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http://dx.doi.org/10.5483/BMBRep.2020.53.12.161

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)
Publication Information
BMB Reports / v.53, no.12, 2020 , pp. 640-645 More about this Journal
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
Inflammasome; Reactive oxygen species (ROS); Suppressors of cytokine signaling (SOCS); Thioredoxin; TLR4 signal;
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