| Abstract: | Tepoxalin, a dual inhibitor of cyclooxygenase (CO) and 5-lipoxygenase (5LO) with cytokine modifying activity, is also a potent inhibitor of the transcription factor, nuclear factor κB (NFκB). NFκB is a pleiotropic activator that is involved in the regulation of many genes whose products participate in immune or inflammatory responses. Tepoxalin inhibited in a dose related manner NFκB activation by PMA + ionomycin or H2O2 in Jurkat and HeLa cells. TNF-α-induced NFκB was also inhibited by tepoxalin in HeLa cells, while relatively less marked inhibition was observed in Jurkat cells. Activation of NFκB in several monocytic cell lines was also suppressed by tepoxalin. However AP-1 stimulation under the same conditions was not affected by tepoxalin. Other CO, LO inhibitors such as naproxen or zileuton did not inhibit NFκB activities. This inhibitory activity of tepoxalin was further illustrated by its suppression of NFκB regulated genes such as IL-6 in PMA stimulated human PBL and c-myc in IL-2 dependent T cell lines. Tepoxalin also blocked PMA + ionomycin-induced IκB degradation in a time-dependent fashion. The possible mechanism of tepoxalin in NFκB activation and its potential clinical application are discussed. |
