TUMOR-NECROSIS-FACTOR-ALPHA UP-REGULATES BCL-2 EXPRESSION AND DECREASES CALCIUM-DEPENDENT APOPTOSIS IN HUMAN B-CELL LINES

Group I and Epstein-Barr virus-negative Burkitt's lymphoma cell lines and the 8104 lymphoma cell line which expresses a phenotype of immatur e B cells undergo apoptosis after cross-linking of their surface Ig re ceptors or after exposure to a calcium ionophore. We show here that tu mor necrosis factor (TNF)-alpha protects these B cell lines against Ca 2+-dependent apoptosis. Protection was associated with up-regulation o f bcl-2 mRNA and protein expression. The increase of Bcl-2 expression induced by TNF-alpha was inhibited by chelerythrine, a specific inhibi tor of protein kinase C (PKC), suggesting that Bcl-2 expression was de pendent on PKC activation. Furthermore, we show that phorbol esters an d cyclosporin A (CsA), which prevent Ca2+-dependent apoptosis, up-regu lated Bcl-2 expression. The effect of CsA on Bcl-2 expression is contr olled by calcineurin since we have shown that FK506 but not rapamycin had the same effect on Bcl-2 expression, whereas okadaic acid, an inhi bitor of phosphatases 1, 2A and 2C, was ineffective. These data provid e direct evidence that TNF-alpha prevents Ca2+-dependent apoptosis by a Bcl-2-dependent mechanism mediated by PKC.