Effects of inhibiting IRE1-XBP1 pathway in Kupffer cells in rats after liver transplant rejection

王润芝; 吴皓; 刘一鸣; 曹丁; 吴涯昆; 李金政; 龚建平

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Effects of inhibiting IRE1-XBP1 pathway in Kupffer cells in rats after liver transplant rejection

更新时间：2026-01-09

- Effects of inhibiting IRE1-XBP1 pathway in Kupffer cells in rats after liver transplant rejection
- Journal of Army Medical University Vol. 38, Issue 22, Pages: 2431-2437(2016)
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  CLC： R392.4;R617;R657.3
- Published：2016
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王润芝,吴皓,刘一鸣,曹丁,吴涯昆,李金政,龚建平.阻断Kupffer细胞IRE1-XBP1通路对大鼠肝移植排斥反应的影响[J].陆军军医大学学报(原第三军医大学学报),2016,38(22):2431-2437.

　Wang Runzhi,Wu Hao,Liu Yiming,Cao Ding,Wu Yakun,Li Jinzheng,Gong Jianping.Effects of inhibiting IRE1-XBP1 pathway in Kupffer cells in rats after liver transplant rejection [J].J Amry Med Univ (J Third Mil Med Univ),2016,38(22):2431-2437.
王润芝,吴皓,刘一鸣,曹丁,吴涯昆,李金政,龚建平.阻断Kupffer细胞IRE1-XBP1通路对大鼠肝移植排斥反应的影响[J].陆军军医大学学报(原第三军医大学学报),2016,38(22):2431-2437. DOI：

　Wang Runzhi,Wu Hao,Liu Yiming,Cao Ding,Wu Yakun,Li Jinzheng,Gong Jianping.Effects of inhibiting IRE1-XBP1 pathway in Kupffer cells in rats after liver transplant rejection [J].J Amry Med Univ (J Third Mil Med Univ),2016,38(22):2431-2437. DOI：

摘要

目的探讨阻断Kupffer细胞IREXBP1通路对大鼠原位肝移植排斥反应的作用。方法术前用GdCl3处理或未处理建立大鼠原位肝移植急性排斥反应模型，未处理大鼠随机数字法分为XBP1-shRNA组（A组），Scrambled-shRNA组（B组），PBS组（C组）；处理大鼠随机分为GdCl

+XBP1-shRNA组（D组），GdCl

+ScrambledshRNA组（E组），GdCl

+PBS组（F组）。未处理组术后检测血清ALT、AST、IFNγ、IL-10、IL-17的表达水平；RT-PCR检测T-bet、RORγt、IFN-γ、IL-17及IL-10 mRNA水平；Western blot检测CD86、CD206、IFNγ、IL-17及IL-10蛋白表达水平，HE染色观察肝组织结构，根据Banff方案进行RAI评分，各组剩余大鼠观察术后生存率。处理组术后检测IFN-γ、IL-17及IL-10 mRNA以及蛋白表达水平，HE染色观察肝组织结构。结果在未处理组中，与B、C组比较，A组各时间点肝功能指标ALT、AST明显下降（P0.05），A组血清表达IFN-γ、IL-10明显受到抑制（P0.05），IL-10的表达水平则呈明显上升趋势（P0.05），与RT-PCR和Western blot结果趋势相符合，另外A组CD86蛋白表明显下降（P0.05），而表达CD206上升（P0.05），Tbet/RORγt mRNA相对表达量也明显下降（P0.05），B、C组上述指标与A组对比则呈相反趋势，而且B、C组之间比较差异无统计学意义（P0.05）；A组RAI评分(3.83±0.14)，明显低于B、C组RAI评分(9.13±0.20)、(8.95±026)（P0.05），并且A组大鼠的生存时间明显高于B、C组大鼠（P0.05)。在处理组中，D、E和F组肝脏局部IFN-γ、IL-17、IL-10 mRNA和蛋白表达情况以及病理组织AcR程度比较无统计学上的差异（P0.05）。结论阻断IRE1-XBP1通路促进了KCs的M1型极化，引起Th1/Th17向Th2/Treg的免疫偏移，在一定程度上减轻了移植肝脏急性排斥反应的程度。

Abstract

Objective To investigate the effects of inhibiting inositol requiring 1-X-Box bind

ing protein 1 (IRE1-XBP1) pathway in Kupffer cells (KCs) on liver transplant rejection in rats. Methods Orthotopic liver transplantation in rats was established with or without GdCl3 treatment pre-operation. In untreated group

the rats were divided randomly into 3 subgroups

that is

XBP1-shRNA group (A)

Scrambled-shRNA group (B)

and PBS group (C). Likewise

the treated group was sub-divided into GdCl

+XBP1-shRNA group (D)

GdCl

+Scrambled-shRNA group (E)

and GdCl

+PBS group (F). In untreated group

the serum levels of alanine aminotransferase (ALT)

aspartate aminotransferase (AST)

interferon-γ (IFN-γ)

interleukin-10 (IL-10) and IL-17 were examined at different time points after operation. Liver tissues were excised for hematoxylin and eosin (HE) staining

mRNA expression levels of transcriptional factors (T-bet and RORγt) and cytokines (IFN-γ

IL-17 and IL-10) quantified by real-time PCR (RT-PCR)

and protein levels of CD86

CD206

IFN-γ

IL-17 and IL-10 by Western blotting. Banff schema was used for grading the acute allograft rejection with rejection activity index (RAI). The survival rate was assessed by Kaplan-Meier curve analysis. In the treated group

the mRNA and the protein expression of IFN-γ

IL-17 and IL-10 was also tested. Results In the untreated group

the serum levels of ALT and AST at different time points were significantly lower in group A compared with groups B and C (P0.05). In group A

IFN-γ and IL-17 were significantly decreased in serum while IL-10 was significantly increased (P0.05). There were consistent with the results of RT-PCR and western blotting. In addition

the relative mRNA expression of T-bet/RORγt was decreased

protein expression of CD86 decreased and CD206 increased

which were all statistically significant (P0.05). In contrast

groups B and C showed inverse trend with respect to the above-mentioned factors

mRNA and protein expressions. Moreover

the differences between group B and C were not significant. The mean RAI sco

re in group A was 3.81±0.14

which was significantly lower than that in groups B (9.13±0.20) and C (8.95±0.26)

respectively (P0.05). The data was also in agreement with the Kaplan-Meier curve

showing that rats in group A significantly survived longer than these in groups B and C (P0.05). However

the expression of IFN-γ

IL-17 and IL-10 both at mRNA and protein levels was not significantly different among the treatment groups D

and F. The same results in pathological examination were observed. Conclusion The blockage of IRE1-XBP1 pathway could alter the polarization of KCs from M1 to M2 type

lead to skewing of Th1/Th17 towards Th2/Treg

and consequently ameliorate acute rejection following liver transplantation in rats.

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