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 natural 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 pleiotropic effects has not been defined yet, several observations propose unifying hypothesis for its complex role: metal ion transport is the primary function of the Bcg/Nramp1 gene, the availability of metal ions as cofactors for many proteins results from this primary function and, in turn, the effect on signal transduction results from ion-regulated expression of cellular proteins and their functions. In the present study, we examined the possible alterations in signal transduction pathways related to different allelic expression of the Bcg locus in B10R (Bcg r /Nramp1 s ) and B10S (Bcg s /Nramp1 r ) macrophages. We have utilized 1-DE and 2-DE immunoblot analyses and investigated phosphorylation of proteins using either anti-phosphotyrosine antibody or antibodies recognizing specific phospho-forms of signaling proteins. In the basal state, B10R macrophages had a superior ability to phosphorylate p38 mitogen-activated protein kinase (MAPK) and manganese superoxide dismutase. B10S counterparts were characterized by increased phosphorylation of Erk1/Erk2 MAPKs. The activation of macrophages revealed higher phosphorylation of signal transducer and activator of transcription in response to interferon gamma and a rapid decline in the level of inhibitory kB-a protein induced by lipopolysaccharide in B10R macrophages compared to B10S. Altogether, our results demonstrate a link between allelic expression of the Bcg/Nramp1 gene and alterations in several macrophage signaling pathways, and support the hypothesis that the allelic expression of Bcg/Nramp1 may be functionally linked to resistance to infectious disease and, inversely, to autoimmune disease susceptibility.