The production of erythropoietin (Epo), the glycoprotein hormone which cont
rols red blood cell formation, is regulated by feedback mechanisms sensing
tissue oxygenation. The mechanism of the putative oxygen sensor has yet to
be elucidated. There is evidence that at least two pathways participate in
hypoxia signal transduction. One appears to involve a specific haem protein
, and a second implicates reactive oxygen species (ROS). Iron catalyses the
generation of intracellular ROS and therefore alters the cellular redox st
ate. We have investigated the effect of modulating intracellular iron conte
nt on Epo production in Hep 3B cells. Iron chelation stimulates Epo product
ion at 20% O-2 and enhances Epo production at 1% O-2, but it has no additiv
e effect on cobalt-induced Epo production. Excess molar iron inhibited Epo
production in response to hypoxia, desferrioxamine (DFO) and cobalt chlorid
e and inhibited the DFO-enhancing effect of hypoxia-induced Epo production.
We found that sulphydryl oxidising agents exert a differential inhibitory
effect on hypoxia-induced versus DFO-induced Epo production, providing furt
her evidence that multiple pathways of oxygen sensing exist.