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SOCS3 down‐regulates ROS signaling and inhibits M1 and M2 human macrophage polarization
Author(s) -
Lee ChoongEun,
Yoon Hyeyoung,
Jeong Hana
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.lb135
Subject(s) - socs3 , proinflammatory cytokine , macrophage polarization , microbiology and biotechnology , inflammation , suppressor of cytokine signaling 1 , cytokine , signal transduction , suppressor of cytokine signalling , chemistry , biology , macrophage , immunology , stat3 , biochemistry , in vitro , suppressor , gene
Initially found as feed‐back regulators of Jak/STAT pathways during cytokine signal transduction, the suppressors of cytokine signaling (SOCS) proteins have been recognized as modulators of inflammation through the regulation of macrophage activity. Macrophages are critical role players in immune‐inflammatory reactions to combat pathogen and to restore tissue homeostasis through the balanced action of distinct phenotypes: pro‐inflammatory M1 vs antiinflammatory M2. While anti‐inflammatory effect of SOCS1 through the inhibition TLR and NF‐kB signaling is well established, the role of SOCS3 in macrophage function has been controversial, being pro‐inflammatory or anti‐inflammatory. In the present work, we have studied regulatory functions of SOCS3 in inflammation employing M1 vs M2 differentiation systems and investigated the regulatory mechanisms involved. Human promonocytic THP1 cells were differentiated by PMA treatment and subject to polarization to M1 vs M2 phenotypes with LPS vs Dex stimulation, respectively for 24 to 48 h. Under such M1 or M2 differentiation condition, intracellular ROS generation and MAPK activation, albeit with different kinetics, were induced which preceded the pro‐inflammatory or anti‐inflammatory markers, respectively. Over‐expression of SOCS3 attenuated the LPS‐ or Dex‐induced ROS generation and suppressed both M1 and M2 differentiation as measured by the expression of proinflammatory (IL‐1beta, TNF‐alpha, and IL‐6) and anti‐inflammatory (TGF‐beta and IL‐10) cytokines. On the contrary, shRNA‐mediated SOCS3 knock‐down has shown the opposite effects. As a mechanism of ROS down‐regulation by SOCS3, we have observed the upregulation of anti‐oxidant factors such as Nrf‐2, Trx, SOD, and Prx in SOCS3 over‐expressing cells. Among MAPK members regulated by ROS signal, SOCS3 inhibited p38 activity critical for IL‐10 production during M2 differentiation with a prominent upregulation of MKP1. As SOCS3 suppressed STAT activation and GILZ expression important for M1 and M2 differentiation, the role of ROS signal in the regulation of these downstream transcription factors is also under investigation. Support or Funding Information < Supported by NRF grants 2015‐003291 and 2016‐911262 > This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .