Role of IL-10 in hepatocyte tight junction alteration in mouse model of experimental colitis
Role of IL-10 in hepatocyte tight junction alteration in mouse model of experimental colitis
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DOI：
10.1007/bf03402016
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发表时间：
2002-07-01
影响因子：
5.7
通讯作者：
Cuzzocrea, S
中科院分区：
文献类型：
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作者：
Mazzon, E;Puzzolo, D;Cuzzocrea, S
背景：慢性炎症性肠病（IBD）患者存在多种肝胆异常。本研究的目的是探讨内源性IL- 10的作用，在肝细胞TJ细胞旁屏障的改变，并在快速transcytiotic囊泡通路的修改与肠道inflammation.Materials和方法：为了解决这个问题，我们使用了一个实验模型的结肠炎，由二硝基苯磺酸（DNBS）诱导。当与DNBS处理的IL-10野生型（IL-10 WT）小鼠相比时，DNBS处理的IL- 10敲除小鼠（IL-10 KO）小鼠经历了结肠损伤的组织学体征的范围和严重程度的更高比率。结肠和肝脏中促炎细胞因子肿瘤坏死因子，白细胞介素-1 β，与野生型小鼠相比，IL-10 KO小鼠中IL-6和白细胞介素-6的表达也大大增强。在DNBS施用后4天，来自IL-10 KO和IL-10 WT的肝组织学未显示任何实质和门脉道炎症。与DNBS-IL-10 KO小鼠相比，DNBS-IL-10 KO小鼠的血清总胆红素和丙氨酸氨基转移酶显著升高。因此，我们发现DNBS处理的IL-10 WT小鼠肝脏中硝酸镧（分子量，433）的紧密连接渗透性增加;镧在整个连接区积聚，直至与管腔接壤的最顶端区域。在IL-10 KO小鼠中，功能性IL-10基因的缺失导致DNBS诱导的结肠炎后镧的顶端扩散显著增强。来自DNBS-IL-10 KO小鼠的冷冻肝切片的免疫荧光标记、针对claudin-1和ZO-1的免疫定位导致与DNBS-IL-10 WT相比，DNBS施用后针对claudin- I和ZO-1的免疫信号的定位的显著改变。最后，我谨指出，我们认为，缺乏IL-10可能代表IBD患者中观察到的肝胆损伤和胆汁淤积的重要病理生理机制。
Background: A variety of hepatobiliary abnormalities have been described in patients with chronic inflammatory bowel diseases (IBDs). The purpose of this study was to investigate the role of endogenous IL- 10 in alteration of hepatocyte TJ paracellular barrier and in the rapid transcytotic vesicular pathway modification associated with intestinal inflammation.Materials and methods: To address this question, we used an experimental model of colitis, induced by dinitrobenzene sulfonic acid (DNBS). When compared to DNBS-treated IL-10 wild-type (IL-10WT) mice, DNBS-treated IL- 10 knock-out mice (IL- 10KO) mice experienced a higher rate of the extent and severity of the histological signs of colon injury.Results: Colon and liver levels of the pro-inflammatory cytokines tumour necrosis factor, interleukin-1beta,6 and interleukin-6 were also greatly enhanced in IL-10KO mice in comparison to wild-type mice. Liver histology from IL-10KO and IL-10WT did not show any parenchymal and portal tract inflammation at 4 days after DNBS administration. Serum total bilirubin and Alanine aminotransferase, were significantly increased in DNBS-IL-10KO mice vs. DNBS-IL-10KO mice.Therefore, we found an increase of tight junctional permeability to lanthanum nitrate (molecular weight, 433) in the livers from DNBS-treated IL-10WT mice; lanthanum accumulated throughout the junctional area up to the most apical region bordering the lumen. Absence of a functional IL-10 gene in IL-10KO mice resulted in a significant augmentation of apical diffusion of lanthanum after DNBS-induced colitis. Immunofluorescent labelling of frozen liver sections from DNBS-IL-10KO mice, immunolocalization for and claudin-1 and ZO-1 resulted in a significant alteration in the localization of the immunosignals for claudin- I and ZO- I after DNBS administration in comparison with DNBS-IL-10WT.Conclusion: In conclusion, we suggest that the absence of IL-10 may represent an important pathophysiological mechanism of hepatobiliary injuries and cholestasis observed in patients with IBD.