FAS ACTIVATES NF-KAPPA-B AND INDUCES APOPTOSIS IN T-CELL LINES BY SIGNALING PATHWAYS DISTINCT FROM THOSE INDUCED BY TNF-ALPHA

The p55 tumor necrosis factor (TNF) receptor and the Fas (CD95/APO-1) receptor share an intracellular domain necessary to induce apoptosis, suggesting they utilize common signaling pathways. To define pathways triggered by Fas and TNF-alpha we utilized human CEM-C7 T-cells. As ex pected, stimulation of either receptor induced apoptosis and TNF-alpha -induced signaling included the activation of NF-kappa B. Surprisingly , Fas-induced signaling also triggered the activation of NF-kappa B in T cells, yet the kinetics of NF-kappa B induction by Fas was markedly delayed. NF-kappa B activation by both pathways was persistent and du e to the sequential degradation of I kappa B-alpha and I kappa B-beta. However, the kinetics of I kappa B degradation were different and the re were differential effects of protease inhibitors and antioxidants o n NF-kappa B activation. Signaling pathways leading to activation of a poptosis were similarly separable and were also independent of NF-kapp a B activation. Thus, the Fas and TNF receptors utilize distinct signa l transduction pathways in T-cells to induce NF-kappa B and apoptosis.