Delineation of an antiapoptotic action of glucocorticoids in hepatoma cells: The role of nuclear factor-kappa B

Glucocorticoids are primarily recognized for their profound antiinflammator y actions and their ability to induce lymphocyte apoptosis. We report here that, in contrast to their effect on cells of the immune system, glucocorti coids suppress serum deprivation induced apoptosis of rat hepatoma (HTC) ce lls. Suppression of apoptosis in these cells occurs at physiological concen trations of glucocorticoid and is abrogated by the glucocorticoid antagonis t RU486. Although HTC cells also express receptors for progesterone, estrog en, and thyroid hormone, ligands for these receptors fail to rescue these c ells from programmed cell death. Because the sensitivity of cells to apopto tic stimuli is often regulated by the ratio of antiapoptotic to proapoptoti c Bcl-2 family members, we analyzed the influence of glucocorticoids and in duction of apoptosis by serum starvation on the expression of these protein s. Bcl-2, Bcl-x(L), Bad, Bak, and Bar levels were not altered by either tre atment. Mitochondrial function has recently been implicated as a critical e arly regulator of apoptosis in many cells including hepatocytes. Dexamethas one treatment blocked a decrease in this potential (Delta psi(m)) during se rum deprivation induced apoptosis in HTC cells, indicating an action of thi s hormone upstream of mitochondria. We also show that the induction of apop tosis in HTC cells is associated with a decrease in nuclear factor (NF)-kap pa B. Treatment with dexamethasone effectively blocked the loss of nuclear NF-kappa B, suggesting that this hormone acts to suppress apoptosis of HTC cells via regulation of this nuclear transcription factor. This hypothesis was confirmed by transfection experiments that show that expression of a su perrepressor of NF-kappa B inhibits the ability of dexamethasone to rescue HTC cells from apoptosis induced by serum deprivation.