Suppressors of signaling protein 3 inhibits glucocorticoid‐induced M2 polarization of monocytic cells by attenuation of ROS/p38 and GILZ‐mediated anti‐inflammatory cytokine production

Abstract

Macrophages respond to diverse environmental cues to acquire different phenotypes, ranging from pro-inflammatory (M1) to anti-inflammatory (M2) types. Suppressors of signaling protein (SOCS) have emerged as critical regulators of inflammation participating in distinct phases of macrophage activation and differentiation. We have recently reported that both SOC1 and SOCS3 attenuated LPS/TLR4-induced inflammatory signaling via down-regulation of ROS levels and inflammasome activation associated with M1 differentiation. We have subsequently observed that SOCS3 also suppresses M2 polarization of THP1 monocytic cells induced by glucocorticoid (GC) and investigated the signaling mechanisms regulated by SOCS3.Treatment of PMA-differentiated THP1 cells with dexamethasone (Dex) induced M2 polarization by reducing TNF-alpha, IL-1 beta and IL-6 and by promoting IL-10 and TGF-beta production with the increased expression of Arg1 and CD163.SOCS3 over-expression reduced, while SOCS3 ablation increased IL-10 and TGF-beta in ROS and p38-dependent manners.A potential mediator of Dex-induced M2 response, glucocorticoid-induced leucine zipper (GILZ) was down-regulated by SOCS3 and up-regulated by shSOCS3. GILZ ablation blocked ROS generation and p38 activation leading to the inhibition of Dex-induced anti-inflammatory cytokines and the expression of M2 markers. Together the data suggest that SOCS3 target ROS/p38-dependent GILZ expression to suppress Dex-induced M2 polarization of THP1 cells. The critical role and detailed regulation mechanism of GILZ as a target of SOCS3 action during GC-induced M2 polarization is under investigation.