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
› Author Affiliations
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).
Further Information

Publication History

Publication Date:
25 July 2020 (online)

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.

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.


 
  • References

  • 1 Weber A, Wasiliew P, Kracht M. Interleukin-1 (IL-1) pathway. Sci Signal 2010; 3 (105) cm1
  • 2 Arend WP, Malyak M, Guthridge CJ, Gabay C. Interleukin-1 receptor antagonist: role in biology. Annu Rev Immunol 1998; 16: 27-55
  • 3 Sekiyama KD, Yoshiba M, Thomson AW. Circulating proinflammatory cytokines (IL-1 β, TNF-α, and IL-6) and IL-1 receptor antagonist (IL-1Ra) in fulminant hepatic failure and acute hepatitis. Clin Exp Immunol 1994; 98 (01) 71-77
  • 4 Zhu RZ, Xiang D, Xie C. , et al. Protective effect of recombinant human IL-1Ra on CCl4-induced acute liver injury in mice. World J Gastroenterol 2010; 16 (22) 2771-2779
  • 5 Xiao JQ, Shi XL, Ma HC. , et al. Administration of IL-1Ra chitosan nanoparticles enhances the therapeutic efficacy of mesenchymal stem cell transplantation in acute liver failure. Arch Med Res 2013; 44 (05) 370-379
  • 6 Shi XL, Zhu W, Tan JJ. , et al. Effect evaluation of interleukin-1 receptor antagonist nanoparticles for mesenchymal stem cell transplantation. World J Gastroenterol 2013; 19 (12) 1984-1991
  • 7 Yuan Y, Wu X, Ou Q. , et al. Differential expression of the genes involved in amino acids and nitrogen metabolisms during liver regeneration of mice. Hepatol Res 2009; 39 (03) 301-312
  • 8 Gehrke N, Hövelmeyer N, Waisman A. , et al. Hepatocyte-specific deletion of IL1-RI attenuates liver injury by blocking IL-1 driven autoinflammation. J Hepatol 2018; 68 (05) 986-995
  • 9 Yu X, Zhou L, Deng Q. , et al. rhIL-1Ra reduces hepatocellular apoptosis in mice with acute liver failure mainly by inhibiting the activities of Kupffer cells. Eur J Pharmacol 2019; 854: 338-346
  • 10 Clawson GA. Mechanisms of carbon tetrachloride hepatotoxicity. Pathol Immunopathol Res 1989; 8 (02) 104-112
  • 11 Krithika R, Verma RJ, Shrivastav PS. Antioxidative and cytoprotective effects of andrographolide against CCl4-induced hepatotoxicity in HepG2 cells. Hum Exp Toxicol 2013; 32 (05) 530-543
  • 12 Chen J, Zhao Y, Tao XY. , et al. Protective effect of blueberry anthocyanins in a CCL4-induced liver cell model. Lebensm Wiss Technol 2015; 60 (2, Part 2): 1105-1112
  • 13 López-Terrada D, Cheung SW, Finegold MJ, Knowles BB. Hep G2 is a hepatoblastoma-derived cell line. Hum Pathol 2009; 40 (10) 1512-1515
  • 14 Li W, Long J, Takikawa Y, Suzuki K, Lin S. Plasma from patients with acute liver failure dampens HepG2 cells to epidermal growth factor induced proliferation response. Hepatogastroenterology 2014; 61 (135) 2021-2027
  • 15 Wu JC, Merlino G, Fausto N. Establishment and characterization of differentiated, nontransformed hepatocyte cell lines derived from mice transgenic for transforming growth factor alpha. Proc Natl Acad Sci U S A 1994; 91 (02) 674-678
  • 16 Wu HJ, Gong X, Yang YT. , et al. Improvement of carbon tetrachloride drug-induced liver injury model in vitro [in Chinese]. Zhongguo Zhongyao Zazhi 2012; 37 (23) 3633-3636
  • 17 Lebel CP, Bondy SC. Sensitive and rapid quantitation of oxygen reactive species formation in rat synaptosomes. Neurochem Int 1990; 17 (03) 435-440
  • 18 Zheng SC, Zhu XX, Xue Y. , et al. Role of the NLRP3 inflammasome in the transient release of IL-1β induced by monosodium urate crystals in human fibroblast-like synoviocytes. J Inflamm (Lond) 2015; 12: 30
  • 19 Zhang K, Watanabe M, Kashiwakura Y. , et al. Expression pattern of REIC/Dkk-3 in various cell types and the implications of the soluble form in prostatic acinar development. Int J Oncol 2010; 37 (06) 1495-1501
  • 20 Weng S, Zhou L, Deng Q. , et al. Niclosamide induced cell apoptosis via upregulation of ATF3 and activation of PERK in Hepatocellular carcinoma cells. BMC Gastroenterol 2016; 16: 25
  • 21 Sakurai T, He G, Matsuzawa A. , et al. Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell 2008; 14 (02) 156-165
  • 22 Hoek JB, Pastorino JG. Ethanol, oxidative stress, and cytokine-induced liver cell injury. Alcohol 2002; 27 (01) 63-68
  • 23 Brenner C, Galluzzi L, Kepp O, Kroemer G. Decoding cell death signals in liver inflammation. J Hepatol 2013; 59 (03) 583-594
  • 24 Li X, Yao Q, Huang J. , et al. Morin hydrate inhibits TREM-1/TLR4-mediated inflammatory response in macrophages and protects against carbon tetrachloride-induced acute liver injury in mice. Front Pharmacol 2019; 10: 1089
  • 25 Carolini Thiesen L, de Oliveira Nunes ML, Meyre-Silva C. , et al. The hydroethanolic Litchi chinensis leaf extract alleviate hepatic injury induced by carbon tetrachloride (CCl4) through inhibition of hepatic inflammation. Biomed Pharmacother 2018; 107: 929-936
  • 26 Choi HY, Lee JH, Jegal KH, Cho IJ, Kim YW, Kim SC. Oxyresveratrol abrogates oxidative stress by activating ERK-Nrf2 pathway in the liver. Chem Biol Interact 2016; 245: 110-121
  • 27 Chen W, Kennedy DO, Kojima A, Matsui-Yuasa I. Polyamines and thiols in the cytoprotective effect of L-cysteine and L-methionine on carbon tetrachloride-induced hepatotoxicity. Amino Acids 2000; 18 (04) 319-327
  • 28 Schroeder JJ, Cousins RJ. Interleukin 6 regulates metallothionein gene expression and zinc metabolism in hepatocyte monolayer cultures. Proc Natl Acad Sci U S A 1990; 87 (08) 3137-3141
  • 29 Tiegs G, Hentschel J, Wendel A. A T cell-dependent experimental liver injury in mice inducible by concanavalin A. J Clin Invest 1992; 90 (01) 196-203
  • 30 Jalan R, Olde Damink SW, Deutz NE. , et al. Moderate hypothermia prevents cerebral hyperemia and increase in intracranial pressure in patients undergoing liver transplantation for acute liver failure. Transplantation 2003; 75 (12) 2034-2039
  • 31 Tuñón MJ, Alvarez M, Culebras JM, González-Gallego J. An overview of animal models for investigating the pathogenesis and therapeutic strategies in acute hepatic failure. World J Gastroenterol 2009; 15 (25) 3086-3098
  • 32 Guo G, Zhu Y, Wu Z. , et al. Circulating monocytes accelerate acute liver failure by IL-6 secretion in monkey. J Cell Mol Med 2018; 22 (09) 4056-4067
  • 33 Mebratu Y, Tesfaigzi Y. How ERK1/2 activation controls cell proliferation and cell death: is subcellular localization the answer?. Cell Cycle 2009; 8 (08) 1168-1175
  • 34 Lu Z, Xu S. ERK1/2 MAP kinases in cell survival and apoptosis. IUBMB Life 2006; 58 (11) 621-631
  • 35 Li Y, Liang R, Zhang X. , et al. Copper chaperone for superoxide dismutase promotes breast cancer cell proliferation and migration via ROS-mediated MAPK/ERK signaling. Front Pharmacol 2019; 10: 356