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CC BY 4.0 · Pharmaceutical Fronts 2020; 02(02): e109-e116
DOI: 10.1055/s-0040-1714139
Original Article
Georg Thieme Verlag KG Stuttgart · New York

IL-1Ra Protects Hepatocytes from CCl4-Induced Hepatocellular Apoptosis via Activating the ERK1/2 Pathway

Ying Zheng‡   *
1   Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People's Republic of China
,
Xinyi Xiao‡   *
1   Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People's Republic of China
,
Zhuoyi Yang
1   Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People's Republic of China
,
Meiqi Zhou
1   Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People's Republic of China
,
Hui Chen
1   Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People's Republic of China
,
Siyi Bai
1   Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People's Republic of China
,
Jianwei Zhu
1   Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People's Republic of China
,
Yunsheng Yuan   *
1   Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People's Republic of China
› Institutsangaben Funding This study was funded by the National Science and Technology Major Project “Key New Drug Creation and Manufacturing Program” of China (Yunsheng Yuan, No. 2019ZX09201001); the National Natural and Science Foundation of China (Yunsheng Yuan, No. 31671388); the Shanghai Pujiang Program (Yunsheng Yuan, No. 16PJ1405000); and SJTU translational medicine funding (Yunsheng Yuan, No. YG2019QNA50).
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Publikationsdatum:
25. Juli 2020 (online)

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Abstract

Interleukin-1 receptor antagonist is an important acute-phase protein and an immune mediator, and its expression is associated with the development of hepatitis or acute liver failure. The aim of this study was to investigate whether recombinant human interleukin-1 receptor antagonist directly targets and improves cell survival in a carbon tetrachloride-induced hepatocyte injury model in vitro. A human hepatoma cell line and a mouse hepatocyte cell line were used to establish carbon tetrachloride-induced cell injury models in vitro, and cell viability, apoptosis, and reactive oxygen species level were determined to assess the degree of hepatocellular damage. Quantitative real-time polymerase chain reaction was used to analyze the level of interleukin-1β, interleukin-6, and tumor necrosis factor-α mRNA in cells; extracellular regulated protein kinases 1/2 phosphorylation in hepatocytes was analyzed using western blotting. Recombinant human interleukin-1 receptor antagonist could directly target hepatocytes, improve cell survival, and decrease carbon tetrachloride-induced cell apoptosis in vitro. In hepatocytes, recombinant human interleukin-1 receptor antagonist remarkably downregulated expression of interleukin-1β, interleukin-6, and tumor necrosis factor-α in hepatocytes exposed to carbon tetrachloride. It also decreased accumulation of reactive oxygen species and abrogated the suppression of extracellular regulated protein kinases 1/2 phosphorylation induced by carbon tetrachloride. However, stimulation of cells with an extracellular regulated protein kinases 1/2 inhibitor blocked the recombinant human interleukin-1 receptor antagonist-induced upregulation of extracellular regulated protein kinase1/2 activation and abrogated the improvement in hepatocyte survival following carbon tetrachloride treatment. Collectively, these findings provide new insights into the hepatocyte-protective mechanism of recombinant human interleukin-1 receptor antagonist.

Keywords

rhIL-1Ra - reactive oxygen species - CCl4 - ERK1/2 - hepatocyte - apoptosis - IL-1Ra

Author Contributions

Yunsheng Yuan designed and coordinated the study; Ying Zheng, Xinyi Xiao, Zhuoyi Yang, Meiqi Zhou, Hui Chen, and Siyi Bai performed the experiments; Yunsheng Yuan, Ying Zheng, and Xinyi Xiao analyzed the data; Yunsheng Yuan wrote the manuscript. All authors read and approved the final version of this manuscript.


* These authors contributed equally to this work.