Regulatory roles of suppressors of cytokine signaling 1 during type I vs type II macrophage polarization and phenotype determination

Abstract

Abstract During infection, activated macrophages display type 1 pro-inflammatory (M1) and type II anti-inflammatory (M2) features for pathogen clearence and the subsequent tissue repair, respectively. While suppressors of cytokine signaling (SOCS) play a role in the regulation of inflammation in diverse systems, the regulatory role of SOCS in M1 vs M2 activity has not been clearly established. We have studied SOCS action in macrophage phenotype determination in vitro employing SOCS gene transfer and knock-down using THP1 cells differentiated with PMA. For the LPS-induced M1 polarization, ROS signaling was crucial as the early ROS generation, MAPK activation, and the production of pro-inflammatory cytokines were all subject to inhibition by NAC, an anti-oxidant. Meanwhile, the dexamethasone (Dex)-induced M2 polarization involved ROS generation and MAPK/MPK1 activation in delayed kinetics, leading to the production of anti-inflammatory cytokines, which was also sensitive to NAC. Our previous studies demonstrated anti-oxidant functions of SOCS1 through the induction of thioredoxin and Nrf-2. In line with this, SOCS1 over-expression significantly inhibited M1 induction with ROS down-regulation, while SOCS1 ablation promoted ROS and pro-inflammatory/M1 cytokine production. In contrast, Dex-induced anti-inflammatory/M2 cytokines were severely reduced by SOCS1 knock-down with the impaired p38 and GILZ induction. The data support the anti-inflammatory action of SOCS1, while suggesting that SOCS1 exerts differential effects on M1 vs M2 polarization. The identification of distinct target molecules of SOCS1 action in M1vs M2 macrophage phenotype determination is under investigation.