MOLECULARANALYSIS ENDOTOXIN-INDUCED-DISEASES

小鼠IL-18被结构性地产生和储存为生物活性不活跃的前体，而前IL-18被在适当刺激下变得活跃的酶裂解成具有生物活性的成熟IL-18。我们研究了IL-18在脂多糖诱导的肝损伤中的病理作用。随后用痤疮丙酸杆菌(P.acnes)和脂多糖治疗的小鼠出现肝脏损伤。联合注射抗IL-18和内毒素可以保护肝脏。此外，Casapase-1缺陷(-/-)小鼠或IL-18-/-小鼠对这种顺序治疗具有抵抗力。这些结果有力地表明IL-18参与了内毒素诱导的肝损伤。事实上，注射IL-18而不是内毒素也会导致经痤疮假单胞菌处理的小鼠肝损伤。由于IL-18可直接或间接诱导干扰素-γ、肿瘤坏死因子和Fas-L，我们推测这些分子在痤疮假单胞菌诱导的小鼠肝损伤中起重要作用。以膜结合形式(LNK细胞)或可溶性形式注射FasL可诱导痤疮假单胞菌感染小鼠的肝损伤。重要的是，给予可溶性FasL可诱导痤疮假单胞菌预处理的caspase-1-/-小鼠的急性肝损伤，而在痤疮肺炎杆菌预处理的IL-18-/-小鼠中不发生这种急性肝损伤，表明IL-18以caspase非依赖性的方式释放在这种肝损伤中是必不可少的。因此，FasL和IL-18之间的正反馈环在内毒素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.