title: Tumor necrosis factor-alpha expressed constitutively in erythroid cells or induced by erythropoietin has negative and stimulatory roles in normal erythropoiesis and erythroleukemia.
abstract: Binding of erythropoietin (EPO) to its receptor (EPOR) on erythroid cells induces the activation of numerous signal transduction pathways, including the mitogen-activated protein kinase Jun-N-terminal kinase (JNK). In an effort to understand the regulation of EPO-induced proliferation and JNK activation, we have examined the role of potential autocrine factors in the proliferation of the murine erythroleukemia cell line HCD57. We report here that treatment of these cells with EPO induced the expression and secretion of tumor necrosis factor alpha (TNF-alpha). EPO-dependent proliferation was reduced by the addition of neutralizing antibodies to TNF-alpha, and exogenously added TNF-alpha induced proliferation of HCD57 cells. EPO also could induce TNF-alpha expression in BAF3 and DA3 myeloid cells ectopically expressing EPOR. Addition of TNF-alpha activated JNK in HCD57 cells, and the activity of JNK was partially inhibited by addition of a TNF-alpha neutralizing antibody. Primary human and murine erythroid progenitors expressed TNF-alpha in either an EPO-dependent or constitutive manner. However, TNF-alpha had an inhibitory effect on both immature primary human and murine cells, suggestive that the proliferative effects of TNF-alpha may be limited to erythroleukemic cells. This study suggests a novel role for autocrine TNF-alpha expression in the proliferation of erythroleukemia cells that is distinct from the effect of TNF-alpha in normal erythropoiesis.
authors.affiliation: Departments of Pharmacology/Toxicology, Radiation Oncology and Physiology, Medical College of Virginia Campus, Richmond 23298, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Jacobs-Helber
authors.forename: Kwan-Ho
authors.initials: KH
authors.lastname: Roh
authors.forename: Daniel
authors.initials: D
authors.lastname: Bailey
authors.forename: Emmanuel N
authors.initials: EN
authors.lastname: Dessypris
authors.forename: John J
authors.initials: JJ
authors.lastname: Ryan
authors.forename: Jingchun
authors.initials: J
authors.lastname: Chen
authors.forename: Amittha
authors.initials: A
authors.lastname: Wickrema
authors.forename: Dwayne L
authors.initials: DL
authors.lastname: Barber
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Sawyer
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D002455:Cell Division; D002460:Cell Line; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000378:metabolism*; D004920:Erythropoiesis / Q000187:drug effects*; D004921:Erythropoietin / Q000494:pharmacology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D004915:Leukemia, Erythroblastic, Acute / Q000473:pathology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000187:drug effects / Q000502:physiology*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D004921:Erythropoietin; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases