Sultan Maya, Ben-Ari Ziv, Masoud Rula, Pappo Orit, Harats Dror, Kamari Yehuda, Safran Michal
The Liver Research Laboratory Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.
The Liver Disease Center Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.
PLoS One. 2017 Sep 27;12(9):e0184084. doi: 10.1371/journal.pone.0184084. eCollection 2017.
Fulminant hepatitis failure (FHF) is marked by the sudden loss of hepatic function, with a severe life-threatening course in persons with no prior history of liver disease. Interleukin (IL)-1α and IL-1β are key inflammatory cytokines but little is known about their role in the development of FHF. The aim of this study was to assess the involvement of IL-1α and IL-1β in the progression of LPS/GalN-induced FHF.
WT, IL-1α or IL-1β deficient mice were injected with LPS/GalN. Blood and liver tissue were collected at different time points, FHF related pathways were examined.
After FHF induction the survival of both IL-1α and IL-1β KO mice was longer than that of WT mice. Lower serum liver enzyme levels, demonstrated reduced hepatic injury in the IL-1α and IL-1βKO mice. Histologically detected liver injury and apoptotic hepatocytes were significantly reduced in the IL-1αand IL-1βKO mice compared to WT mice. Reduced hepatic IkB levels and upregulated NFκB activity in WT mice remained inhibited in IL-1α and IL-1β KO mice. Hepatic expression levels of TNFα and IL-6 were significantly increased in WT mice but not in IL-1α and IL-1β KO mice.
IL-1α and IL-1β play a central role in the pathogenesis of LPS/GalN-induced FHF. These interleukins are associated with the activation of NFκB signaling, upregulation of the pro-inflammatory cytokines and liver damage and apoptosis. Since neither IL-1α nor IL-1β depletions completely rescued the phenotype, we believe that IL-1α and IL-1β have a similar and probably complementary role in FHF progression.
暴发性肝衰竭（FHF）的特征是肝功能突然丧失，在无肝病既往史的患者中病程凶险，危及生命。白细胞介素（IL）-1α和IL-1β是关键的炎性细胞因子，但它们在FHF发生发展中的作用尚不清楚。本研究旨在评估IL-1α和IL-1β在脂多糖/氨基半乳糖（LPS/GalN）诱导的FHF进展中的作用。
给野生型（WT）、IL-1α或IL-1β基因敲除小鼠注射LPS/GalN。在不同时间点采集血液和肝组织，检测FHF相关通路。
诱导FHF后，IL-1α和IL-1β基因敲除小鼠的存活时间均长于WT小鼠。血清肝酶水平较低，表明IL-1α和IL-1β基因敲除小鼠的肝损伤减轻。与WT小鼠相比，组织学检测显示IL-1α和IL-1β基因敲除小鼠的肝损伤和凋亡肝细胞明显减少。WT小鼠肝脏中IκB水平降低和NFκB活性上调在IL-1α和IL-1β基因敲除小鼠中仍受到抑制。WT小鼠肝脏中肿瘤坏死因子α（TNFα）和IL-6的表达水平显著升高，而IL-1α和IL-1β基因敲除小鼠中则未升高。
IL-1α和IL-1β在LPS/GalN诱导的FHF发病机制中起核心作用。这些白细胞介素与NFκB信号通路激活、促炎细胞因子上调以及肝损伤和凋亡有关。由于IL-1α和IL-1β的缺失均未完全挽救该表型，我们认为IL-1α和IL-1β在FHF进展中具有相似且可能互补的作用。
