Reactive oxygen intermediate-dependent NF-kappa B activation by interleukin-1 beta requires 5-lipoxygenase or NADPH oxidase activity

We previously reported that the role of reactive oxygen intermediates (ROIs ) in NF-kappa B activation by proinflammatory cytokines was cell specific. However, the sources for ROIs in various cell types are Set to be determine d and might include 5-lipoxygenase (5-LOX) and NADPH oxidase. 5-LOX and 5-L OX activating protein (FLAP) are coexpressed in lymphoid cells but not in m onocytic or epithelial cells. Stimulation of lymphoid cells with interleuki n-1 beta (IL-1 beta) led to ROI production and NF-kappa B activation, which could both be blocked by antioxidants or FLAP inhibitors, confirming that 5-LOX was the source of ROIs and was required for NF-kappa B activation in these cells. IL-1 alpha stimulation of epithelial cells did not generate an y ROIs and NF-kappa B induction was not influenced by 5-LOX inhibitors. How ever, reintroduction of a functional 5-LOX system in these cells allowed RO I production and 5-LOX-dependent NF-kappa B activation. In monocytic cells, IL-1 beta treatment led to a production of ROIs which is independent of th e 5-LOX enzyme but requires the NADPH oxidase activity. This pathway involv es the Rad and Cdc42 GTPases, two enzymes which are not required for NF-kap pa B activation by IL-1 beta in epithelial cells. In conclusion, three diff erent cell-specific pathways lead to NP-kappa B activation by IL-I beta: a pathway dependent on ROI production by 5-LOX in lymphoid cells, an ROI- and 5-LOX-independent pathway in epithelial cells, and a pathway requiring ROI production by NADPH oxidase in monocytic tells.