Fas ligand induces cell-autonomous NF-κB activation and interleukin-8 production by a mechanism distinct from that of tumor necrosis factor-α

Abstract

Fas ligand (FasL) has been well characterized as a death factor. However, recent studies revealed that FasL possesses inflammatory activity. Here we found that FasL induces production of the inflammatory chemokine IL-8 without inducing apoptosis in HEK293 cells. Reporter gene assays involving wild-type and mutated IL-8 promoters and NF-κB- and AP-1 reporter constructs indicated that an FasL-induced NF-κB and AP-1 activity are required for maximal promoter activity. FasL induced NF-κB activation with slower kinetics than did TNF-α, yet this response was cell autonomous and not mediated by secondary paracrine factors. The death domain of Fas, FADD, and caspase-8 were required for NF-κB activation by FasL. A dominant-negative mutant of IKKγ inhibited the FasL-induced NF-κB activation. However, TRADD and RIP, which are essential for the TNF-α-induced NF-κB activation, were not involved in the FasL-induced NF-κB activation. Moreover, CLARP/FLIP inhibited the FasL- but not the TNF-α-induced NF-κB activation. These results show that FasL induces NF-κB activation and IL-8 production by a novel mechanism, distinct from that of TNF-α. In addition, we found that mouse FADD had a dominant-negative effect on the FasL-induced NF-κB activation in HEK293 cells, which may indicate a species difference between human and mouse in the FasL-induced NF-κB activation.