Possible role of cytokine-induced tryptophan degradation in anaemia of inflammation.

Anaemia of inflammation (AI) is a frequent complication in patients suffering from chronic inflammatory disorders including infections, autoimmune and malignant disease. Cytokine imbalance with a shift towards T-helper (Th)1-type immune response seems to be important in the pathogenesis of this type of anaemia. Interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha may affect the growth and differentiation of erythroid progenitor cells. In macrophages, IFN-gamma strongly induces indoleamine (2,3)-dioxygenase, an enzyme which degrades tryptophan (trp) to kynurenine (kyn). Trp availability is rate limiting for protein biosynthesis and thus cell growth, including erythropoiesis. In this study, trp and kyn concentrations and their relationship to haemoglobin concentrations and to immune activation was examined in 22 patients with AI. Patients with AI presented with lower trp concentrations than healthy controls of similar age, and a significantly higher kyn to trp ratio, suggesting enhanced trp degradation and, because of a positive correlation with neopterin, immune activation. The kyn to trp ratio was inversely correlated to haemoglobin levels. Thus, the limitation of trp availability to erythroid progenitors may be a key mechanism in cytokine-mediated inhibition of erythropoiesis, and the therapeutic modulation of indoleamine (2,3)-dioxygenase and trp levels may be promising targets for AI therapy.