NAKANISHI Kenji Hyogo College of Medicine, Professor, 医学部, 教授 (60172350)
AKIRA Shizuo Hyogo College of Medicine, Professor, 医学部, 教授 (50192919)
OKAMURA Haruki Hyogo College of Medicine, Associated Professor, 医学部, 助教授 (60111043)
|Budget Amount *help
¥3,600,000 (Direct Cost : ¥3,600,000)
Fiscal Year 1998 : ¥1,100,000 (Direct Cost : ¥1,100,000)
Fiscal Year 1997 : ¥2,500,000 (Direct Cost : ¥2,500,000)
IL-18 is a pleiotropic cytokine. IL-18 induces IFN-gamma in lymphocytes, upregulates functional Fas ligand expression of lymphocytes and also augments NK activity. Initially, IL-18 was discovered in the injured liver of the mice that had been sequentially administered with heat-killed Propionibacterium acnes (P.acnes) and endotoxin (LPS). IL- 18 is secreted by LPS-activated P.acnes-elicited Kupffer cells. IL-18 is produced by these cells as biologically inactive precursor form (prolL-18), and prolL-18 is cleaved into mature IL-18 by intracellular cysteine proteinase, caspase-l. In this study, we investigated the precise mechanism how IL-18 is involved in endotoxin-induced liver injury and found the followings. First, IL-18-deficient mice are resistant to endotoxin-induced liver injury, but highly sensitive to endotoxin-induced lethality, suggesting that IL-18 might be critical to endotoxin-induced liver injury. In addition, T cells in IL-18-deficient mice are impaired in the differentiation into Th1, a prototpe to inflammation, and NK activity of the mice also is defective, indicating that IL-18 is essential for functional development of immune system. Second, receptor for IL-18 is constitutively expressed on NK cells, whereas its expression on T cells is induced after stimulation with IL-12. MyD 88, an adapter molecule for the activation of receptor for IL-1 is critical for the signal transduction of IL-18. Lymphocytes from MyD88-deficient mice do not respond to IL-18 as well as IL-1. Third, caspase-1 deficient mice are resistant to the endotoxin-induced liver injury without showing early elevation of serum IL- 18 level, suggesting caspase- 1 is critical for IL- 18 secretion after stimulation with LPS.These results suggested that IL-18 might be an essential factor for endotoxin-induced liver injury.