Expression and modulation of cellular receptors for interferon‐γ, tumour necrosis factor, and Fas on human bone marrow CD34⁺ cells

Abstract

Summary.Interferon-g (IFN-g), tumour necrosis factor-a (TNF-a) and Fas-ligand can mediate potent inhibitory signals in haemopoietic cells. Clinical and laboratory studies have suggested the involvement of these cytokines in the regulation of normal haemopoiesis and in the pathophysiology of bone marrow (BM) failure syndromes. As the effects of cytokines may also be regulated at the cellular receptor level, we studied the expression and modulation of TNF receptor (TNFR), IFN-gR and Fas-R on haemopoietic progenitor cells. In freshly isolated BM, using flow cytometry, TNFR1 (p55), TNFR2 (p75), IFN-gR, and Fas-R were detected on 5-12% of mononuclear cells. Two-colour staining showed comparable receptor expression on a CD34 þ population, which includes haemopoietic progenitor and stem cells. Using reverse transcriptase-PCR (RT-PCR) transcription of mRNA coding for these receptors was demonstrated in fresh, highly purified CD34 þ cells. These findings indicate that the effects of these factors on progenitor cells may be directly mediated. In cultured BM cells, expression of TNFR1 was not influenced by IFN-g, TNF-a or apoptosis-inducing anti-Fas monoclonal antibody (mAb). IFN-g decreased CD34 þ cell TNFR2 expression. CD34 þ cell Fas-R expression was increased by IFN-g and TNF-a. IFN-gR expression was enhanced by antiFas mAb and to lesser degree with TNF-a. Similar results were obtained with RT-PCR analysis in cultured CD34 þ cells. Potentiation of anti-Fas mAb-mediated inhibition of haemopoietic colony formation by IFN-g and TNF-a was observed. Similarly, anti-Fas mAb enhanced the inhibitory effects of IFN-g. These results suggest that, in addition to interacting at the level of intracellular signalling pathways, IFN-g, TNF-a or Fas-ligand may potentiate or antagonize their effects through modulation of cytokine receptor expression.

Localization of Fas and Fas ligand in bone marrow cells demonstrating myelodysplasia

“…11 Raza et al 4,21 also observed an increase of TNF-␣, TGF-␤ and IL-1␤ in the bone marrow of MDS. Sato et al 31 have reported that IFN-␥,TNF-␣ and FasL can mediate potent inhibitory signals in hematopoietic cells. Fas antigen expression on CD34-positive bone marrow cells was increased by TNF-␣ and IFN-␥ in vitro.…”

Transforming growth factor β and tumor necrosis factor α inhibit both apoptosis and proliferation of activated rat hepatic stellate cells

“…In contrast, it has been shown that TGF-␤ or TNF-␣ both influence the CD95/ CD95L system by modulating CD95R expression in blood cells. 49,50 The influence of both cytokines on CD95L has not been described so far.…”

MycN and IFNγ cooperate in apoptosis of human neuroblastoma cells

“…It included both a modulation of death signaling through the death receptor CD95 as well as an increase of Bcl-2 related proteins promoting apoptosis. Cooperation at the level of CD95 involved as one element the IFNg mediated increase of cell surface expression of CD95, which has previously also been seen in other cell types (Friesen et al, 1996;Sato et al, 1997;Ossina et al, 1997). The other element was the MycN mediated increase of cellular susceptibility towards the death signal that is initiated from CD95.…”