Attenuation of MHC class II expression in macrophages infected with Mycobacterium bovis bacillus Calmette-Guerin involves class II transactivator anddepends on the Nramp1 gene

The natural resistance associated macrophage protein 1 (Nramp1) gene determ ines the ability of murine macrophages to control infection with a group of intracellular pathogens, including Salmonella typhimurium, Leishmania dano vani, and Mycobacterium bovis bacillus Calmette-Guerin (BCG). The expressio n of the resistant allele of the Nramp1 gene in murine macrophages is assoc iated with a more efficient expression of several macrophape activation-ass ociated genes, including class II: MHC loci, In this study, we investigated the molecular mechanisms involved in IFN-gamma-induced MHC class Il expres sion in three types of macrophages: those expressing a wild-type allele of the Nramp1 gene (B10R and 129/M phi), those carrying a susceptible farm of the Namp1 gene (B10S), and those derived from 129-Nramp1-knockout mice (129 /Nramp1-KO). Previously, we published results showing that Ia protein expre ssion is significantly higher in the IFN-gamma-induced B10R macrophages, co mpared with its susceptible counterpart. In this paper, we also show that t he higher expression of Ia protein in B10R cells is associated with higher I-A(beta) mRNA expression, which correlates with a higher level of IFN-gamm a-induced phosphorylation of the STAT1-alpha protein and subsequently with elevated expression of class II transactivator (CIITA) mRNA, compared with BIOS. Furthermore, we demonstrate that the infection of macrophages with M. bovis BCG results in a down-regulation of CIITA mRNA expression and, conse quently, in the inhibition of Ia induction. Therefore, our data explain, at least in part, the: molecular mechanism involved in the inhibition of I-A( beta) gene expression in M. bovis BCG-infected macrophages activated with I FN-gamma.