title: I-A beta gene expression regulation in macrophages derived from mice susceptible or resistant to infection with M. bovis BCG.
abstract: The innate capacity of mice to control mycobacterial multiplication early after infection is controlled by the resistant allele of the Nramp-1/Bcg gene. The Bcg gene seems to be involved in a pathway leading to macrophage activation. It differentially affects the ability of BCG-resistant and -susceptible strains of mice to express important macrophage genes including Major Histocompatibility Complex (MHC) class II genes. An inhibition of Nramp1 gene by Nramp1-ribozyme transfection in macrophages resulted in the impairment of MHC class II gene induction by IFN gamma. In this study, we have investigated the molecular mechanisms involved in IFN-gamma-induced MHC class II expression using macrophages derived from mice resistant or susceptible to mycobacterial infections (B10R and B10S, respectively). We have found that the difference in the IFN gamma-induced Ia surface protein expression between B10R and B10S macrophages correlate with a higher rate of I-A beta gene transcription. We have also studied the binding of proteins prepared from nuclear extracts of non-stimulated and IFN-gamma-stimulated B10R and B10S macrophages to the S, X and Y cis-acting elements of the I-A beta promoter. Differences observed in protein binding to the X box may explain the difference in transcription activation of the I-A beta gene. We have also found that I-A alpha and I-A beta mRNA half-lives measured in IFN gamma-stimulated cells are significantly longer in B10R, compared to B10S macrophages. Overall, our data suggest that both transcriptional and posttranscriptional regulatory mechanisms are responsible for the more efficient expression of I-A beta gene in macrophages carrying a resistant allele of Nramp1 gene.
authors.affiliation: Centre for the Study of Host Resistance, McGill University, Montreal General Hospital, Quebec, Canada.
authors.forename: L F
authors.initials: LF
authors.lastname: Barrera
authors.forename: I
authors.initials: I
authors.lastname: Kramnik
authors.forename: E
authors.initials: E
authors.lastname: Skamene
authors.forename: D
authors.initials: D
authors.lastname: Radzioch
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000096:biosynthesis; D001667:Binding, Competitive / Q000276:immunology; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000276:immunology; D003080:Cold Temperature; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism; D004198:Disease Susceptibility; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D005802:Genes, MHC Class II / Q000187:drug effects / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D009163:Mycobacterium bovis / Q000276:immunology*; D011401:Promoter Regions, Genetic / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D013045:Species Specificity; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000276:immunology; D015533:Transcriptional Activation / Q000235:genetics / Q000276:immunology; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology
chemical_list: D000954:Antigens, Surface; D004268:DNA-Binding Proteins; D000949:Histocompatibility Antigens Class II; D012333:RNA, Messenger; D014157:Transcription Factors; D007371:Interferon-gamma