Tumor necrosis factor-alpha inhibits stem cell factor-induced proliferation of human bone marrow progenitor cells in vitro. Role of p55 and p75 tumor necrosis factor receptors.
Stem cell factor (SCF), a key regulator of hematopoiesis, potently synergizes with a number of hematopoietic growth factors. However, little is known about growth factors capable of inhibiting the actions of SCF. TNF-alpha has been shown to act as a bidirectional regulator of myeloid cell proliferation and differentiation. This study was designed to examine interactions between TNF-alpha and SCF. Here, we demonstrate that TNF-alpha potently and directly inhibits SCF-stimulated proliferation of CD34+ hematopoietic progenitor cells. Furthermore, TNF-alpha blocked all colony formation stimulated by SCF in combination with granulocyte colony-stimulating factor (CSF) or CSF-1. The synergistic effect of SCF observed in combination with GM-CSF or IL-3 was also inhibited by TNF-alpha, resulting in colony numbers similar to those obtained in the absence of SCF. These effects of TNF-alpha were mediated through the p55 TNF receptor, whereas little or no inhibition was signaled through the p75 TNF receptor. Finally, TNF-alpha downregulated c-kit cell-surface expression on CD34+ bone marrow cells, and this was predominantly a p55 TNF receptor-mediated event as well.
Rusten
L S
LS
Department of Immunology, Norwegian Radium Hospital, Oslo.
Smeland
E B
EB
Jacobsen
F W
FW
Lien
E
E
Lesslauer
W
W
Loetscher
H
H
Dubois
C M
CM
Jacobsen
S E
SE
D000328:Adult; D015703:Antigens, CD / Q000032:analysis; D018952:Antigens, CD34; D001854:Bone Marrow Cells; D002455:Cell Division / Q000187:drug effects; D016298:Hematopoietic Cell Growth Factors / Q000037:antagonists & inhibitors*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000032:analysis; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis; D016184:Receptors, Colony-Stimulating Factor / Q000032:analysis; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D019089:Stem Cell Factor; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D015703:Antigens, CD; D018952:Antigens, CD34; D016298:Hematopoietic Cell Growth Factors; D007377:Interleukin-3; D011518:Proto-Oncogene Proteins; D016184:Receptors, Colony-Stimulating Factor; D018124:Receptors, Tumor Necrosis Factor; D019089:Stem Cell Factor; D014409:Tumor Necrosis Factor-alpha; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases