Interferon-gamma-mediated pathways are induced in human CD34(+) haematopoietic stem cells.
Pro-inflammatory cytokines like interferon-gamma (IFN-gamma) are considered to be important in the development of anaemia of chronic disease (ACD). Both, inhibitory and stimulatory activities of IFN-gamma on erythropoiesis have been observed in vitro earlier. IFN-gamma 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-gamma-mediated pathways were investigated in human CD34(+) progenitor cells, and effects of IFN-gamma 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-gamma in different doses (either 5000U/ml once or 200 and 400U/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-gamma stimulated higher kynurenine and neopterin formation in cells cultivated in EGFCM, stimulation with 400U IFN-gamma every other day was most effective. IFN-gamma 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-gamma activates IDO and neopterin formation, and it also exerts an influence on the proliferation of various stem cell populations.
Kurz
Katharina
K
Clinical Immunology and Infectious Diseases, Department of Internal Medicine, Innsbruck Medical University, Innsbruck, Austria.
Gluhcheva
Yordanka
Y
Zvetkova
Elissaveta
E
Konwalinka
Guenther
G
Fuchs
Dietmar
D
D000740:Anemia / Q000276:immunology / Q000378:metabolism; D018952:Antigens, CD34; D000998:Antiviral Agents / Q000494:pharmacology*; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D015672:Erythroid Precursor Cells / Q000201:enzymology* / Q000276:immunology; D004920:Erythropoiesis / Q000187:drug effects* / Q000276:immunology; D006136:GTP Cyclohydrolase / Q000276:immunology / Q000378:metabolism; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000276:immunology / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology*; D009000:Monocytes / Q000276:immunology; D019798:Neopterin / Q000096:biosynthesis* / Q000276:immunology; D014364:Tryptophan / Q000276:immunology / Q000378:metabolism
D018952:Antigens, CD34; D000998:Antiviral Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D019798:Neopterin; D007371:Interferon-gamma; D014364:Tryptophan; D006136:GTP Cyclohydrolase