title: 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 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.
  
  
  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-γ 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- γ responses to vary with the IL-28B genotype, with carriers of a T/T genotype displaying the lowest frequency of IFN-γ(+)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- γ 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.
authors: Department of Internal Medicine I, University of Bonn, Bonn, Germany.|German Center for Infection Research (DZIF), Bonn, Germany.
authors: Benjamin
authors: http://orcid.org/0000-0002-1385-9709
authors: B
authors: Krämer
authors: Department of Internal Medicine I, University of Bonn, Bonn, Germany.|German Center for Infection Research (DZIF), Bonn, Germany.
authors: Claudia
authors: C
authors: Finnemann
authors: Department of Infectious Diseases, Institute for Health Research (IRYCIS), University Hospital Ramón y Cajal, Madrid, Spain.|AIDS Research Network (RIS-RETICS), Madrid, Spain.
authors: Beatriz
authors: B
authors: Sastre
authors: Department of Internal Medicine I, University of Bonn, Bonn, Germany.|German Center for Infection Research (DZIF), Bonn, Germany.
authors: Philipp
authors: P
authors: Lutz
authors: Department of Internal Medicine I, University of Bonn, Bonn, Germany.|German Center for Infection Research (DZIF), Bonn, Germany.
authors: Andreas
authors: A
authors: Glässner
authors: Department of Internal Medicine I, University of Bonn, Bonn, Germany.|German Center for Infection Research (DZIF), Bonn, Germany.
authors: Franziska
authors: F
authors: Wolter
authors: Department of Internal Medicine I, University of Bonn, Bonn, Germany.|German Center for Infection Research (DZIF), Bonn, Germany.
authors: Felix
authors: F
authors: Goeser
authors: Department of Internal Medicine I, University of Bonn, Bonn, Germany.|German Center for Infection Research (DZIF), Bonn, Germany.
authors: Pavlos
authors: P
authors: Kokordelis
authors: Department of Internal Medicine I, University of Bonn, Bonn, Germany.|German Center for Infection Research (DZIF), Bonn, Germany.
authors: Dominik
authors: D
authors: Kaczmarek
authors: Department of Internal Medicine I, University of Bonn, Bonn, Germany.|German Center for Infection Research (DZIF), Bonn, Germany.
authors: Hans-Dieter
authors: HD
authors: Nischalke
authors: Department of Internal Medicine I, University of Bonn, Bonn, Germany.|German Center for Infection Research (DZIF), Bonn, Germany.
authors: Christian P
authors: CP
authors: Strassburg
authors: Department of Internal Medicine I, University of Bonn, Bonn, Germany.|German Center for Infection Research (DZIF), Bonn, Germany.
authors: Ulrich
authors: U
authors: Spengler
authors: Department of Internal Medicine I, University of Bonn, Bonn, Germany.|German Center for Infection Research (DZIF), Bonn, Germany.
authors: Jacob
authors: J
authors: Nattermann
mesh_terms: D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006526:Hepatitis C / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007372:Interferons; D018664:Interleukin-12 / Q000096:biosynthesis; D007378:Interleukins / Q000235:genetics*; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology* / Q000378:metabolism; D000095022:Interferon Lambda
chemical_list: D007372:Interferons; D018664:Interleukin-12; D007378:Interleukins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda