Involvement of IL-17 in Fas ligand-induced inflammation
Involvement of IL-17 in Fas ligand-induced inflammation
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DOI：
10.1093/intimm/dxh111
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发表时间：
2004-08-01
影响因子：
4.4
通讯作者：
Suda, T
中科院分区：
文献类型：
--
作者：
Umemura, M;Kawabe, T;Suda, T
Fas配体（FasL）是一种死亡因子。然而，最近的研究表明，异位表达的FasL诱导炎症与大量的中性粒细胞浸润。我们以前证明了FasL的中性粒细胞浸润诱导活性部分依赖于IL-1 β，但部分独立于IL-1 β。在这里，我们研究了从接受i. p.注射FFL（一种表达FasL的肿瘤细胞系）的小鼠中获得的腹腔灌洗液的细胞因子谱。我们发现，FFL注射不仅引起IL-1 β的显著增加，而且引起IL-6、IL-17、IL-18、KC/趋化因子CXC配体1和巨噬细胞炎性蛋白（MIP）-2的显著增加，但不引起IL-1 α、IFN-γ、TGF-β或TNF-α的显著增加。在Fas缺陷型Ipr小鼠中未观察到FFL诱导的细胞因子产生。在单独表达IL-1 β、IL-6、IL-17或IL-18的转染细胞中，仅表达IL-1 β和IL-17的细胞诱导中性粒细胞浸润。在这些分析中，少至20 pg的腹膜IL-17诱导中性粒细胞浸润。在IL-1缺陷小鼠中，FFL注射后腹膜IL-17水平大大降低。然而，IL-17水平仍高于中性粒细胞浸润的阈值。与此一致，抗IL-17抗体与FFL的共同施用减少了IL-1缺陷小鼠中的腹膜KC水平和中性粒细胞浸润。此外，肿瘤细胞表达IL-17抑制野生型和裸鼠中的肿瘤生长。这些结果表明，FasL是一种上游炎症因子，在体内诱导多种其他炎症细胞因子，并表明IL-17参与FasL诱导的炎症在IL-1 β的情况下。
Fas ligand (FasL) has been well characterized as a death factor. However, recent studies revealed that ectopic expression of FasL induces inflammation associated with massive neutrophil infiltration. We previously demonstrated that the neutrophil infiltration-inducing activity of FasL is partly dependent on, but partly independent of, IL-1beta. Here we investigated the cytokine profile of peritoneal lavage fluid obtained from mice that received i.p. injections of FFL, a FasL-expressing tumor cell line. We found that FFL injection caused a marked increase of not only IL-1beta but also IL-6, IL-17, IL-18, KC/chemokine CXC ligand 1 and macrophage inflammatory protein (MIP)-2, but not of IL-1alpha, IFN-gamma, TGF-beta or TNF-alpha. The FFL-induced cytokine production was not observed in Fas-deficient Ipr mice. Among cells transfected to express individually IL-1beta, IL-6, IL-17, or IL-18, only those expressing IL-1beta and IL-17 induced neutrophil infiltration. In these analyses, as little as 20 pg of peritoneal IL-17 induced neutrophil infiltration. The peritoneal IL-17 levels after FFL-injection were greatly diminished in IL-1-deficient mice. However, the IL-17 level was still above the threshold for neutrophil infiltration. Consistent with this, co-administration of the anti-IL-17 antibody with FFL diminished the peritoneal KC levels and neutrophil infiltration in IL-1-deficient mice. In addition, the expression of IL-17 by the tumor cells inhibited tumor growth in wild-type and nude mice. These results indicate that FasL is an upstream inflammatory factor that induces a variety of other inflammatory cytokines in vivo, and suggest that IL-17 is involved in FasL-induced inflammation in the absence of IL-1beta.