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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Anti-inflammatory mechanisms of suppressors of cytokine signaling target ROS via NRF-2/thioredoxin induction and inflammasome activation in macrophages

  • Kim, Ga-Young (Department of Biological Science, College of Science, Sungkyunkwan University) ;
  • Jeong, Hana (Department of Biological Science, College of Science, Sungkyunkwan University) ;
  • Yoon, Hye-Young (Department of Biological Science, College of Science, Sungkyunkwan University) ;
  • Yoo, Hye-Min (Department of Biological Science, College of Science, Sungkyunkwan University) ;
  • Lee, Jae Young (Department of Biological Science, College of Science, Sungkyunkwan University) ;
  • Park, Seok Hee (Department of Biological Science, College of Science, Sungkyunkwan University) ;
  • Lee, Choong-Eun (Department of Biological Science, College of Science, Sungkyunkwan University)
  • Received : 2020.07.31
  • Accepted : 2020.10.22
  • Published : 2020.12.31
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Abstract

Suppressors of cytokine signaling (SOCS) exhibit diverse anti-inflammatory effects. Since ROS acts as a critical mediator of inflammation, we have investigated the anti-inflammatory mechanisms of SOCS via ROS regulation in monocytic/macrophagic cells. Using PMA-differentiated monocytic cell lines and primary BMDMs transduced with SOCS1 or shSOCS1, the LPS/TLR4-induced inflammatory signaling was investigated by analyzing the levels of intracellular ROS, antioxidant factors, inflammasome activation, and pro-inflammatory cytokines. The levels of LPS-induced ROS and the production of pro-inflammatory cytokines were notably down-regulated by SOCS1 and up-regulated by shSOCS1 in an NAC-sensitive manner. SOCS1 up-regulated an ROS-scavenging protein, thioredoxin, via enhanced expression and binding of NRF-2 to the thioredoxin promoter. SOCS3 exhibited similar effects on NRF-2/thioredoxin induction, and ROS downregulation, resulting in the suppression of inflammatory cytokines. Notably thioredoxin ablation promoted NLRP3 inflammasome activation and restored the SOCS1-mediated inhibition of ROS and cytokine synthesis induced by LPS. The results demonstrate that the anti-inflammatory mechanisms of SOCS1 and SOCS3 in macrophages are mediated via NRF-2-mediated thioredoxin upregulation resulting in the downregulation of ROS signal. Thus, our study supports the anti-oxidant role of SOCS1 and SOCS3 in the exquisite regulation of macrophage activation under oxidative stress.

Keywords

References

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