Fas/Apo-1 activates nuclear factor kappa B and induces interleukin-6 production.
Fas antigen/Apo-1 (Fas) and the p55 tumor necrosis factor receptor (TNF-R) are two related cell surface molecules that induce apoptosis in susceptible cells. With regard to their cytoplasmic homology region, we investigated whether Fas like the TNF-R activates nuclear factor kappa B (NF-kappa B), using human SV80 fibroblasts transfected with the cDNA encoding human Fas. In this cell line Fas mobilizes the p50/p65 heterodimeric form of NF-kappa B and induces interleukin-6 (IL-6) production. Compared to NF-kappa B activation via the TNF-R differences in kinetics and signal intensity were observed. Peak activation occurred 2 hr after Fas compared to 1 hr after TNF-R stimulation. Furthermore, when equitoxic concentrations of anti-Fas antibody and TNF were applied, TNF triggered a stronger NF-kappa B response. Studies using inhibitors of signal transduction suggest that both receptors mediate NF-kappa B activation via similar routes: D609, an inhibitor of the phospatidylcholine-specific phospholipase C, had an inhibitory effect, while the protein kinase C inhibitor staurosporine had an enhancing effect on both Fas and TNF-R induced NF-kappa B mobilization. Interestingly, D609 had no influence on Fas and TNF-R mediated cytotoxicity arguing against an involvement of NF-kappa B in the cell death pathway triggered by these receptors. This is the first indication that Fas may activate genes via NF-kappa B and may thus in addition to its role as a cell death inducing receptor serve a much broader range of biological functions.
Rensing-Ehl
A
A
Institute for Immunology, University of Munich, Germany.
Hess
S
S
Ziegler-Heitbrock
H W
HW
Riethmüller
G
G
Engelmann
H
H
D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis; D001483:Base Sequence; D002461:Cell Line, Transformed; D005347:Fibroblasts / Q000378:metabolism; D016325:HIV Long Terminal Repeat; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis*; D007700:Kinetics; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D013539:Simian virus 40; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019014:fas Receptor / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*
D000906:Antibodies; D015850:Interleukin-6; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor