Natural resistance to intracellular pathogens: Modulation of macrophage signal transduction related to the expression of the Bcg locus

In mice, the Bcg/Nramp1 gene of the chromosome 1 has been implicated in nat ural resistance or susceptibility to infection with several intramacrophage microorganisms. Functional studies of Bcg/Nramp1 congenic macrophages have shown that this gene has many pleiotropic effects on macrophage activation and function. Although a specific role of Bcg/Nramp1 in the control of ple iotropic effects has not been defined yet, several observations propose uni fying hypothesis for its complex role: metal ion transport is the primary f unction of the Scg/Nramp1 gene, the availability of metal ions as cofactors for many proteins results from this primary function and, in turn, the eff ect on signal transduction results from ion-regulated expression of cellula r proteins and their functions. In the present study, we examined the possi ble alterations in signal transduction pathways related to different alleli c expression of the Beg locus in B10R (Bcg(r)/Nramp1(s)) and B10S (Bcg(s)/N ramp1(r)) macrophages. We have utilized 1-DE and 2-DE immunoblot analyses a nd investigated phosphorylation of proteins using either anti-phosphotyrosi ne antibody or antibodies recognizing specific phospho-forms of signaling p roteins. In the basal state, B10R macrophages had a superior ability to pho sphorylate p38 mitogen-activated protein kinase (MAPK) and manganese supero xide dismutase. B10S counterparts were characterized by increased phosphory lation of Erk1/Erk2 MAPKs. The activation of macrophages revealed higher ph osphorylation of signal transducer and activator of transcription in respon se to interferon gamma and a rapid decline in the level of inhibitory kappa B-alpha protein induced by lipopolysaccharide in B10R macrophages compared to B10S. Altogether, our results demonstrate a link between allelic express ion of the Bcg/Nramp1 gene and alterations in several macrophage signaling pathways, and support the hypothesis that the allelic expression of Bcg/Nra mp1 may be functionally linked to resistance to infectious disease and, inv ersely, to autoimmune disease susceptibility.