I-A beta gene expression regulation in macrophages derived from mice susceptible or resistant to infection with M-bovis BCG

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 Beg 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 BIOS, respectively). We have found that the difference in the IFN gamma-induced Ia surface protein expression between B10R and BIOS 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 BIOS macrophages. Overall, our data suggest that both transcriptional and posttranscriptional regulatory mechanisms are responsible for the more efficient expression of 1-A beta gene in macrophages carrying a resistant allele of Nramp1 gene. (C) 1997 Published by Elsevier Science Ltd.