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. © FASEB.