Toll样受体4介导脂多糖诱导的小鼠肝脏血红素加氧酶-1表达：肿瘤坏死因子-α和白细胞介素-1β的作用
TLR4 mediates LPS-induced HO-1 expression in mouse liver: role of TNF-alpha and IL-1beta.
作者信息
Song Yong, Shi Yi, Ao Li-Hua, Harken Alden H, Meng Xian-Zhong
机构信息
Department of Respiratory Diseases, Nanjing Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, Jiangsu Province, China.
出版信息
World J Gastroenterol. 2003 Aug;9(8):1799-803. doi: 10.3748/wjg.v9.i8.1799.
AIM
Heme oxygenase (HO)-1 catalyzes the conversion of heme to biliverdin, iron and carbon monoxide. HO-1 is induced by many stimuli including heme, Hb, heat stress,lipopolysaccharide (LPS) and cytokines. Previous studies demonstrated that LPS induced HO-1 gene activation and HO-1 expression in liver. However, the mechanisms of LPS-induced HO-1 expression in liver remain unknown. The effect of toll-like receptor-4 (TLR4) on LPS-induced liver HO-1 expression and the role of TNF-alpha and IL-1beta in this condition were determined.
METHODS
HO-1 expression was determined by immunofluorescent staining and immunoblotting. Double immunofluorescent staining was performed to determine the cell type of HO-1 expression in liver.
RESULTS
A low dose of LPS significantly increased HO-1 expression in the liver which was localized in Kupffer cells only. Furthermore, HO-1 expression was enhanced by three doses of LPS. HO-1 expression was significantly inhibited in the liver of TLR4 mutant mice. While the liver HO-1 expression in TNF KO mice was much lower than that in C57 mice following the same LPS treatment, IL-1beta KO had a slight influence on liver HO-1 expression following LPS treatment.
CONCLUSION
The present results confirm that macrophages are the major source of HO-1 in the liver induced by LPS. This study demonstrates that TLR4 plays a dominant role in mediating HO-1 expression following LPS. LPS-induced HO-1 expression is mainly mediated by endogenous TNF-alpha, but only partially by endogenous IL-1beta.
目的
血红素加氧酶（HO）-1催化血红素转化为胆绿素、铁和一氧化碳。HO-1可被多种刺激诱导，包括血红素、血红蛋白、热应激、脂多糖（LPS）和细胞因子。先前的研究表明，LPS可诱导肝脏中HO-1基因激活和HO-1表达。然而，LPS诱导肝脏中HO-1表达的机制仍不清楚。本研究确定了Toll样受体4（TLR4）对LPS诱导的肝脏HO-1表达的影响以及肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）在此过程中的作用。
方法
通过免疫荧光染色和免疫印迹法检测HO-1表达。采用双重免疫荧光染色法确定肝脏中HO-1表达的细胞类型。
结果
低剂量LPS可显著增加肝脏中HO-1的表达，且仅定位于库普弗细胞。此外，三种剂量的LPS均可增强HO-1表达。在TLR4突变小鼠的肝脏中，HO-1表达显著受到抑制。相同LPS处理后，TNF基因敲除（KO）小鼠肝脏中的HO-1表达远低于C57小鼠，而IL-1β KO小鼠在LPS处理后肝脏HO-1表达受到轻微影响。
结论
本研究结果证实巨噬细胞是LPS诱导肝脏中HO-1的主要来源。本研究表明，TLR4在介导LPS诱导的HO-1表达中起主导作用。LPS诱导的HO-1表达主要由内源性TNF-α介导，但仅部分由内源性IL-1β介导。
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