Kynurenine, by activating aryl hydrocarbon receptor, decreases erythropoietin and increases hepcidin production in HepG2 cells: A new mechanism for anemia of inflammation.
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.
Department of Nephrology, Medical School, University of Thessaly, Larissa, Greece. Electronic address: teleftheriadis@yahoo.com.
Theodoros
T
Eleftheriadis
Department of Nephrology, Medical School, University of Thessaly, Larissa, Greece.
Georgios
G
Pissas
Department of Nephrology, Medical School, University of Thessaly, Larissa, Greece.
Georgia
G
Antoniadi
Department of Nephrology, Medical School, University of Thessaly, Larissa, Greece.
Vassilios
V
Liakopoulos
Department of Nephrology, Medical School, University of Thessaly, Larissa, Greece.
Ioannis
I
Stefanidis
D000740:Anemia / Q000209:etiology*; D004921:Erythropoietin / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D056945:Hep G2 Cells; D064451:Hepcidins / Q000096:biosynthesis*; D006801:Humans; D007249:Inflammation / Q000150:complications*; D007737:Kynurenine / Q000502:physiology*; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*
D064451:Hepcidins; D018336:Receptors, Aryl Hydrocarbon; D004921:Erythropoietin; D007737:Kynurenine