A negative autoregulatory link between Nramp1 function and expression

Nramp1 (natural resistance-associated macrophage protein) controls resistan ce to infection by intracellular pathogens in mice, Nramp1 regulates the mi croenvironment of the invading pathogen by increasing the luminal iron that participates in the Haber-Weiss reaction, producing radicals that attack t he pathogen, We have studied the effect of inflammatory stimuli, iron, and sodium nitroprusside on Nramp1 expression in bone marrow macrophages. inves tigations show all three up-regulate Nramp1 expression with a parallel incr ease in immunoreactivity to an amino-terminal antibody and Nramp1 mRNA, Gro wth rates are reduced in macrophage cell lines expressing Nramp1, This is t hrough a decrease in iron availability, shown by an increase in IRP2 activi ty and a reciprocal decrease in conventional protein kinase C beta-1 expres sion. We propose that Nramp1 activity may control its Own expression via a negative autoregulatory loop that is important for iron homeostasis and mai ntenance of low cytoplasmic redox active iron levels in the macrophage.