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Anti-inflammatory mechanisms of suppressors of cytokine signaling action by targeting ROS through NRF-2/thioredoxin induction and inhibition of inflammasome activation in macrophagic cells
Choong-Eun Lee 7,* (Professor), Ga-Young Kim1,# (Graduate student), Hana Jeong2,# (Graduate student), Hye-Young Yoon3 (Graduate Student), Seok Hee Park6 (professor), Jae-Young Lee5 (Graduate student), Hye-Min Yoo4 (Graduate student)
1Department of Biological Science, Sungkyunkwan University
Suppressors of cytokine signaling (SOCS) have been reported for anti-inflammatory actions. Since ROS acts as a critical mediator of inflammatory signaling, we have investigated anti-inflammatory mechanisms of SOCS action through 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 examined by analyzing intracellular ROS, anti-oxidant factors, inflammasome activation, and pro-inflammatory cytokine production. The LPS-induced ROS levels and production of pro-inflammatory cytokines were notably down-regulated by SOCS1 and up-regulated by shSOCS1 in NAC-sensitive manners. As a mechanism of anti-inflammatory action, SOCS1 up-regulated an ROS-scavenging protein, thioredoxin, through enhanced expression and binding of NRF-2 to the thioredoxin promoter. SOCS3 exhibited similar effects on NRF-2/thioredoxin induction, ROS down-regulation and the resulting suppression of inflammatory cytokines. Notably thioredoxin ablation promoted NLRP3 inflammasome activation and restored the SOCS1-mediated inhibition of ROS and cytokine production induced by LPS. The data demonstrate that mechanisms of anti-inflammatory action of SOCS1 and SOCS3 in macrophages both involve NRF-2-mediated thioredoxin up-regulation resulting in the down-regulation of ROS signal. Thus our study supports the anti-oxidant function of SOCS1 and SOCS3 for a fine-tuned regulation of macrophage activation under oxidative stress.
Abstract, Accepted Manuscript(in press) [Submitted on July 31, 2020, Accepted on October 22, 2020]
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