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Published 2 August 2004. doi:10.1083/jcb.200401036
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 166, Number 3, 369-380
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Article

 NF{kappa}B activation by Fas is mediated through FADD, caspase-8, and RIP and is inhibited by FLIP

Sebastian Kreuz1, Daniela Siegmund1, Jost-Julian Rumpf2, Dierk Samel1, Martin Leverkus3, Ottmar Janssen4, Georg Häcker5, Oliver Dittrich-Breiholz6, Michael Kracht6, Peter Scheurich1, and Harald Wajant2

1 Institute of Cell Biology and Immunology, University of Stuttgart, 70569 Stuttgart, Germany
2 Department of Molecular Internal Medicine, Medical Polyclinic, University of Wuerzburg, 97070 Wuerzburg, Germany
3 Department of Dermatology, University of Wuerzburg Medical School, 97080 Wuerzburg, Germany
4 Institute of Immunology, Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
5 Institute for Medical Microbiology, Immunology, and Hygiene, Technical University Munich, 81675 Munich, Germany
6 Institute of Pharmacology, Medical School Hannover, 30625 Hannover, Germany

Address correspondence to H. Wajant, Dept. of Molecular Medicine, Medical Polyclinic, University of Wuerzburg, Roentgenring 11, 97070 Wuerzburg, Germany. Tel.: 49-931-201-71010. Fax: 49-931-201-71070. email: harald.wajant{at}mail.uni-wuerzburg.de

Fas (APO-1/CD95) is the prototypic death receptor, and the molecular mechanisms of Fas-induced apoptosis are comparably well understood. Here, we show that Fas activates NF{kappa}B via a pathway involving RIP, FADD, and caspase-8. Remarkably, the enzymatic activity of the latter was dispensable for Fas-induced NF{kappa}B signaling pointing to a scaffolding-related function of caspase-8 in nonapoptotic Fas signaling. NF{kappa}B was activated by overexpressed FLIPL and FLIPS in a cell type–specific manner. However, in the context of Fas signaling both isoforms blocked FasL-induced NF{kappa}B activation. Moreover, down-regulation of both endogenous FLIP isoforms or of endogenous FLIPL alone was sufficient to enhance FasL-induced expression of the NF{kappa}B target gene IL8. As NF{kappa}B signaling is inhibited during apoptosis, FasL-induced NF{kappa}B activation was most prominent in cells that were protected by Bcl2 expression or caspase inhibitors and expressed no or minute amounts of FLIP. Thus, protection against Fas-induced apoptosis in a FLIP-independent manner converted a proapoptotic Fas signal into an inflammatory NF{kappa}B-related response.

Key Words: apoptosis; Bcl2; CD95; FasL; IL8

Abbreviations used in this paper: CHX, cycloheximide; DISC, death-inducing signaling complex; IAP, inhibitor of apoptosis; RPA, RNase protection assay; siRNA, small interfering RNA.


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