Tumor necrosis factor (TNF)-alpha directly inhibits human erythropoiesis in vitro: role of p55 and p75 TNF receptors.
Two tumor necrosis factor receptors (TNFRs) with molecular weights of 55 kD (TNFR-p55) and 75 kD (TNFR-p75) have recently been identified and cloned. In previous studies, TNFR-p55 has been shown to exclusively mediate bidirectional effects of TNF-alpha on committed bone marrow granulocyte-macrophage progenitor cells, whereas both TNFR-p55 and TNFR-p75 can mediate inhibition of primitive progenitors requiring multiple cytokines to proliferate. We show here that TNF-alpha potently and directly inhibits the in vitro growth of committed erythroid progenitor cells in response to multiple cytokine combinations, and that TNF-alpha-induced inhibition of burst-forming unit-erythroid colony formation is mainly mediated through TNFR-p55, although TNFR-p75-mediated inhibition could be observed on progenitors responsive to erythropoietin alone. Moreover, at low TNF-alpha concentrations (2 ng/mL), TNF-alpha stimulates interleukin-3-dependent in vitro growth of committed granulocyte-macrophage progenitor cells, whereas it potently inhibits erythroid progenitor cell proliferation, showing that one concentration of TNF-alpha can simultaneously and bidirectionally modulate interleukin-3-dependent growth of committed granulocyte-macrophage (stimulation) and erythroid progenitor cells (inhibition).
Department of Immunology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo.
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LS
Rusten
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SE
Jacobsen
D015703:Antigens, CD / Q000032:analysis; D002469:Cell Separation / Q000379:methods; D003001:Cloning, Molecular; D003114:Colony-Forming Units Assay; D004305:Dose-Response Relationship, Drug; D004920:Erythropoiesis / Q000187:drug effects*; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D006133:Growth Substances / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D008970:Molecular Weight; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D015703:Antigens, CD; D006133:Growth Substances; D007377:Interleukin-3; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha