Role of glucocorticoid‐induced leucine zipper during type II macrophage differentiation induced by dexamethasone and IL‐4

Abstract

Macrophages, central role players in the immune‐inflammatory response, exist in diverse phenotypes in specific tissue environments, ranging from pro‐inflammatory (M1) to anti‐inflammatory (M2) types. Various factors in the microenvironment of infected tissues may lead to M1 vs M2 activation, which include LPS, TNF‐alpha and IFN‐gamma for M1 and glucocorticoid (GC), IL‐4 or IL‐13 for M2, respectively. While GC is considered as a strong inducer of M2 mainly through the inhibition of inflammatory cytokine expression, molecular mechanisms directly responsible for M2 phenotype induction by GC are not well understood. As a GC‐induced signaling mediator, we have investigated the role of glucocorticoid‐induced leucine zipper (GILZ) during dexamethasone (Dex)‐ and IL‐4‐induced M2 differentiation. We have observed that in PMA‐treated THP1 cells representing M0 state, GILZ is induced by Dex or IL‐4 under M2 polarization condition. The induction of GILZ by Dex is ROS‐ and p38‐dependent, which in turn mediates Dex‐induced expression of IL‐10 and other molecular markers of M2 such as Arg1. Importantly GILZ knock‐out resulted in a severe suppression of IL‐10 induced by Dex or IL‐4. On the other hand, STAT6 knock‐out did not negatively affect Dex‐induced M2 response, while substantially reduced IL‐4‐induced IL‐10 levels. Finally, GILZ‐ablated macrophages exhibited a complete inhibition of ROS generation required for M2 polarization induced by Dex. Together these data strongly suggest that GILZ plays a critical role as a common mediator of M2 differentiation induced by GC and IL‐4.