Attenuation of MHC class II expression in macrophages infected with Mycobacterium bovis bacillus Calmette-Guérin involves class II transactivator and depends on the Nramp1 gene.
The natural resistance associated macrophage protein 1 (Nramp1) gene determines the ability of murine macrophages to control infection with a group of intracellular pathogens, including Salmonella typhimurium, Leishmania donovani, and Mycobacterium bovis bacillus Calmette-Guérin (BCG). The expression of the resistant allele of the Nramp1 gene in murine macrophages is associated with a more efficient expression of several macrophage activation-associated genes, including class II MHC loci. In this study, we investigated the molecular mechanisms involved in IFN-gamma-induced MHC class II expression in three types of macrophages: those expressing a wild-type allele of the Nramp1 gene (B10R and 129/Mphi), those carrying a susceptible form of the Nramp1 gene (B10S), and those derived from 129-Nramp1-knockout mice (129/Nramp1-KO). Previously, we published results showing that Ia protein expression is significantly higher in the IFN-gamma-induced B10R macrophages, compared with its susceptible counterpart. In this paper, we also show that the higher expression of Ia protein in B10R cells is associated with higher I-Abeta mRNA expression, which correlates with a higher level of IFN-gamma-induced phosphorylation of the STAT1-alpha protein and subsequently with elevated expression of class II transactivator (CIITA) mRNA, compared with B10S. Furthermore, we demonstrate that the infection of macrophages with M. bovis BCG results in a down-regulation of CIITA mRNA expression and, consequently, in the inhibition of Ia induction. Therefore, our data explain, at least in part, the molecular mechanism involved in the inhibition of I-Abeta gene expression in M. bovis BCG-infected macrophages activated with IFN-gamma.
Wojciechowski
W
W
McGill University, Department of Experimental Medicine, Montreal General Hospital Research Institute, Quebec, Canada.
DeSanctis
J
J
Skamene
E
E
Radzioch
D
D
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D027682:Cation Transport Proteins; D002460:Cell Line; D004198:Disease Susceptibility; D005786:Gene Expression Regulation / Q000276:immunology; D005802:Genes, MHC Class II; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis* / Q000235:genetics; D007113:Immunity, Innate; D050832:Interferon-Stimulated Gene Factor 3; D007371:Interferon-gamma / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009163:Mycobacterium bovis / Q000276:immunology*; D009687:Nuclear Proteins; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D000099173:Natural Resistance-associated Macrophage Protein 1
D002352:Carrier Proteins; D027682:Cation Transport Proteins; D000949:Histocompatibility Antigens Class II; D050832:Interferon-Stimulated Gene Factor 3; D007371:Interferon-gamma; D008565:Membrane Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; D014443:Tyrosine; D000099173:Natural Resistance-associated Macrophage Protein 1; C083728:MHC class II transactivator protein; C079868:gamma interferon activation factor