Expression and role in growth regulation of tumour necrosis factor receptors p55 and p75 in acute myeloblastic leukaemia cells

Abstract

Tumour necrosis factor (TNF)-alpha exerts multiple effects on human acute myeloblastic leukaemia (AML) cells in vitro, including (1) synergistic stimulation of proliferation with interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF); (2) inhibition of granulocyte-CSF (G-CSF) and stem cell factor (SCF)-induced growth; (3) suppression of multiplication of clonogenic leukaemic cells; (4) induction of autocrine growth. Recently, two distinct TNF receptors (TNF-Rs), TNF-Rp55 and TNF-Rp75, have been identified. In this study we show that both receptors are expressed on freshly isolated AML blasts, with p75 being the predominant TNF-receptor type. This study investigates the roles of these two receptors in TNF-alpha-driven growth regulation of AML blasts in vitro. Using a receptor-specific antibody, it is shown that both receptor types participate in TNF-alpha-mediated stimulation of GM-CSF/IL-3-induced proliferation and in TNF-alpha-induced autocrine growth. In contrast, the TNF-alpha-triggered growth inhibition (antiproliferation) and the potent suppression of G-CSF- and SCF-induced proliferation exclusively result from activation of TNF-Rp55. Taken together, these results suggest that the proliferative effects of TNF-alpha on AML blasts are mediated through both p55 and p75 TNF receptors, whereas the TNF-alpha-signalled growth inhibition is exclusively transduced via TNF-Rp55.

Elevated NF-κB responses and FLIP levels in leukemic but not normal lymphocytes: reduction by salicylate allows TNF-induced apoptosis

“…The majority of TNF-induced NF-B activation (34), growth inhibition, and suppression of proliferation also resulted exclusively from activation of TNFR1 (31,35). In other studies, TNF-induced apoptotic and cytotoxic effects were mediated almost entirely by TNFR1, with TNFR2 having only a minimal effect (34,36,37).…”

Granulocyte macrophage-colony stimulating factor and interleukin-3 increase expression of type II tumour necrosis factor receptor, increasing susceptibility to tumour necrosis factor-induced apoptosis. Control of leukaemia cell life/death switching

“…19,20 The majority of TNF-induced nuclear factor-kB (NF-kB) activation, 21 growth inhibition and suppression of proliferation also resulted exclusively from activation of TNFR1. 22 Although TNF has a cytotoxic or cytostatic effect when tested with various malignant cell lines, clinical trials in cancer patients have revealed high systemic toxicity of TNF. 23,24 It is at present unclear which of the receptors are responsible for the various effects of TNF, although TNFR1 appears to be the predominant receptor that signals both cytotoxic and inflammatory responses.…”

Serum levels of p55 and p75 soluble TNF receptors in adult acute leukaemia at diagnosis: correlation with clinical and biological features and outcome

“…Experimental evidence suggests that tumour necrosis factor (TNF) is involved in the proliferation of acute leukaemia cells ( Hoang et al , 1989 ; Oster et al , 1989 ; Elbaz et al , 1991a , b; Delwel et al , 1992 ; Carter et al , 1994 , 1996). TNF acts as a pleiotropic cytokine enhancing leukaemic growth ( Hoang et al , 1989 ; Oster et al , 1989 ; Carter et al , 1994 , 1996), inducing the transcription of other proliferation‐relevant cytokine or cytokine receptor genes ( Elbaz et al , 1991a , b; Delwel et al , 1992 ; Vinante et al , 1993 , 1996; Khoury et al , 1994 ; Carter et al , 1996 ) and triggering apoptosis ( Elbaz et al , 1991b ; Delwel et al , 1992 ; Khoury et al , 1994 ; Carter et al , 1996 ).…”