MOLECULARANALYSIS ENDOTOXIN-INDUCED-DISEASES

鼠IL-18组成性产生并作为生物学上无活性的前体储存，并且pro-IL-18被在适当刺激下变得有活性的酶切割成生物学上有活性的成熟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.acnes）和LPS处理的小鼠遭受肝损伤。抗IL-18和LPS的共注射保护该肝脏。此外，Casapase-1缺陷（-/-）小鼠或IL-18-/-小鼠对这种顺序治疗具有抗性。这些结果强烈表明IL-18参与了LPS诱导的肝损伤。事实上，注射IL-18代替LPS也诱导痤疮丙酸杆菌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，我们假设这些分子负责在这些痤疮丙酸杆菌预处理的小鼠中诱导肝损伤。注射FasL作为膜结合（LNK细胞）或可溶形式诱导痤疮丙酸杆菌预处理小鼠的肝损伤。重要的是，可溶性FasL的施用在痤疮丙酸杆菌预处理的半胱天冬酶-1-/-小鼠中诱导急性肝损伤，但在痤疮丙酸杆菌预处理的IL-18 -/-小鼠中不诱导急性肝损伤，表明IL-18以半胱天冬酶非依赖性方式释放对于这种肝损伤是必需的。因此，FasL与IL-18之间的正反馈环在LPS肝损伤的发病机制中起重要作用。

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.