Transforming growth factor-β1 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-γ (IFN-γ) and TNF-α can induce Fas expression and render hematopoietic progenitor cells susceptible to Fas-induced growth suppression and apoptosis. Transforming growth factor-β 1 (TGF-β 1 ) is an essential anti-inflammatory cytokine, thought to play a key role in regulating hematopoiesis. In the present studies we investigated whether TGF-β 1 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-β 1 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-β 1 showed that the ability of TGF-β 1 to inhibit Fas-induced growth suppression was directly mediated on the progenitor cells and not indirect through potentially contaminating accessory cells. Furthermore, TGF-β 1 blocked Fas-induced apoptosis of Lin − BM cells, but did not affect Fas-induced apoptosis of thymocytes. TGF-β 1 also downregulated the expression of Fas on Lin − BM cells. Thus, TGF-β 1 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-β 1 might act to protect hematopoietic progenitor cells from enhanced Fas expression and function associated with proinflammatory responses.