半胱天冬酶-1非依赖性、Fas/Fas配体介导的巨噬细胞白细胞介素-18分泌导致小鼠急性肝损伤。

Caspase-1-independent, Fas/Fas ligand-mediated IL-18 secretion from macrophages causes acute liver injury in mice.

作者信息

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

机构信息

Department of Immunology and Medical Zoology, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Japan.

出版信息

Immunity. 1999 Sep;11(3):359-67. doi: 10.1016/s1074-7613(00)80111-9.

DOI:10.1016/s1074-7613(00)80111-9

PMID:10514014

Abstract

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.

摘要

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。