Interferon-γ-mediated pathways are induced in human CD34+ haematopoietic stem cells

Pro-inflammatory cytokines like interferon-γ (IFN-γ) are considered to be important in the development of anaemia of chronic disease (ACD). Both, inhibitory and stimulatory activities of IFN-γ on erythropoiesis have been observed in vitro earlier. IFN-γ induces several biochemical pathways in human monocytes, among them neopterin formation by GTP-cyclohydrolase I (GTP-CH I) and tryptophan degradation by the enzyme indoleamine 2,3-dioxygenase (IDO). IDO-mediated tryptophan deprivation efficiently inhibits the growth of proliferating cells and microbes, thus we wanted to examine whether enhanced tryptophan degradation by monocytic precursor cells also suppresses erythropoiesis.Therefore, IFN-γ-mediated pathways were investigated in human CD34+ progenitor cells, and effects of IFN-γ on the proliferative activity of different progenitor subpopulations were studied. Cells were either cultivated in agar-conditioned medium (ACM) or in medium containing erythroid growth factors interleukin-3 (IL-3) and stem cell factor (SCF; EGFCM).Stimulation of CD34+ cells with IFN-γ in different doses (either 5000 U/ml once or 200 and 400 U/ml every other day) induced tryptophan degradation and in parallel also neopterin formation. Unstimulated cells cultured with ACM produced higher amounts of neopterin and kynurenine (all p<0.05). IFN-γ stimulated higher kynurenine and neopterin formation in cells cultivated in EGFCM, stimulation with 400 U IFN-γ every other day was most effective. IFN-γ stimulated the growth and proliferation of CFU-E and BFU-E (3–8) in both media.In conclusion, stimulation of haematopoietic stem cells with IFN-γ activates IDO and neopterin formation, and it also exerts an influence on the proliferation of various stem cell populations.