MOLECULARANALYSIS ENDOTOXIN-INDUCED-DISEASES

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。

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.