Iron chelators and hypoxia mimetics inhibit IFNgamma-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 IFNgamma-mediated induction of IFN regulatory factor 1 in endothelial cells. To define the mechanisms mediating inhibition of IFNgamma-induced genes, we examined IFNgamma-induced signaling pathways in EC after treatment with chelators. Treatment resulted in inhibition of IFNgamma-induced STAT1 nuclear translocation. This was associated with inhibition of IFNgamma-induced STAT1 phosphorylation and loss of expression of the R1 subunit of the IFNgamma receptor (IFNgammaR) complex, without changes in expression of IFNgammaR complex subunits. Downregulation of IFNgammaR1 was not mediated through alterations in IFNgammaR1 gene transcription, but was induced by inhibition of IFNgammaR1 mRNA translation superimposed on a constitutively high receptor turnover through endosomal degradation. Furthermore, inhibition of IFNgamma signaling and downregulation of IFNgammaR1 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.
Gira
Amy K
AK
Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Kowalczyk
Andrew P
AP
Feng
Yue
Y
Swerlick
Robert A
RA
D021581:Active Transport, Cell Nucleus; D002614:Chelating Agents / Q000494:pharmacology*; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D007371:Interferon-gamma / Q000378:metabolism*; D007501:Iron / Q000737:chemistry / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism*; D008833:Microcirculation; D010100:Oxygen / Q000737:chemistry; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
D002614:Chelating Agents; D012333:RNA, Messenger; D050791:STAT Transcription Factors; D007371:Interferon-gamma; D007501:Iron; D053612:Janus Kinases; D010100:Oxygen