Department of Infectious Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Liver Int. 2018 Feb;38(2):229-238. doi: 10.1111/liv.13503. Epub 2017 Jul 20.
BACKGROUND & AIMS: Patients with acute-on-chronic liver failure (ACLF) usually exhibit defective monocyte function and excessive systemic inflammatory response. Interleukin-33 (IL-33) acts as a danger-associated molecular pattern (DAMP) to modulate immune response. However, the role of IL-33 in regulating monocyte function during hepatitis B-precipitated ACLF (HB-ACLF) in response to lipopolysaccharide (LPS) has not been clear.
In this study, the levels of IL-33/ST2 in blood and liver samples collected from patients with HB-ACLF, chronic hepatitis B (CHB) and normal controls and the associated of those findings with disease severity were analysed. HLA-DR and CD80 expression, phagocytosis capacity, cytokine secretion and MAP kinase activation induced by LPS were detected to explore the role of IL-33/ST2 signal in regulating monocyte function in patients.
The expression levels of IL-33/ST2 were significantly increased in peripheral blood and livers of patients with HB-ACLF, as compared with patients with CHB and controls. It was found that serum IL-33 level was associated with severity of liver disease. Treatment with IL-33 on monocytes significantly increased HLA-DR, CCR2 and CD80 expression, enhanced LPS-stimulated TNF-α, IL-6 and IL-1β secretion, but did not affect the phagocytic capacity. Furthermore, IL-33 signalling enhanced the ERK1/2 activation of monocytes in response to LPS.
DAMP molecular IL-33 augmented the 'storm' of monocytic inflammation in response to LPS through ERK1/2 activation during HB-ACLF.
慢加急性肝衰竭（ACLF）患者通常表现出单核细胞功能缺陷和过度的全身炎症反应。白细胞介素-33（IL-33）作为一种危险相关分子模式（DAMP），可调节免疫反应。然而，IL-33 在调节乙型肝炎诱发的 ACLF（HB-ACLF）患者单核细胞功能方面的作用，在脂多糖（LPS）刺激下尚不清楚。
本研究分析了来自 HB-ACLF、慢性乙型肝炎（CHB）和正常对照患者的血液和肝组织样本中 IL-33/ST2 的水平及其与疾病严重程度的关系。检测 LPS 诱导的 HLA-DR 和 CD80 表达、吞噬能力、细胞因子分泌和 MAP 激酶激活，以探讨 IL-33/ST2 信号在调节患者单核细胞功能中的作用。
与 CHB 患者和对照组相比，HB-ACLF 患者外周血和肝脏中 IL-33/ST2 的表达水平显著升高。结果发现，血清 IL-33 水平与肝脏疾病的严重程度相关。IL-33 处理单核细胞后，显著增加 HLA-DR、CCR2 和 CD80 的表达，增强 LPS 刺激的 TNF-α、IL-6 和 IL-1β 的分泌，但不影响吞噬能力。此外，IL-33 信号通过 ERK1/2 激活增强了单核细胞对 LPS 的反应。
在 HB-ACLF 期间，DAMP 分子 IL-33 通过 ERK1/2 激活增强了单核细胞对 LPS 的炎症“风暴”。
