Tsutsui H, Kayagaki N, Kuida K, Nakano H, Hayashi N, Takeda K, Matsui K, Kashiwamura S, Hada T, Akira S, Yagita H, Okamura H, Nakanishi K
Department of Immunology and Medical Zoology, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Japan.
Immunity. 1999 Sep;11(3):359-67. doi: 10.1016/s1074-7613(00)80111-9.
IL-18, produced as a biologically inactive precursor, is processed by caspase-1 in LPS-activated macrophages. Here, we investigated caspase-1-independent processing of IL-18 in Fas ligand (FasL)-stimulated macrophages and its involvement in liver injury. Administration of Propionibacterium acnes (P. acnes) upregulated functional Fas expression on macrophages in an IFNgamma-dependent manner, and these macrophages became competent to secrete mature IL-18 upon stimulation with FasL. This was also the case for caspase-1-deficient mice. Administration of recombinant soluble FasL (rFasL) after P. acnes priming induced comparable elevation of serum IL-18 in parallel with elevated serum liver enzyme levels. However, liver injury was not induced in IL-18-deficient mice after rFasL administration. These results indicate a caspase-1-independent pathway of IL-18 secretion from FasL-stimulated macrophages and its critical involvement in FasL-induced liver injury.
白细胞介素-18（IL-18）以生物无活性前体形式产生，在脂多糖激活的巨噬细胞中由半胱天冬酶-1进行加工处理。在此，我们研究了在Fas配体（FasL）刺激的巨噬细胞中IL-18的非半胱天冬酶-1依赖性加工处理及其在肝损伤中的作用。痤疮丙酸杆菌（P. acnes）的给药以干扰素γ依赖性方式上调巨噬细胞上功能性Fas的表达，并且这些巨噬细胞在受到FasL刺激后能够分泌成熟的IL-18。半胱天冬酶-1缺陷小鼠的情况也是如此。在痤疮丙酸杆菌致敏后给予重组可溶性FasL（rFasL）可诱导血清IL-18水平相应升高，同时血清肝酶水平也升高。然而，在给予rFasL后，IL-18缺陷小鼠并未发生肝损伤。这些结果表明，FasL刺激的巨噬细胞存在一条非半胱天冬酶-1依赖性的IL-18分泌途径，且其在FasL诱导的肝损伤中起关键作用。
