title: A possible mechanism of impaired NK cytotoxicity in cancer patients: down-regulation of DAP10 by TGF-beta1.
abstract: OBJECTIVE
  Elevated TGF-BETA1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. However, the molecular mechanism of immunosuppression by TGF-BETA1 is not yet clarified.
  
  
  METHODS
  IL-2-activated human NK cells were cultured with TGF-BETA1. Protein levels of NKG2D and DAP10 were examined by FACS or immunoblot analyses. Real-time RTPCR was performed to quantify the transcription levels. MAPK inhibitors were used to investigate intracellular signaling.
  
  
  RESULTS
  TGF-BETA1 down-regulated total and surface NKG2D, which was partially dependent on transcriptional regulation. TGF-BETA1 treatment of human NK cells resulted in significant changes in both transcriptional and translational levels of DAP10. Moreover, treatment with bafilomycin A1 or folimycin restored total NKG2D levels in TGF-BETA1-treated NK cells. The impaired NKG2D down-modulation by TGF-BETA1 was not associated with activation of the MAPK signaling pathway.
  
  
  CONCLUSIONS
  TGF-BETA1 down-modulates surface NKG2D expression by controlling the transcriptional and translational levels of DAP10.
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: June-Chul
authors.initials: JC
authors.lastname: Lee
authors.forename: Kyung-Mi
authors.initials: KM
authors.lastname: Lee
authors.forename: Yong-Oon
authors.initials: YO
authors.lastname: Ahn
authors.forename: Beomseok
authors.initials: B
authors.lastname: Suh
authors.forename: Dae Seog
authors.initials: DS
authors.lastname: Heo
mesh_terms: D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D015536:Down-Regulation; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D007376:Interleukin-2 / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology / Q000378:metabolism*; D009369:Neoplasms / Q000276:immunology*; D046188:Protein Modification, Translational; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D053773:Transforming Growth Factor beta1 / Q000276:immunology / Q000378:metabolism*
chemical_list: C120528:HCST protein, human; D007376:Interleukin-2; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D053773:Transforming Growth Factor beta1; D020928:Mitogen-Activated Protein Kinases