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 induces cell-autonomous NF-κB activation and interleukin-8 production by a mechanism distinct from that of tumor necrosis factor-α
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DOI：
10.1074/jbc.m403226200
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发表时间：
2004-11-05
影响因子：
4.8
通讯作者：
Suda, T
中科院分区：
文献类型：
--
作者：
Imamura, R;Konaka, K;Suda, T
Fas配体（FasL）是一种死亡因子。然而，最近的研究表明，FasL具有炎症活性。在这里，我们发现FasL诱导HEK 293细胞中炎性趋化因子IL-8的产生而不诱导凋亡。涉及野生型和突变型IL-8启动子和NF-κ B-和AP-1报告基因构建体的报告基因测定表明，FasL诱导的NF-κ B和AP-1活性是最大启动子活性所必需的。FasL诱导NF-κ B活化的动力学比TNF-α慢，但这种反应是细胞自主的，不受次级旁分泌因子介导。Fas、FADD和caspase-8的死亡结构域是FasL激活NF-κ B所必需的。IKK γ的显性阴性突变体抑制FasL诱导的NF-κ B活化。然而，TRADD和RIP，这是必要的TNF-α诱导的NF-κ B激活，不参与FasL诱导的NF-κ B激活。此外，BMPs/FLIP抑制FasL-但不抑制TNF-α-诱导的NF-κ B活化。这些结果表明，FasL诱导NF-κ B活化和IL-8的生产通过一种新的机制，不同的TNF-α。此外，我们发现小鼠FADD对FasL诱导的HEK 293细胞NF-κ B活化具有显性负效应，这可能表明人和小鼠在FasL诱导的NF-κ B活化方面存在种属差异。
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-kappaB- and AP-1 reporter constructs indicated that an FasL-induced NF-kappaB and AP-1 activity are required for maximal promoter activity. FasL induced NF-kappaB activation with slower kinetics than did TNF-alpha, 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-kappaB activation by FasL. A dominant-negative mutant of IKKgamma inhibited the FasL-induced NF-kappaB activation. However, TRADD and RIP, which are essential for the TNF-alpha-induced NF-kappaB activation, were not involved in the FasL-induced NF-kappaB activation. Moreover, CLARP/FLIP inhibited the FasL- but not the TNF-alpha-induced NF-kappaB activation. These results show that FasL induces NF-kappaB activation and IL-8 production by a novel mechanism, distinct from that of TNF-alpha. In addition, we found that mouse FADD had a dominant-negative effect on the FasL-induced NF-kappaB activation in HEK293 cells, which may indicate a species difference between human and mouse in the FasL-induced NF-kappaB activation.