Inhibition of nuclear factor-kappa B sensitises anterior pituitary cells to tumour necrosis factor-alpha- and lipopolysaccharide-induced apoptosis.

摘要

Nuclear factor-kappa B (NF-kappaB), an important pro-inflammatory factor, is a crucial regulator of cell survival. Both lipopolysaccharide (LPS) and tumour necrosis factor (TNF)-alpha activate NF-kappaB signalling. Oestrogens were shown to suppress NF-kappaB activation. Oestrogens exert a sensitising action to pro-apoptotic stimuli such as LPS and TNF-alpha in anterior pituitary cells. In the present study, we show by western blotting that 17beta-oestradiol (E(2)) decreases TNF-alpha-induced NF-kappaB/p65 and p50 nuclear translocation in primary cultures of anterior pituitary cells from ovariectomised (OVX) rats. Also, the in vivo administration of E(2) decreases LPS-induced NF-kappaB/p65 and p50 nuclear translocation. To investigate whether the inhibition of NF-kappaB pathway sensitises anterior pituitary cells to pro-apoptotic stimuli, we used an inhibitor of NF-kappaB activity, BAY 11-7082 (BAY). BAY, at a concentration that fails to induce apoptosis, has permissive action on TNF-alpha-induced apoptosis of lactotrophs and somatotrophs from OVX rats, as assessed by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL). Pharmacological inhibition of NF-kappaB signalling enhances E(2)-sensitising effect to TNF-alpha-induced apoptosis in lactotrophs but not in somatotrophs. In vivo administration of BAY allowed LPS-induced apoptosis in anterior pituitary cells from OVX rats (determined by fluorescence activated cell sorting). Furthermore, LPS-induced expression of Bcl-xL in pituitaries of OVX rats is decreased by E(2) administration. Our results show that inhibition of the NF-kappaB signalling pathway sensitises anterior pituitary cells to the pro-apoptotic action of LPS and TNF-alpha. Because E(2) inhibits LPS- and TNF-alpha-activated NF-kappaB nuclear translocation, the present study suggests that E(2) sensitises anterior pituitary cells to TNF-alpha- and LPS-induced apoptosis by inhibiting NF-kappaB activity.