A negative autoregulatory link between Nramp1 function and expression.

Nramp1 (natural resistance-associated macrophage protein) controls resistance to infection by intracellular pathogens in mice. Nramp1 regulates the microenvironment of the invading pathogen by increasing the luminal iron that participates in the Haber-Weiss reaction, producing radicals that attack the pathogen. We have studied the effect of inflammatory stimuli, iron, and sodium nitroprusside on Nramp1 expression in bone marrow macrophages. Investigations show all three up-regulate Nramp1 expression with a parallel increase in immunoreactivity to an amino-terminal antibody and Nramp1 mRNA. Growth rates are reduced in macrophage cell lines expressing Nramp1. This is through a decrease in iron availability, shown by an increase in IRP2 activity and a reciprocal decrease in conventional protein kinase Cbeta-1 expression. We propose that Nramp1 activity may control its own expression via a negative autoregulatory loop that is important for iron homeostasis and maintenance of low cytoplasmic redox active iron levels in the macrophage.