Tumour necrosis factor-α (TNFα) has been reported to induce potent growth inhibition of committed myeloid progenitor cells, whereas it is a potential growth stimulator of human CD34+CD38- multipotent haematopoietic cells. The present study was aimed at evaluating the respective role of two phospholipases, phosphatidylcholine-specific phospholipase C (PC-PLC) and phospholipase D (PLD) in the response of the CD34+ CD38- KG1a cells to TNFα. In these cells TNFα triggered phosphoinositide 3-kinase (PI3K)-dependent PC hydrolysis within 4–8min with concomitant production of both diacylglycerol (DAG) and phosphocholine (P-chol). DAG and P-chol production was accompanied by extracellular-signal-related protein kinase-1 (‘ERK-1’) activation and DNA-synthesis stimulation. PC-PLC stimulation was followed by PI3K-independent PLD activation with concomitant phosphatidic acid (PA) production followed by PA-derived DAG accumulation and sustained nuclear factor κB (NF-κB) activation. PLD/NF-κB signalling activation played no role in the TNFα proliferative effect and conferred no consistent protection of KG1a cells towards antileukaemic agents. Altogether these results suggest that, in KG1a cells, TNFα can stimulate in parallel PC-PLC and PLD, whose lipid products activate in turn mitogen-activated protein kinase (MAP kinase) and NF-κB signalling respectively. Finally, our study suggests that PC-PLC, but not PLD, plays a role in the TNFα proliferative effect in immature myeloid cells.

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