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Interferon-γ down-regulates NKG2D ligand expression and impairs the NKG2D-mediated cytolysis of MHC class I-deficient melanoma by natural killer cells
- Source :
- International Journal of Cancer. 124:1594-1604
- Publication Year :
- 2009
- Publisher :
- Wiley, 2009.
-
Abstract
- NKG2D operates as an activating receptor on natural killer (NK) cells and costimulates the effector function of alphabeta CD8(+) T cells. Ligands of NKG2D, the MHC class I chain-related (MIC) and UL16 binding protein (ULBP) molecules, are expressed on a variety of human tumors, including melanoma. Recent studies in mice demonstrated that NKG2D mediates tumor immune surveillance, suggesting that antitumor immunity in humans could be enhanced by therapeutic manipulation of NKG2D ligand (NKG2DL) expression. However, signals and mechanisms regulating NKG2DL expression still need to be elucidated. Here, we asked whether the proinflammatory cytokine Interferon-gamma (IFN-gamma) affects NKG2DL expression in melanoma. Cell lines, established from MHC class I-negative and -positive melanoma metastases, predominantly expressed MICA and ULBP2 molecules on their surface. Upon IFN-gamma treatment, expression of MICA, in some cases, also of ULBP2 decreased. Besides melanoma, this observation was made also for glioma cells. Down-regulation of NKG2DL surface expression was dependent on the cytokine dose and the duration of treatment, but was neither due to an intracellular retention of the molecules nor to an increased shedding of ligands from the tumor cell surface. Instead, quantitative RT-PCR revealed a decrease of MICA-specific mRNA levels upon IFN-gamma treatment and siRNA experiments pointed to an involvement of STAT-1 in this process. Importantly, IFN-gamma-treated MHC class I-negative melanoma cells were less susceptible to NKG2D-mediated NK cell cytotoxicity. Our study suggests that IFN-gamma, by down-regulating ligand expression, might facilitate escape of MHC class I-negative melanoma cells from NKG2D-mediated killing by NK cells.
- Subjects :
- Cancer Research
medicine.medical_treatment
Blotting, Western
CD1
Enzyme-Linked Immunosorbent Assay
chemical and pharmacologic phenomena
GPI-Linked Proteins
Transfection
Natural killer cell
Interferon-gamma
Cell Line, Tumor
MHC class I
medicine
Humans
Interferon gamma
Melanoma
biology
Reverse Transcriptase Polymerase Chain Reaction
Histocompatibility Antigens Class I
Glioma
Flow Cytometry
NKG2D
Immunohistochemistry
Killer Cells, Natural
medicine.anatomical_structure
Cytokine
ULBP2
Gene Expression Regulation
Oncology
NK Cell Lectin-Like Receptor Subfamily K
biology.protein
Cancer research
Intercellular Signaling Peptides and Proteins
CD8
medicine.drug
Subjects
Details
- ISSN :
- 10970215 and 00207136
- Volume :
- 124
- Database :
- OpenAIRE
- Journal :
- International Journal of Cancer
- Accession number :
- edsair.doi.dedup.....c549bcc17bb1215f0ac7780aab892316