title: Interferon-gamma-induced MHC class I expression and defects in Jak/Stat signalling in methylcholanthrene-induced sarcomas.
abstract: Seventy-eight uncloned tumour cell lines, each established from a primary sarcoma induced with methyl-cholanthrene in immunocompetent nu/+ BALB/c and C.B.-17 mice or in immunodeficient nu/nu BALB/c and severe combined immunodeficient (SCID) mice, were examined for sensitivity to interferon-gamma (IFN-gamma) as measured by tumour cell augmentation of major histocompatibility complex (MHC) class I expression. The tumour cells were cultured with IFN-gamma and their expression of Kd, Dd and Ld was measured by fluorescence-activated cell sorter analysis. All but three of the 78 tumour lines up-regulated Kd, Dd and Ld to a variable degree in response to IFN-gamma, indicating that IFN-gamma resistance is not a common property of these sarcomas. The tumour cell lines varied greatly in their MHC class I expression before as well as after IFN-gamma stimulation. There was a tendency towards a higher MHC expression after IFN-gamma stimulation in tumour lines from immunocompetent mice compared to immunodeficient mice, but no common maximum MHC class I expression level was found for the 78 tumour cell lines. Three of the tumour lines, all from immunodeficient mice, completely failed to respond to IFN-gamma by up-regulating MHC class I expression. The same three also displayed absence of IFN-gamma-induced Stat1 beta tyrosine phosphorylation and low Stat1 alpha tyrosine phosphorylation, indicating a defect in the signal transduction pathway affecting phosphorylation of Stat1. These findings strongly suggest a link between defects in Stat1 phosphorylation and the failure to up-regulate MHC class I. In all tumour lines tested, the Stat1 Western blotting revealed a 78 kDa protein (p78) not previously described.
authors.affiliation: Institute for Medical Microbiology and Immunology, University of Copenhagen, Panum Institute, Denmark.
authors.forename: I M
authors.initials: IM
authors.lastname: Svane
authors.forename: A M
authors.initials: AM
authors.lastname: Engel
authors.forename: M
authors.initials: M
authors.lastname: Nielsen
authors.forename: O
authors.initials: O
authors.lastname: Werdelin
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology*; D053614:Janus Kinase 2; D008748:Methylcholanthrene; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D017471:Receptors, Interferon / Q000096:biosynthesis; D050794:STAT1 Transcription Factor; D012513:Sarcoma, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism; D000096743:Interferon gamma Receptor
chemical_list: D004268:DNA-Binding Proteins; D015395:Histocompatibility Antigens Class I; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma; D053614:Janus Kinase 2; D008748:Methylcholanthrene; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D014443:Tyrosine; D000096743:Interferon gamma Receptor; C494080:Stat1 protein, mouse; C507926:Jak2 protein, mouse