I. Department of Medicine, University Medical Center Mainz, Germany.
Institute for Molecular Medicine, University Medical Center Mainz, Germany.
J Hepatol. 2018 May;68(5):986-995. doi: 10.1016/j.jhep.2018.01.008. Epub 2018 Jan 31.
BACKGROUND & AIMS: Interleukin (IL)-1-type cytokines including IL-1α, IL-1β and interleukin-1 receptor antagonist (IL-1Ra) are among the most potent molecules of the innate immune system and exert biological activities through the ubiquitously expressed interleukin-1 receptor type 1 (IL-1R1). The role of IL-1R1 in hepatocytes during acute liver failure (ALF) remains undetermined.
The role of IL-1R1 during ALF was investigated using a novel transgenic mouse model exhibiting deletion of all signaling-capable IL-1R isoforms in hepatocytes (Il1r1).
ALF induced by D-galactosamine (D-GalN) and lipopolysaccharide (LPS) was significantly attenuated in Il1r1 mice leading to reduced mortality. Conditional deletion of Il1r1 decreased activation of injurious c-Jun N-terminal kinases (JNK)/c-Jun signaling, activated nuclear factor-kappa B (NF-κB) p65, inhibited extracellular signal-regulated kinase (ERK) and prevented caspase 3-mediated apoptosis. Moreover, Il1r1 mice exhibited reduced local and systemic inflammatory cytokine and chemokine levels, especially TNF-α, IL-1α/β, IL-6, CC-chemokine ligand 2 (CCL2), C-X-C motif ligand 1 (CXCL-1) and CXCL-2, and a reduced neutrophil recruitment into the hepatic tissue in response to injury. NLRP3 inflammasome expression and caspase 1 activation were suppressed in the absence of the hepatocellular IL-1R1. Inhibition of IL-1R1 using IL-1ra (anakinra) attenuated the severity of liver injury, while IL-1α administration exaggerated it. These effects were lost ex vivo and at later time points, supporting a role of IL-1R1 in inflammatory signal amplification during acute liver injury.
IL-1R1 in hepatocytes plays a pivotal role in an IL-1-driven auto-amplification of cell death and inflammation in the onset of ALF.
Acute liver injury which can cause lethal liver failure is medicated by a class of proteins called cytokines. Among these, interleukin-1 (IL-1) and the corresponding receptor IL-1R1 play a prominent role in the immune system, but their role in the liver is undetermined. In the current study, a novel mouse model with defective IL-1R1 in liver cells was studied. Mice lacking this receptor in liver cells were protected from cell death to a certain extent. This protection occurred only in the presence of other, neighboring cells, arguing for the involvement of proteins derived from these cells. This effect is called paracrine signaling and the current study has for the first time shown that the IL-1R1 receptor on hepatocytes is involved in acute liver failure in this context. The approved drug anakinra - which blocks IL-1R1 - had the same effect, supporting the proposed mechanism of action. The findings of this study suggest new treatment options for patients with acute liver failure by blocking defined signals of the immune system.
白细胞介素（IL）-1 型细胞因子，包括 IL-1α、IL-1β 和白细胞介素-1 受体拮抗剂（IL-1Ra），是先天免疫系统中最有效的分子之一，通过广泛表达的白细胞介素-1 受体 1（IL-1R1）发挥生物学活性。IL-1R1 在急性肝衰竭（ALF）期间在肝细胞中的作用仍未确定。
使用新型转基因小鼠模型，该模型在肝细胞中缺失所有具有信号转导能力的 IL-1R 同工型（Il1r1），研究了 IL-1R1 在 ALF 中的作用。
用半乳糖胺（D-GalN）和脂多糖（LPS）诱导的 ALF 在 Il1r1 小鼠中明显减轻，导致死亡率降低。条件性缺失 Il1r1 可降低损伤性 c-Jun N 末端激酶（JNK）/c-Jun 信号的激活，激活核因子-κB（NF-κB）p65，抑制细胞外信号调节激酶（ERK）并阻止半胱天冬酶 3 介导的细胞凋亡。此外，Il1r1 小鼠表现出局部和全身炎症细胞因子和趋化因子水平降低，尤其是 TNF-α、IL-1α/β、IL-6、CC 趋化因子配体 2（CCL2）、C-X-C 基序配体 1（CXCL-1）和 CXCL-2，以及损伤后中性粒细胞向肝组织的募集减少。NLRP3 炎性小体表达和半胱天冬酶 1 激活在缺乏肝细胞 IL-1R1 的情况下受到抑制。使用 IL-1Ra（anakinra）抑制 IL-1R1 可减轻肝损伤的严重程度，而 IL-1α 给药则加重了肝损伤。这些作用在体外和稍后的时间点丧失，支持 IL-1R1 在急性肝损伤期间炎症信号放大中的作用。
肝细胞中的 IL-1R1 在 IL-1 驱动的细胞死亡和炎症的自我放大中发挥关键作用，从而导致 ALF 的发生。
可导致致命性肝功能衰竭的急性肝损伤是由一类称为细胞因子的蛋白质介导的。在这些细胞因子中，白细胞介素-1（IL-1）和相应的受体 IL-1R1 在免疫系统中发挥突出作用，但它们在肝脏中的作用尚不确定。在目前的研究中，研究了一种新型的肝细胞中 IL-1R1 缺失的小鼠模型。缺乏这种肝细胞中受体的小鼠在一定程度上受到细胞死亡的保护。这种保护仅在存在其他相邻细胞的情况下发生，这表明涉及来自这些细胞的蛋白质。这种效应称为旁分泌信号，目前的研究首次表明，肝细胞中的 IL-1R1 受体在这种情况下参与了急性肝衰竭。已批准的药物 anakinra-其阻断 IL-1R1-具有相同的作用，支持所提出的作用机制。这项研究的结果通过阻断免疫系统的特定信号为急性肝衰竭患者提供了新的治疗选择。
