Fas Ligand Induces Cell-autonomous NF-κB Activation and Interleukin-8 Production by a Mechanism Distinct from That of Tumor Necrosis Factor-α

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. 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. The tumor necrosis factor (TNF) 1The abbreviations used are: TNF, tumor necrosis factor; TNFR1, TNF receptor type I; CTD, C-terminal domain; DD, death domain; DED, death effector domain; FasL, Fas ligand; fmk, fluoromethylketone; mAb, monoclonal antibody; RLU, relative luciferase units; Z, benzyloxycarbonyl; ELISA, enzyme-linked immunosorbent assay; EMSA, electrophoretic mobility shift assay; IL, interleukin; siRNA, short interfering RNA; RT-PCR, reverse transcription-PCR; GFP, green fluorescent protein; HEK, human embryonic kidney; CLARP, caspase-like apoptosis regulatory protein. receptor family is a still growing group of cytokine receptors that regulate cell proliferation, differentiation, and death. A subset of this family called death receptors possesses a characteristic cytoplasmic region named death domain (DD) (1Nagata S. Cell. 1997; 88: 355-365Abstract Full Text Full Text PDF PubMed Scopus (4561) Google Scholar). Activation of these receptors induces recruitment of the death-inducing signaling complex, which consists of adaptor molecules (such as FADD and/or TRADD) and upstream caspases (such as caspase-8 and -10); this complex in turn initiates the activation cascade of caspases, which eventually results in apoptotic cell death. Like other members of the TNF receptor family, all the death receptors (TNF receptor type I (TNFR1), Fas, DR3, DR4, DR5, and DR6) have been reported to induce the activation of NF-κB (2Rensing-Ehl A. Hess S. Ziegler-Heitbrock H.W. Riethmuller G. Engelmann H. J. Inflamm. 1995; 45: 161-174PubMed Google Scholar, 3Ponton A. Clement M.V. Stamenkovic I. J. Biol. Chem. 1996; 271: 8991-8995Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 4Marsters S.A. Sheridan J.P. Donahue C.J. Pitti R.M. Gray C.L. Goddard A.D. Bauer K.D. Ashkenazi A. Curr. Biol. 1996; 6: 1669-1676Abstract Full Text Full Text PDF PubMed Google Scholar, 5Chaudhary P.M. Eby M. Jasmin A. 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Cell. 1997; 88: 355-365Abstract Full Text Full Text PDF PubMed Scopus (4561) Google Scholar). The Fas-FasL system plays pivotal roles in various aspects of immune regulation and function, such as self-tolerance, and cell-mediated cytotoxicity (9Suda T. Nagata S. J. Allergy Clin. Immunol. 1997; 100: S97-S101Abstract Full Text Full Text PDF PubMed Google Scholar). It has been proposed that FasL is expressed in “immune privileged” organs (such as the eye and testis) and protects them from destructive inflammation by counterattacking inflammatory cells (10Griffith T.S. Brunner T. Fletcher S.M. Green D.R. Ferguson T.A. Science. 1995; 270: 1189-1192Crossref PubMed Scopus (1879) Google Scholar, 11Bellgrau D. Gold D. Selawry H. Moore J. Franzusoff A. Duke R.C. Nature. 1995; 377: 630-632Crossref PubMed Scopus (1103) Google Scholar). In contrast, ectopic expression of FasL by genetic engineering induces inflammation accompanied by massive neutrophil infiltration in animals (12Seino K. 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These results indicate that secondary is essential for the FasL-induced NF-κB activation. with a D.A. Google Scholar), of and in the of the NF-κB induced by FasL not that FasL and induce a NF-κB The of Fas and FADD a for the FasL-induced NF-κB clarify which cytoplasmic region of the Fas receptor was for the FasL-induced NF-κB activation, we expressed a of of in HEK293 cells. expression of the wild-type and mutant Fas on the cell of was by with of NF-κB of the C-terminal from its to induce apoptosis N. Nagata S. J. Biol. Chem. Full Text PDF PubMed Google Scholar). However, this did not its to induce NF-κB activation. the other the of Fas to a of the and the to in the which its N. Nagata S. J. Biol. Chem. Full Text PDF PubMed Google Scholar), its to activate These results indicate that the C-terminal of are but the of Fas is for its to activate We the of FADD, which is essential to caspase-8 and to induce apoptosis upon Fas ligation A. Y. H. Y. Nagata S. J. 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PubMed Scopus Google Scholar, J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, C. D. A. Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar). However, a mutant of the is to its type in that the of is not required for to activate It was reported that Fas ligation induces apoptosis but not NF-κB activation in mouse cell K. J. PubMed Scopus Google Scholar). We to the FasL-induced NF-κB activation mouse cell cell cell and embryonic cell induced NF-κB activation in HEK293 cells, we the of to activate the of was than that of in HEK293 cells and induced apoptosis as as in cells not to induce NF-κB activation in induced this response but in the cell is that the of to induce NF-κB activation FasL not induce NF-κB activation in mouse cell inhibited FasL- but not TNF-α-induced NF-κB activation and We molecules between and to clarify the region of for NF-κB activation. 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However, caspase-8 is essential for FasL-induced NF-κB activation not has not been directly We this by caspase-8 expression in HEK293 cells in the caspase-8 caspase-8 expression in HEK293 cells. inhibited NF-κB activation induced by FasL but not by and and caspase-8 the FasL-induced NF-κB activation, and for and effect of these a effect on the TNF-α-induced NF-κB activation not the of to did not is a to that the the FasL-induced NF-κB activation To the of caspase-8 in the FasL-induced NF-κB activation, we used the cell with A. Y. H. Y. Nagata S. J. Biol. 1998; PubMed Scopus Google Scholar), cells were to FasL-induced wild-type cells were to not cells were with FasL in the of apoptosis was and NF-κB activity was TNF-α-induced NF-κB activation was in and cells, the FasL-induced NF-κB activation was in cells in the of and not as well as of an expression wild-type caspase-8 the FasL-induced NF-κB activation in cells, that the of caspase-8 was the for this in cells. expression of a mutant of caspase-8 the FasL-induced NF-κB activation in cells in the of these results indicate that caspase-8 plays an important in the FasL-induced NF-κB activation, and that are and for this NF-κB Activation by is a caspase-8 that the death apoptosis M. Tschopp J. Nat. Immunol. PubMed Scopus Google Scholar). is expressed in the consists of and a caspase-like and the short has the of with FADD and caspase-8 and FasL-induced with P.M. Eby Jasmin A. A. Liu L. Hood L. PubMed Scopus Google Scholar, H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), of a of expression induced NF-κB activation in HEK293 cells, expression to induced NF-κB activation not In contrast, we found that expression of a of inhibited FasL- but not TNF-α-induced NF-κB activation effect than family had effect on FasL- and TNF-α-induced NF-κB activation. In addition, and inhibited the FasL- but not TNF-α-induced NF-κB activation in cells These results that is an than a for the FasL-induced NF-κB activation, may induce NF-κB activation other of of RIP, and IKKγ on the FasL-induced NF-κB RIP, and IKKγ are involved in the NF-κB activation. in a dominant-negative mutant of IKKγ inhibited FasL- and TNF-α-induced NF-κB activation, a of TRADD inhibited the but not FasL-induced NF-κB activation. The of had such effect on NF-κB activation by FasL TNF-α. has been to involved in the FasL-induced NF-κB activation T. R.C. Holler N. Thome M. M. Burns K. M. N. M. Tschopp J. Curr. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar), a mutant of that inhibited the TNF-α-induced NF-κB activation had effect on the FasL-induced NF-κB activation results indicate that FasL and induce NF-κB activation It has been that a variety of cell types IL-8 in response to Fas and activation of NF-κB has been with the FasL-induced IL-8 production A. J. Immunol. 1995; Google Scholar, C. Yagita H. T. T. K. Okumura K. 1996; PubMed Scopus Google Scholar, N. K. Kawasaki M. M. Y. Kunitake R. Maeyama T. T. Hara N. J. Biol. 1999; PubMed Scopus Google Scholar, S.A. S.M. Nat. Med. 6: PubMed Scopus Google Scholar, J.H. S.M. J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, C. H. H. Google Scholar, D.A. Google Scholar, M. A. Y. Y. T. J. PubMed Scopus Google Scholar). However, has been that NF-κB activation is essential for this that the FasL-induced NF-κB activation is a We that the NF-κB is essential for the FasL-induced reporter gene activity the IL-8 promoter In addition, the and a that NF-κB activation inhibited FasL-induced IL-8 production These results indicate that NF-κB activation is for the FasL-induced IL-8 the kinetics of IL-8 production by FasL was slower than of the IL-8 production induced by and involving of of cells with the reporter gene indicated for the that NF-κB activation, and IL-8 production by FasL is cell autonomous and is not mediated by a secondary factor A and The from a death receptor to NF-κB activation has been for V. M. Biol. 11: Full Text Full Text PDF PubMed Scopus Google Scholar). The most RIP, and TRADD directly with the of and a to and These molecules activate the complex, which in turn induces the and of the other how FasL induces NF-κB activation is still have the molecular of NF-κB activation by ligation of Fas (2Rensing-Ehl A. Hess S. Ziegler-Heitbrock H.W. Riethmuller G. Engelmann H. J. Inflamm. 1995; 45: 161-174PubMed Google Scholar, 3Ponton A. Clement M.V. Stamenkovic I. J. Biol. Chem. 1996; 271: 8991-8995Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, D.A. Google Scholar, P.M. Eby Jasmin A. A. Liu L. Hood L. PubMed Scopus Google Scholar, H. R. S. G. M. C. P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). from Fas to to to activate However, results indicated that a of signaling molecules are used for the FasL-induced NF-κB activation from used for the TNF-α-induced FADD and important molecules for the mediated NF-κB activation induced by FasL but not by TNF-α. the of the Fas to apoptosis and NF-κB activation of is to the in which the of plays an important in apoptosis and NF-κB activation Immunol. Full Text Full Text PDF PubMed Scopus Google Scholar), and from the in which the is the to the NF-κB activation. the other TRADD and were not essential for the FasL-induced NF-κB activation It has been reported that a dominant-negative of NF-κB activation induced by of FADD caspase-8 H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). FADD and caspase-8 have that are from the death on the of of these molecules J.L. A. M. A. K. Science. 1998; PubMed Scopus Google Scholar, J. D. A. A. 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The expression of a mutant of caspase-8 in cells the FasL-induced NF-κB activation that a in cells. In addition, the FasL-induced NF-κB activation was in cells, that caspase-8 is required for the we the FasL-induced NF-κB activation in and cell in the of is the in cells. had a dominant-negative effect on FasL-induced NF-κB activation in HEK293 cells. has a to for the of its that the of of is important for to activate NF-κB may an to the for the FasL-induced NF-κB activation in human cells. cells from but not show J. D. A. A. Nature. 1998; PubMed Scopus Google Scholar), that FADD plays an essential in a of receptors other than was reported that in the of is by a cell C. J. I. I. J. Immunol. PubMed Scopus Google Scholar), and that of of but not its cell J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Furthermore, was that of in which to in is involved in the regulation of cell C. D. A. Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar). However, we found that the of this is not required for its to activate NF-κB these results not indicate that the of is not essential for to induce NF-κB activation, but that NF-κB activation is not required for the In results that FasL induce an inflammatory and by NF-κB in a a that is distinct from that of TNF-α. of this to to the FasL-induced inflammation. We I. for and with