Abstract
Abstract In mammals, infection results in the production of inflammatory cytokines and acute-phase reactants in the liver, including the synthesis of the antimicrobial peptide, hepcidin. Hepcidin controls extracellular iron by regulating its intestinal absorption and release from macrophages. It acts by binding to and mediating the degradation of the sole iron export protein ferroportin 1. Here, we investigated the expression of hepcidin in mouse macrophages infected with the intracellular pathogens Mycobacterium avium and Mycobacterium tuberculosis H37Rv. We show that stimulation with mycobacteria and IFN-γ synergistically induce hepcidin mRNA in mouse macrophages. The induction of hepcidin mRNA by M. tuberculosis was found to be dependent on TLR2, TLR4, and STAT1. IL-6 and IL-1β, which induce hepcidin expression in liver hepatocytes, did not induce hepcidin mRNA expression in RAW264.7 cells. Iron loading, which induces hepcidin mRNA in the liver, inhibited hepcidin mRNA expression induced by IFN-γ and M. avium. These results implicate differential expression of hepcidin in macrophages and hepatocytes. Immunofluorescence studies show that hepcidin is present in the M. avium- and M. tuberculosis-containing phagosomes. These results suggest that hepcidin production by infected macrophages is an IFN-γ induced host defense mechanism against mycobacteria. This work was supported by grant NIH-RO1DK-57667
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