Tumor necrosis factor alpha directly and indirectly regulates hematopoietic progenitor cell proliferation: role of colony-stimulating factor receptor modulation.
Tumor necrosis factor alpha (TNF-alpha) has been shown to both stimulate and inhibit the proliferation of hematopoietic progenitor cells (HPCs) in vitro, but its mechanisms of action are not known. We demonstrate that the direct effects of TNF-alpha on murine bone marrow progenitors are only inhibitory and mediated at least in part through downmodulation of colony-stimulating factor receptor (CSF-R) expression. The stimulatory effects of TNF-alpha are indirectly mediated through production of hematopoietic growth factors, which subsequently results in increased granulocyte-macrophage CSF and interleukin 3 receptor expression. In addition, the effects of TNF-alpha (stimulatory or inhibitory) are strictly dependent on the particular CSF stimulating growth as well as the concentration of TNF-alpha present in culture. A model is proposed to explain how TNF-alpha might directly and indirectly regulate HPC growth through modulation of CSF-R expression.
Jacobsen
S E
SE
Laboratory of Molecular Immunoregulation, National Cancer Institute-Frederick Cancer Research and Development Center, Maryland 21702.
Ruscetti
F W
FW
Dubois
C M
CM
Keller
J R
JR
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D016184:Receptors, Colony-Stimulating Factor / Q000187:drug effects / Q000378:metabolism*; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000187:drug effects / Q000378:metabolism; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D016184:Receptors, Colony-Stimulating Factor; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor