Iron Chelators and Hypoxia Mimetics Inhibit IFNγ-Mediated Jak-STAT Signaling

Treatment of cultured cells with iron chelators causes profound changes in gene expression and inhibition of cytokine signaling pathways, suggesting an important role for iron in inflammation. We have previously shown the treatment of cells with chelators which preferentially bind iron inhibits IFNγ-mediated induction of IFN regulatory factor 1 in endothelial cells. To define the mechanisms mediating inhibition of IFNγ-induced genes, we examined IFNγ-induced signaling pathways in EC after treatment with chelators. Treatment resulted in inhibition of IFNγ-induced STAT1 nuclear translocation. This was associated with inhibition of IFNγ-induced STAT1 phosphorylation and loss of expression of the R1 subunit of the IFNγ receptor (IFNγR) complex, without changes in expression of IFNγR complex subunits. Downregulation of IFNγR1 was not mediated through alterations in IFNγR1 gene transcription, but was induced by inhibition of IFNγR1 mRNA translation superimposed on a constitutively high receptor turnover through endosomal degradation. Furthermore, inhibition of IFNγ signaling and downregulation of IFNγR1 was also mediated by nonmetal-binding hypoxia mimetics and reduced oxygen tensions. These data suggest that the target for chelator effects may be through iron requirements for oxygen-requiring dioxygenase enzymes.