rhIL-1Ra reduces hepatocellular apoptosis in mice with acute liver failure mainly by inhibiting the activities of Kupffer cells.
rhIL-1Ra reduces hepatocellular apoptosis in mice with acute liver failure mainly by inhibiting the activities of Kupffer cells.
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DOI：
10.1016/j.ejphar.2019.03.031
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发表时间：
2019-07
影响因子：
5
通讯作者：
Xiaolan Yu;Liang Zhou;Q. Deng;Xiaoyue Chen;Quanhui Tan;Huili Lu;Xiaoer Wei;Wen Hu;M. Bai;Li Zhou;Yong-Sheng Yu;Zheng-hao Tang;Yan Yu;Jianjun Hu
中科院分区：
文献类型：
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作者：
Xiaolan Yu;Liang Zhou;Q. Deng;Xiaoyue Chen;Quanhui Tan;Huili Lu;Xiaoer Wei;Wen Hu;M. Bai;Li Zhou;Yong-Sheng Yu;Zheng-hao Tang;Yan Yu;Jianjun Hu
临床上仍然没有药物可以明显提高急性肝衰竭（ALF）患者的生存率。我们已经证实，重组人IL-1受体拮抗剂（rhIL-1 Ra）显着提高对乙酰氨基酚（APAP）诱导的ALF小鼠的生存率，通过减少肝细胞凋亡。本研究旨在探讨rhIL-1 Ra对APAP诱导的ALF小鼠的作用机制，并探讨rhIL-1 Ra的关键靶细胞。观察小鼠存活率、血清IL-1 Ra和IL-1β水平、肝脏IL-1受体I（IL-1 RI）和CD 163表达以及枯否细胞（KCs）吞噬活性。此外，在体外研究了与ALF小鼠血清共培养条件下肝细胞和KCs的增殖。在本研究中，在肝叶III区发现了大量活化的大KCs。GdCl 3和rhIL-1 Ra均能显著减少大KCs的数量。在所有小鼠中，肝细胞和肝非实质细胞而不是KC表达低水平的IL-1 RI，而大的KC表达高水平的IL-1 RI。IL-1 Ra/IL-1β比值升高与rhIL-1 Ra功能有关。GdCl 3和rhIL-1 Ra均能显著抑制KCs的吞噬功能; KCs能显著抑制体外共培养条件下肝细胞的增殖。结论：大KCs是rhIL-1 Ra的主要靶细胞，rhIL-1 Ra主要通过抑制KCs活性发挥其抗肝细胞凋亡的作用。
In clinic, there is still no drug that can significantly improve the survival rate of patients with acute liver failure (ALF). We have confirmed that recombinant human IL-1 receptor antagonist (rhIL-1Ra) significantly improves the survival rate of acetaminophen (APAP)-induced ALF mice by reducing hepatocellular apoptosis. Here, we investigated the mechanism of this and the key target cells of rhIL-1Ra.In vivo, APAP-induced ALF mice were treated with rhIL-1Ra and gadolinium chloride (Gdcl3), respectively. Survival rates of mice, serum IL-1Ra and IL-1β levels, IL-1 receptor type I (IL-1RI) and CD163 expression in the livers, and the phagocytic activities of Kupffer cells (KCs) were investigated. Additionally, the proliferation of hepatocytes and KCs in co-culture conditions with the serum of ALF mice were investigated in vitro. In this study, a large number of activated large KCs were found in liver lobe region III. Both GdCl3and rhIL-1Ra significantly decreased the quantity of large KCs. In all of the mice, hepatocytes and liver non-parenchymal cells other than KCs expressed low levels of IL-1RI, whereas large KCs expressed high levels of IL-1RI. The high ratio of endogenous IL-1Ra/IL-1β was related to rhIL-1Ra function. Additionally, the phagocytic activities of KCs were significantly inhibited by GdCl3and rhIL-1Ra.In vitro, the proliferation of hepatocytes in co-culture conditions were significantly inhibited by KCs. In conclusion, large KCs were the key target cells of rhIL-1Ra, and rhIL-1Ra could play its role of reducing hepatocellular apoptosis mainly by inhibiting the activities of KCs.