Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Sci Rep. 2018 Jan 9;8(1):188. doi: 10.1038/s41598-017-18380-0.
Acute liver injury (ALI) is characterized by hepatocyte damage and inflammation. In the present study, we examined whether the absence of Sprouty-related EVH1-domain-containing protein 2 (Spred2), a negative regulator of the Ras/Raf/ERK/MAPK pathway, influences ALI induced by D-galactosamine (D-GalN) and lipopolysaccharide (LPS). Compared to wild-type mice, Spred2 mice developed exacerbated liver injury represented by enhanced hepatocyte damage and inflammation. Enhanced ERK activation was observed in Spred2-livers, and the MEK/ERK inhibitor U0126 ameliorated ALI. Hepatic tumour necrosis factor α (TNFα) and interleukin (IL)-1β levels were increased in Spred-2-livers, and the neutralization of TNFα dramatically ameliorated ALI, which was associated with decreased levels of endogenous TNFα and IL-1β. When mice were challenged with D-GalN and TNFα, much severer ALI was observed in Spred2 mice with significant increases in endogenous TNFα and IL-1β in the livers. Immunohistochemically, Kupffer cells were found to produce TNFα, and isolated Kupffer cells from Spred2 mice produced significantly higher levels of TNFα than those from wild-type mice after LPS stimulation, which was significantly decreased by U0126. These results suggest that Spred2 negatively regulates D-GalN/LPS-induced ALI under the control of TNFα in Kupffer cells. Spred2 may present a therapeutic target for the treatment of ALI.
急性肝损伤（ALI）的特征是肝细胞损伤和炎症。在本研究中，我们研究了 Sprouty 相关 EVH1 结构域蛋白 2（Spred2）缺失，一种 Ras/Raf/ERK/MAPK 通路的负调节剂，是否会影响 D-半乳糖胺（D-GalN）和脂多糖（LPS）诱导的 ALI。与野生型小鼠相比，Spred2 小鼠表现出更严重的肝损伤，表现为增强的肝细胞损伤和炎症。在 Spred2 肝脏中观察到增强的 ERK 激活，而 MEK/ERK 抑制剂 U0126 改善了 ALI。Spred-2 肝脏中的肝肿瘤坏死因子α（TNFα）和白细胞介素（IL）-1β水平增加，TNFα 的中和显著改善了 ALI，这与内源性 TNFα 和 IL-1β水平降低有关。当小鼠受到 D-GalN 和 TNFα 挑战时，Spred2 小鼠观察到更严重的 ALI，肝脏中内源性 TNFα 和 IL-1β显著增加。免疫组化显示，Kupffer 细胞产生 TNFα，并且从 Spred2 小鼠分离的 Kupffer 细胞在 LPS 刺激后产生明显高于野生型小鼠的 TNFα，这一水平通过 U0126 显著降低。这些结果表明，Spred2 在 Kupffer 细胞中 TNFα 的控制下负调控 D-GalN/LPS 诱导的 ALI。Spred2 可能是治疗 ALI 的治疗靶点。
