EXPRESSION AND ROLE IN GROWTH-REGULATION OF TUMOR-NECROSIS-FACTOR RECEPTORS P55 AND P75 IN ACUTE MYELOBLASTIC-LEUKEMIA CELLS

Tumour necrosis factor (TNF)-alpha exerts multiple effects on human ac ute myeloblastic leukaemia (AML) cells in vitro, including (1) synergi stic stimulation of proliferation with interleukin-3 (IL-3) and granul ocyte-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) ind uction of autocrine growth. Recently, two distinct TNF receptors (TNF- Rs), TNF-Rp55 and TNF-Rp75, have been identified. In this study we sho w that both receptors are expressed on freshly isolated AML blasts, wi th p75 being the predominant TNF-receptor type. This study investigate s the roles of these two receptors in TNF-alpha-driven growth regulati on of AML blasts in vitro. Using a receptor-specific antibody, it is s hown that both receptor types participate in TNF-alpha-mediated stimul ation of GM-CSF/IL-3-induced proliferation and in TNF-alpha-induced au tocrine growth. In contrast, the TNF-alpha-triggered growth inhibition (antiproliferation) and the potent suppression of G-CSF- and SCF-indu ced proliferation exclusively result from activation of TNF-Rp55. Take n together, these results suggest that the proliferative effects of TN F-alpha on AML blasts are mediated through both p55 and D75 TNF recept ors, whereas the TNF-alpha-signalled growth inhibition is conclusively transduced via TNP-Rp55.