程序性死亡 1 及其配体在自身免疫性肝炎 C57BL/6 小鼠肝脏中的表达。

Expression of programmed death 1 and its ligands in the liver of autoimmune hepatitis C57BL/6 mice.

机构信息

Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

出版信息

Chin Med J (Engl). 2009 Aug 20;122(16):1941-6.

PMID:19781375

Abstract

BACKGROUND

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease with unknown etiology. Programmed death 1 (PD-1) and its ligands (PD-L1 and PD-L2), B7-H1/PD-L1 and B7-DC/PD-L2, are new CD28-B7 family members that are involved in the regulation of immune responses. Previous observation suggests that PD-1 system plays an inhibitory role in regulating peripheral blood T cells, B cells and myeloid cells, thus their abnormality may be related to autoimmune diseases. This study aimed to explore the role of PD-1/PD-L1, L2 system in the pathogenesis of AIH.

METHODS

The mice model of experimental autoimmune hepatitis (EAH) was established in C57BL/6 mice and the expression levels of PD-1 and PD-L1, L2 in the murine liver and the cytokines, including interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha and interleukin (IL)-4 in the spleen were detected using reverse transcription-polymerase chain reaction (RT-PCR), and the results were compared with those of normal controls.

RESULTS

The expression levels of PD-1, PD-L1, PD-L2 mRNA were higher in EAH compared with normal controls (P < 0.05), the PD-L2/PD-1 ratio was relatively lower in EAH (EAH -0.08 +/- 0.35, normal controls 0.52 +/- 0.07, P = 0.009). In the EAH, the expression of the three cytokines were all upregulated compared with normal controls. PD-L1 had a positive correlation with the expression of IFN-gamma (r = 0.289, P < 0.05), while PD-L2 showed a positive correlation with both expressions of IL-4 (r = 0.378, P< 0.01) and IFN-gamma (r = 0.261, P < 0.05). While TNF-alpha showed no correlation with PD-L1 (r = 0.044, P = 0.736) or PD-L2 (r = 0.127, P = 0.335).

CONCLUSIONS

The expression of PD-1/PD-L1, L2 is upregulated in EAH and regulated by IFN-gamma and IL-4. PD-1 system may play an important role in the pathogenesis of AIH.

摘要

背景

自身免疫性肝炎（AIH）是一种病因不明的慢性炎症性肝病。程序性死亡受体 1（PD-1）及其配体（PD-L1 和 PD-L2）、B7-H1/PD-L1 和 B7-DC/PD-L2 是新的 CD28-B7 家族成员，参与免疫反应的调节。先前的观察表明，PD-1 系统在调节外周血 T 细胞、B 细胞和髓样细胞中发挥抑制作用，因此其异常可能与自身免疫性疾病有关。本研究旨在探讨 PD-1/PD-L1、L2 系统在 AIH 发病机制中的作用。

方法

采用 C57BL/6 小鼠建立实验性自身免疫性肝炎（EAH）模型，采用逆转录-聚合酶链反应（RT-PCR）检测小鼠肝组织中 PD-1 和 PD-L1、L2 的表达水平，以及脾组织中干扰素（IFN）-γ、肿瘤坏死因子（TNF）-α 和白细胞介素（IL）-4 等细胞因子的表达水平，并与正常对照组进行比较。

结果

与正常对照组相比，EAH 小鼠肝组织中 PD-1、PD-L1、PD-L2 mRNA 的表达水平均升高（P<0.05），EAH 小鼠 PD-L2/PD-1 比值相对较低（EAH-0.08±0.35，正常对照组 0.52±0.07，P=0.009）。在 EAH 中，三种细胞因子的表达均较正常对照组上调。PD-L1 与 IFN-γ 的表达呈正相关（r=0.289，P<0.05），而 PD-L2 与 IL-4（r=0.378，P<0.01）和 IFN-γ（r=0.261，P<0.05）的表达均呈正相关。而 TNF-α 与 PD-L1（r=0.044，P=0.736）或 PD-L2（r=0.127，P=0.335）均无相关性。