title: Alcohol suppresses IL-2-induced CC chemokine production by natural killer cells.
abstract: BACKGROUND
  Natural killer (NK) cells are a critical component of the host innate immune system. We investigated whether alcohol impairs NK cell function, particularly production of CC chemokines induced by interleukin (IL)-2, the natural ligands for CCR5 receptor.
  
  
  METHODS
  Primary NK cells and NK cell line (YTS) were cultured with or without alcohol (10 to 80 mM) for three hours. The culture supernatants were then harvested and used to treat human peripheral blood monocyte-derived macrophages and a HeLa cell line, which expresses CD4, CCR5, and CXCR4 receptors (MAGI cells). CC chemokine expression by YTS and primary NK cells treated with or without alcohol was analyzed with the real-time RT-PCR and ELISA. [Ca(2)(+)]i and Western blot assays were used to determine calcium-mediated intracellular signaling pathway and NF-kappaB p65 expression. HIV strains (Bal and UG024) were used to infect macrophages and MAGI cells. In addition, ADA (macrophage-tropic strain) and murine leukemia virus (MLV) envelope-pseudotyped HIV infection was carried out in macrophages. HIV infectivity was determined by HIV reverse transcriptase (RT) and beta-galactosidase activity assays.
  
  
  RESULTS
  Alcohol inhibited IL-2-induced CC chemokine (CCL3 and CCL4) expression by NK cells. Functional tests demonstrated that this reduced expression of CC chemokines was associated with diminished anti-HIV ability of NK cells. Alcohol also reduced the ability of NK cells to response to CCL3-mediated chemotaxis. Alcohol inhibited IL-2-induced NF-kappaB p65 protein expression and calcium mobilization by NK cells.
  
  
  CONCLUSIONS
  Alcohol, through the inhibition of IL-2-induced NF-kappaB p65 protein expression and intracellular calcium mobilization, suppressed NK cell production of CC chemokines. This suppression of CC chemokine production was associated with diminished anti-HIV activity of NK cells. Thus, by inhibiting NK cell-mediated innate immunity against HIV, alcohol consumption may have a cofactor role in the immunopathogenesis of HIV disease.
authors.affiliation: Department of Pediatrics, Division of Allergy and Immunology, Joseph Stokes Jr. Research Institute at The Children's Hospital of Philadelphia, PA 19104, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Chang-Jiang
authors.initials: CJ
authors.lastname: Guo
authors.forename: Steven D
authors.initials: SD
authors.lastname: Douglas
authors.forename: David S
authors.initials: DS
authors.lastname: Metzger
authors.forename: Charles P
authors.initials: CP
authors.lastname: O'Brien
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Yan-Jian
authors.initials: YJ
authors.lastname: Wang
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.forename: Wen-Zhe
authors.initials: WZ
authors.lastname: Ho
mesh_terms: D000328:Adult; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC / Q000096:biosynthesis*; D000431:Ethanol / Q000494:pharmacology*; D015658:HIV Infections / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000037:antagonists & inhibitors*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis*; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors
chemical_list: C066507:CCL4 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC; D007376:Interleukin-2; D019402:Macrophage Inflammatory Proteins; D051996:Transcription Factor RelA; D000431:Ethanol