Fas activates NF-kappaB 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 expected, stimulation of either receptor induced apoptosis and TNF-alpha-induced signaling included the activation of NF-kappaB. Surprisingly, Fas-induced signaling also triggered the activation of NF-kappaB in T cells, yet the kinetics of NF-kappaB induction by Fas was markedly delayed. NF-kappaB activation by both pathways was persistent and due to the sequential degradation of IkappaB-alpha and IkappaB-beta. However, the kinetics of IkappaB degradation were different and there were differential effects of protease inhibitors and antioxidants on NF-kappaB activation. Signaling pathways leading to activation of apoptosis were similarly separable and were also independent of NF-kappaB activation. Thus, the Fas and TNF receptors utilize distinct signal transduction pathways in T-cells to induce NF-kappaB and apoptosis.
Packham
G
G
Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Lahti
J M
JM
Fee
B E
BE
Gawn
J M
JM
Coustan-Smith
E
E
Campana
D
D
Douglas
I
I
Kidd
V J
VJ
Ghosh
S
S
Cleveland
J L
JL