DISTINCT SIGNAL-TRANSDUCTION PATHWAYS MEDIATE NUCLEAR FACTOR-KAPPA-B INDUCTION BY IL-1-BETA IN EPITHELIAL AND LYMPHOID-CELLS

We previously demonstrated that IL-1 beta-mediated induction of the nu clear factor-kappa B (NF-kappa B) transcription factor proceeds throug h the production of reactive oxygen intermediates in lymphoid cells, w hile it occurs independently of any oxidative stress in epithelial tra nsformed cells, Indeed, inhibition of receptor internalization as well as NH4Cl and chloroquine blocked IL-1 beta-mediated induction of NF-k appa B in OVCAR-3 and in other epithelial cell lines but not in lympho id cells, indicating that distinct pathways are involved. Conversely, while we observed phospholipase A2 activity in both cell types followi ng IL-1 beta stimulation, specific inhibitors of this enzyme inhibited NF-kappa B induction only in lymphoid cells. Moreover, expression of the 5-lipoxygenase (5-LOX) enzyme was not detected in epithelial cells , and inhibition of this enzyme blocked NF-kappa B induction bay IL-1 beta only in lymphoid cells. This study thus indicates that the activa tion of NF-kappa B following IL-1 beta treatment involves the activati on of phospholipase A2 anti 5-LOX and the production of reactive oxyge n intermediates (ROIs) in lymphoid cells, while in epithelial cells, a nother pathway predominates and could involve the acid sphingomyelinas e, Moreover, arachidonic acid could induce NF-kappa B in epithelial an d lymphoid cells, but this activation involved the 5-LOX enzyme and th e production of ROIs only in lymphoid cells. The inefficiency of the R OI pathway in epithelial cells is probably the consequence of both low ROI production due to undetectable expression of 5-LOX and rapid degr adation of hydrogen peroxide due to high catalase activity.