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Cereblon Deletion Ameliorates Lipopolysaccharide-induced Proinflammatory Cytokines through 5'-Adenosine Monophosphate-Activated Protein Kinase/Heme Oxygenase-1 Activation in ARPE-19 Cells

  • Yun Kyu Kim (Department of Convergence Medicine, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center) ;
  • Soo Chul Chae (Department of Integrative Medical Sciences, Nambu University) ;
  • Hun Ji Yang (Department of Convergence Medicine, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center) ;
  • Da Eun An (Department of Convergence Medicine, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center) ;
  • Sion Lee (Department of Convergence Medicine, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center) ;
  • Myeong Gu Yeo (Department of Integrative Medical Sciences, Nambu University) ;
  • Kyung Jin Lee (Department of Convergence Medicine, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center)
  • Received : 2020.03.26
  • Accepted : 2020.06.20
  • Published : 2020.06.30
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Abstract

Cereblon (CRBN), a negative modulator of AMP-activated protein kinase (AMPK), is highly expressed in the retina. We confirmed the expression of CRBN in ARPE-19 human retinal cells by Western blotting. We also demonstrated that CRBN knock-down (KD) could effectively downregulate IL-6 and MCP-1 protein and gene expression in LPS-stimulated ARPE-19 cells. Additionally, CRBN KD increased the phosphorylation of AMPK/acetylcoenzyme A carboxylase (ACC) and the expression of heme oxygenase-1 (HO-1) in ARPE-19 cells. Furthermore, CRBN KD significantly reduced LPS-induced nuclear translocation of NF-κB p65 and activation of NF-κB promoter activity. However, these processes could be inactivated by compound C (inhibitor of AMPK) and zinc protoporphyrin-1 (ZnPP-1; inhibitor of HO-1). In conclusion, compound C and ZnPP-1 can rescue LPS-induced levels of proinflammatory cytokines (IL-6 and MCP-1) in CRBN KD ARPE-19 cells. Our data demonstrate that CRBN deficiency negatively regulates proinflammatory cytokines via the activation of AMPK/HO-1 in the retina.

Keywords

Acknowledgement

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) and funded by the Ministry of Education, Science and Technology (2018R1D1A1B07050192, 2017R1D1A1A02018653). It was also supported by a grant (1631040) from the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea, as well as a grant from Nambu University, 2016.

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