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 (TN F-R) are two related cell surface molecules that induce apoptosis in s usceptible cells. With regard to their cytoplasmic homology region, we investigated whether Fas like the TNF-R activates nuclear factor kapp a B (NF-kappa B), using human SV80 fibroblasts transfected with the cD NA encoding human Fas. In this cell line Fas mobilizes the p50/p65 het erodimeric form of NF-kappa B and induces interleukin-6 (IL-6) product ion. Compared to NF-kappa B activation via the TNF-R differences in ki netics and signal intensity were observed. Peak activation occurred 2 hr after Fas compared to 1 hr after TNF-R stimulation. Furthermore, wh en 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 phospatidylc holine-specific phospholipase C, had an inhibitory effect while the pr otein 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 a n involvement of NF-kappa B in the cell death pathway triggered by the se 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 i nducing receptor serve a much broader range of biological functions. ( C) 1995 Wiley-Liss, Inc.