?=?.006). When patients were classified by viral genotype, factors that had significant independent associations with advanced liver fibrosis in patients with HCV-1 infection included diabetes (OR/CI: 2.379/1.452-3.896, P?=?.001), ?-fetoprotein (OR/CI: 1.023/1.012-1.035, P?<?.001), platelet count (OR/CI: 0.99/0.987-0.994, P?<?.001), and carriage of the rs8099917 non-TT genotype (OR/CI: 0.529/0.328-0.854, P?=?.009). In patients who had advanced liver fibrosis but not HCV-1 infection, factors that had significant independent associations with advanced liver fibrosis included age (OR/CI: 1.039/1.016-1.063, P?=?.001) and platelet count (OR/CI: 0.99/0.986-0.995, P?<?.001); additionally, IL-28B genetic variants were not associated with liver disease severity.Unfavorable IL-28B genetic variants were associated with advanced liver disease. The genetic effect is limited to patients with HCV-1 infection.

Dataset Information

IL-28B Genetic Variants Determine the Extent of Monocyte-Induced Activation of NK Cells in Hepatitis C.

Background

Methods

Results

Conclusions

Publications

IL-28B Genetic Variants Determine the Extent of Monocyte-Induced Activation of NK Cells in Hepatitis C.

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