It is known that inadequate
erythropoietin (EPO) production contributes to the pathogenesis of
anemia of
inflammation, although the exact molecular mechanism is unknown.
Aryl hydrocarbon receptor (AhR) may compete with
hypoxia-inducible factor 2α (HIF-2α), the master regulator of EPO production, for binding with HIF-1β. The effect of
kynurenine, an endogenous AhR activator that increases in
inflammation, on EPO and
hepcidin production was evaluated. HepG2 cells were treated with the
hypoxia mimetic CoCl2,
kynurenine, the AhR inhibitor
CH223191, and combinations of these. EPO and
hepcidin production was measured with
enzyme-linked
immunosorbent assay. HIF-2α and
CYP1A1 levels, a transcriptional target of AhR, were assessed by Western blotting. CoCl2 increased EPO production and decreased
hepcidin and
CYP1A1.
Kynurenine exerted the opposite effects. Wherever
CH223191 was added, the inhibitor overcorrected
kynurenine-induced alterations in both the presence and the absence of CoCl2. Also, treatment with
CH223191 alone increased EPO and decreased
hepcidin, indicating that there is a degree of constitutive AhR activation, possibly by other endogenous AhR activators. In conclusion,
kynurenine, by competing with HIF-2α, may contribute to
anemia of
inflammation by decreasing EPO and increasing
hepcidin production. The fact that inactivation of AhR alone induces EPO makes this
transcription factor a potential therapeutic target in situations that require increased EPO.