MOLECULARANALYSIS ENDOTOXIN-INDUCED-DISEASES

分子分析内毒素引起的疾病

• 批准号: 10470071
• 负责人: NAKANISHI Kenji
• 金额: $ 5.31万
• 依托单位: HYOGO COLLEGE OF MEDICINE
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10470071/
• 关键词: interleukin 18; LPS-induced liver injury; caspase-1-deficient mice; IL-18-deficient mice; Fas ligand; 劇症肝炎; caspase-1; エンドトキシン; 肝炎; IL-12; IL-18; FasL; TNF-α

Murine IL-18 is constitutively produced and stored as a biologically inactive precursor, and pro-IL-18 is cleaved into biologically active mature IL-18 by enzymes that become active under proper stimulation. We studied pathological roles of IL-18 for LPS-induced liver injury. Mice subsequently treated with Propionibacterium acnes (P.acnes) and LPS suffer from liver injury. Coinjection of anti-IL-18 and LPS protects this liver. Furthermore, casapase-1 deficient(-/-) mice or IL-18-/- mice are resistant to this sequential treatments. These results strongly indicated the involvement of IL-18 in this LPS-induced liver injury. Indeed, injection of IL-18 instead of LPS also induced liver injury in P.acnes-pretreated mice. Since IL-18 induces IFN-γ, TNF and FasL either directly or indirectly, we assumed these molecules are responsible for inducing liver injury in these P.acnes-pretreated mice. Injection of FasL as a from of membrane bound (LNK cells) or soluble form induces liver injury in P.acnes-pretreated mice. Importantly, administration of soluble FasL induces acute liver injury in P.acnes-pretreated caspase-1 -/- mice but does not do so in P.acnes-pretreated IL-18 -/- mice, indicating the IL-18 release in a caspase-independent fashion is essential for this liver injury. Therefore, positive feedback loop between FasL and IL-18 plays an important role in pathogenesis of LPS liver injury.

小鼠IL-18是组成性地作为无生物活性的前体产生和储存的，前IL-18在适当的刺激下被酶裂解成具有生物活性的成熟IL-18。我们研究了IL-18在lps诱导的肝损伤中的病理作用。随后用痤疮丙酸杆菌（p.a nnes）和LPS治疗小鼠肝损伤。联合注射抗il -18和LPS保护肝脏。此外，casapase-1缺陷（-/-）小鼠或IL-18-/-小鼠对这种顺序治疗具有抗性。这些结果强烈提示IL-18参与了lps诱导的肝损伤。事实上，注射IL-18而不是LPS也会引起p.a nnes预处理小鼠的肝损伤。由于IL-18直接或间接诱导IFN-γ、TNF和FasL，我们假设这些分子在这些p.a nys预处理的小鼠中诱导肝损伤。注射FasL作为膜结合（LNK细胞）或可溶性形式可诱导痤疮前处理小鼠肝损伤。重要的是，可溶性FasL在p.a nnes预处理的caspase-1 -/-小鼠中诱导急性肝损伤，但在p.a nnes预处理的IL-18 -/-小鼠中没有这种作用，这表明IL-18以caspase不依赖的方式释放对这种肝损伤是必不可少的。因此，FasL与IL-18之间的正反馈回路在LPS肝损伤的发病机制中起着重要作用。

项目成果

Hyodo,Y.,et al.: "Interleukin 18 upregulates perforin-mediated NK activity without increasing perforin messenger RNA expression by binding to constitutively expressed IL-18 receptor"J.Immunol.. 162. 1662-1668 (1999)

Hyodo，Y.，等人：“白细胞介素 18 通过与组成型表达的 IL-18 受体结合，上调穿孔素介导的 NK 活性，而不增加穿孔素信使 RNA 表达”J.Immunol.. 162. 1662-1668 (1999)

Tsutsui, H., Kayagaki, N., Kuida, k., Nakano, H., Hayashi, N., Takeda, K., Matsui, K., Kashiwamura, S-I., Hada, T., Akira, S., Yagita, H., Okamura, H. and Nakanishi, K.: "Caspase-1-independent , Fas/Fas ligand-mediated IL-18 secretion from macrophanges ca

Tsutsui, H.、Kayagaki, N.、Kuida, k.、Nakano, H.、Hayashi, N.、Takeda, K.、Matsui, K.、Kashiwamura, S-I.、Hada, T.、Akira, S.、

Yoshimoto,T.et al.: "LPS-stimulated SJL macrophages produce IL-12 and IL-18 that inhibit IgE production in vitro by induction of IFN-γ production from CD3^<int>IL-2R β^+T cells." J.Immunol.161. 1483-1492 (1998)

Yoshimoto, T. 等人：“LPS 刺激的 SJL 巨噬细胞产生 IL-12 和 IL-18，通过诱导 CD3^<int>IL-2R β^+T 细胞产生 IFN-γ，抑制体外 IgE 的产生。免疫学杂志 161. 1483-1492 (1998)

Hayashi,N., et al.: "Kupffer cells from Schistosoma mansoni-infected mice participate in the prompt type 2-differentiation of hepatic T cells in response to worm antigens."J.Immunol.. 163. 6702-6711 (1999)

Hayashi,N., et al.：“曼氏血吸虫感染小鼠的 Kupffer 细胞参与响应蠕虫抗原的肝 T 细胞的快速 2 型分化。”J.Immunol.. 163. 6702-6711 (1999)

Tomura,M.et al.: "Diffential capacities of CD4^+,CD8^+ and CD4^- CD8^- T cell subsets to express IL-18 receptor and produce IFN-γ in response to IL-18." J.Immunol.160. 3759-3765 (1998)

Tomura, M. 等人：“CD4^+、CD8^+ 和 CD4^- CD8^- T 细胞亚群表达 IL-18 受体并响应 IL-18 产生 IFN-γ 的能力不同。”免疫学160。3759-3765（1998）