Transforming growth factor-beta1 abrogates Fas-induced growth suppression and apoptosis of murine bone marrow progenitor cells.
Fas, a member of the tumor necrosis factor (TNF ) receptor superfamily is a critical downregulator of cellular immune responses. Proinflammatory cytokines like interferon-gamma (IFN-gamma) and TNF-alpha can induce Fas expression and render hematopoietic progenitor cells susceptible to Fas-induced growth suppression and apoptosis. Transforming growth factor-beta1 (TGF-beta1 ) is an essential anti-inflammatory cytokine, thought to play a key role in regulating hematopoiesis. In the present studies we investigated whether TGF-beta1 might regulate growth suppression and apoptosis of murine hematopoietic progenitor cells signaled through Fas. In the presence of TNF, activation of Fas almost completely blocked clonogenic growth of lineage-depleted (Lin-) bone marrow (BM) progenitor cells in response to granulocyte-macrophage colony-stimulating factor (GM-CSF ), CSF-1, or a combination of multiple cytokines. Whereas TGF-beta1 alone had no effect or stimulated growth in response to these cytokines, it abrogated Fas-induced growth suppression. Single-cell studies and delayed addition of TGF-beta1 showed that the ability of TGF-beta1 to inhibit Fas-induced growth suppression was directly mediated on the progenitor cells and not indirect through potentially contaminating accessory cells. Furthermore, TGF-beta1 blocked Fas-induced apoptosis of Lin- BM cells, but did not affect Fas-induced apoptosis of thymocytes. TGF-beta1 also downregulated the expression of Fas on Lin- BM cells. Thus, TGF-beta1 potently and directly inhibits activation-dependent and Fas-mediated growth suppression and apoptosis of murine BM progenitor cells, an effect that appears to be distinct from its ability to induce progenitor cell-cycle arrest. Consequently, TGF-beta1 might act to protect hematopoietic progenitor cells from enhanced Fas expression and function associated with proinflammatory responses.
Dybedal
I
I
Hipple Cancer Research Center, Dayton, OH, USA.
Guan
F
F
Borge
O J
OJ
Veiby
O P
OP
Ramsfjell
V
V
Nagata
S
S
Jacobsen
S E
SE
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000473:pathology* / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000473:pathology* / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology* / Q000502:physiology; D019014:fas Receptor / Q000502:physiology*
D016212:Transforming Growth Factor beta; D019014:fas Receptor