title: Tumor necrosis factor alpha is a potent synergistic factor for the proliferation of primitive human hematopoietic progenitor cells and induces resistance to transforming growth factor beta but not to interferon gamma.
abstract: Since tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and transforming growth factor (TGF)-beta have all been shown to be specific inhibitors of early human hematopoiesis, we wanted to investigate the interactions of these three cytokines on very primitive human adult bone marrow CD34++CD38- hematopoietic progenitor cells, using a pre-colony-forming cell (pre-CFC) assay, which detects the effects of these cytokines on the initial phases of the differentiation of these primitive progenitors, which are unresponsive to interleukin (IL) 3 alone. Surprisingly, TNF-alpha was a very potent stimulator of the proliferation of CD34++CD38- cells and was the most potent synergistic factor for the IL-3-induced proliferation of these cells of all cytokines tested (IL-1, IL-6, granulocyte colony-stimulating factor, kit ligand). TNF-alpha was the only cytokine that, as a single added factor, induced substantial proliferation in CD34++CD38- cells in the presence of IL-3, except for kit ligand, which induced very limited proliferation. TNF-alpha, moreover, induced a high degree of resistance to the inhibitory effects of TGF-beta in a dose-dependent way. The inhibitory effects of IFN-gamma, however, were not affected by the presence of TNF-alpha. We hypothesize that in situations of the hematopoietic stress, TNF-alpha may abrogate the inhibitory effect of ambient TGF-beta in the bone marrow microenvironment to allow primitive stem cells to proliferate and differentiate in response to an increased demand for mature blood cells.
authors.affiliation: Laboratory of Experimental Hematology, University of Antwerp, Belgium.
authors.forename: H W
authors.initials: HW
authors.lastname: Snoeck
authors.forename: S
authors.initials: S
authors.lastname: Weekx
authors.forename: A
authors.initials: A
authors.lastname: Moulijn
authors.forename: F
authors.initials: F
authors.lastname: Lardon
authors.forename: M
authors.initials: M
authors.lastname: Lenjou
authors.forename: G
authors.initials: G
authors.lastname: Nys
authors.forename: P C
authors.initials: PC
authors.lastname: Van Ranst
authors.forename: D R
authors.initials: DR
authors.lastname: Van Bockstaele
authors.forename: Z N
authors.initials: ZN
authors.lastname: Berneman
mesh_terms: D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D015703:Antigens, CD; D018952:Antigens, CD34; D000943:Antigens, Differentiation; D001854:Bone Marrow Cells; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D008562:Membrane Glycoproteins; D009699:N-Glycosyl Hydrolases; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D015703:Antigens, CD; D018952:Antigens, CD34; D000943:Antigens, Differentiation; D008562:Membrane Glycoproteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D009699:N-Glycosyl Hydrolases; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1