TRANSFORMING GROWTH FACTOR-BETA(1) 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. Proinflammat ory cytokines like interferon-gamma (IFN-gamma) and TNF-alpha can indu ce Fas expression and render hematopoietic progenitor cells susceptibl e to Fas-induced growth suppression and apoptosis. Transforming growth factor-beta(1) (TGF-beta(1)) is an essential anti-inflammatory cytoki ne, thought to play a key role in regulating hematopoiesis. In the pre sent studies we investigated whether TGF-beta(1) might regulate growth suppression and apoptosis of murine hematopoietic progenitor cells si gnaled through Fas. In the presence of TNF, activation of Fas almost c ompletely blocked clonogenic growth of lineage-depleted (Lin(-)) bone marrow (BM) progenitor cells in response to granulocyte-macrophage col ony-stimulating factor (GM-CSF), CSF-1, or a combination of multiple c ytokines. Whereas TGF-beta (1) alone had no effect or stimulated growt h in response to these cytokines, it abrogated Fas-induced growth supp ression. Single-cell studies and delayed addition of TGF-P, showed tha t the ability of TGF-beta(1) to inhibit Fas-induced growth suppression was directly mediated on the progenitor cells and not indirect throug h potentially contaminating accessory cells. Furthermore, TGF-beta(1) blocked Fas-induced apoptosis of Lin(-) BM cells, hut did not affect F as-induced apoptosis of thymocytes, TGF-beta(1) also downregulated the expression of Fas on Lin(-) BM cells. Thus, TGF-beta(1) potently and directly inhibits activation-dependent and Fas-mediated growth suppres sion and apoptosis of murine BM progenitor cells, an effect that appea rs to be distinct from its ability to induce progenitor cell-cycle arr est. Consequently, TGF-beta(1) might act to protect hematopoietic prog enitor cells from enhanced Fas expression and function associated with proinflammatory responses. (C) 1997 by The American Society of Hemato logy.