title: Immunomodulatory Function of Interleukin 28B during primary infection with cytomegalovirus.
abstract: BACKGROUND
  Feedback mechanisms between interferons α and λ (IFNs) may be affected by single nucleotide polymorphisms (SNP) in interleukin 28B (IL-28B; IFN-λ3) promoter region and may influence cytomegalovirus (CMV) replication.
  
  
  METHODS
  We associated IL-28B SNPs with the risk of CMV replication after transplantation. Next, we examined the effect of IL-28B genotypes on IL-28B, and IFN-stimulated gene (ISG) expression, and CMV replication in human foreskin fibroblast (HFF) and peripheral blood mononuclear cells (PBMCs).
  
  
  RESULTS
  Transplant recipients with an IL-28B SNP (rs8099917) had significantly less CMV replication (P = .036). Both HFF-cells and PBMCs with a SNP showed lower IL-28B expression during infection with CMV, but higher "antiviral" ISG expression (eg, OAS1). Fibroblasts with a SNP had a 3-log reduction of CMV replication at day 4 (P = .004). IL-28B pretreatment induced ISG expression in noninfected fibroblasts, but a relative decrease of ISG expression could be observed in CMV-infected fibroblasts. The inhibitory effects of IL-28B could be abolished by siRNA or antagonistic peptides against the IL-28 receptor. In fibroblasts, inhibition of IL-28 signaling resulted in an increase of ISG expression and 3-log reduction of CMV-replication (P = .01).
  
  
  CONCLUSIONS
  We postulate that IL-28B may act as a key regulator of ISG expression during primary CMV infection. IL-28B SNPs may be associated with higher antiviral ISG expression, which results in better replication control.
authors.affiliation: Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada Infection Biology, Department Biomedicine, University of Basel, Switzerland.
authors.forename: Adrian
authors.initials: A
authors.lastname: Egli
authors.affiliation: Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Aviad
authors.initials: A
authors.lastname: Levin
authors.affiliation: Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Deanna M
authors.initials: DM
authors.lastname: Santer
authors.affiliation: Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Joyce
authors.affiliation: Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Daire
authors.initials: D
authors.lastname: O'Shea
authors.affiliation: Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Brad S
authors.initials: BS
authors.lastname: Thomas
authors.affiliation: Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Luiz F
authors.initials: LF
authors.lastname: Lisboa
authors.affiliation: Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada Department of Engineering Mathematics and Physics, Fayoum University, Egypt;
authors.forename: Khaled
authors.initials: K
authors.lastname: Barakat
authors.affiliation: Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Bhat
authors.affiliation: Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Karl P
authors.initials: KP
authors.lastname: Fischer
authors.affiliation: Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Houghton
authors.affiliation: Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: D Lorne
authors.initials: DL
authors.lastname: Tyrrell
authors.affiliation: Department of Medicine and Multi-organ Transplant Program, University Health Network, Toronto, Ontario, Canada.
authors.forename: Deepali
authors.initials: D
authors.lastname: Kumar
authors.affiliation: Department of Medicine and Multi-organ Transplant Program, University Health Network, Toronto, Ontario, Canada.
authors.forename: Atul
authors.initials: A
authors.lastname: Humar
mesh_terms: D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000276:immunology* / Q000502:physiology; D003586:Cytomegalovirus Infections / Q000235:genetics* / Q000276:immunology*; D005260:Female; D005347:Fibroblasts / Q000821:virology; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000235:genetics* / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000821:virology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D014180:Transplantation; D014779:Virus Replication; D000095022:Interferon Lambda
chemical_list: D007372:Interferons; D007378:Interleukins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda
keywords: T-cell priming; adaptive immune response; cytomegalovirus; feedback mechanism; immunosuppression; innate immune response; interferon λ; interferon-stimulated gene; interleukin 28; solid organ transplantation