Glucocorticoid-Induced Leucine Zipper: A Critical Factor in Macrophage Endotoxin Tolerance

Abstract

Induction of glucocorticoid-induced leucine zipper (GILZ) by glucocorticoids plays a key role in their anti-inflammatory action. In activated macrophages, GILZ levels are downregulated via tristetraprolin-mediated GILZ mRNA destabilization. To assess the functional significance of GILZ downregulation, we generated myeloid-specific GILZ knockout (KO) mice. GILZ-deficient macrophages displayed a higher responsiveness toward LPS, as indicated by increased TNF-α and IL-1β expression. This effect was due to an activation of ERK, which was significantly amplified in GILZ KO cells. The LPS-induced activation of macrophages is attenuated upon pretreatment of macrophages with low-dose LPS, an effect termed endotoxin tolerance. In LPS-tolerant macrophages, GILZ mRNA was stabilized, whereas ERK activation was strongly decreased. In contrast, GILZ KO macrophages exhibited a strongly reduced desensitization. To explore the contribution of GILZ expression in macrophages to endotoxin tolerance in vivo, we treated GILZ KO mice with repeated i.p. injections of low-dose LPS followed by treatment with high-dose LPS. LPS pretreatment resulted in reduced proinflammatory mediator expression upon high-dose LPS treatment in serum and tissues. In contrast, cytokine induction was preserved in tolerized GILZ KO animals. In summary, our data suggest that GILZ is a key regulator of macrophage functions.

Role of the glucocorticoid‐induced leucine zipper gene in dexamethasone‐induced inhibition of mouse neutrophil migration via control of annexin A1 expression

“…We found that both in vitro and in vivo GILZ expression was enhanced as early as 3 h after GC (DEX) treatment. Upregulation of GILZ by DEX was previously also reported in circulating neutrophils in humans and correlated with apoptosis (16); thus, it seems that neutrophils are another myeloid cell type in which GILZ plays an important role (15,30,35).…”

“…In cells of the innate immune system, GILZ, like GCs, prevents dendritic cells from activating antigen-specific T lymphocytes, and in macrophages, down-regulation of GILZ induces a proinflammatory response (14,15). There is little information on the function of GILZ in neutrophils, and only one recent work has demonstrated that GILZ is important for neutrophil apoptosis in humans (16).…”

Generation and functional characterization of MDSC-like cells

“…Importantly, we found TSC22D3, also known as GILZ, among the genes which were specifically upregulated in IL-10-APC. This transcription factor is described to be a critical factor in macrophage endotoxin tolerance 13 and could explain the absent response of IL-10-APC to LPS. The immunoregulatory actions of TSC22D3 are considered to be mediated, in part, via the inhibition of NF-kB and AP-1.…”

Induction of Glucocorticoid-induced Leucine Zipper (GILZ) Contributes to Anti-inflammatory Effects of the Natural Product Curcumin in Macrophages

“…Loss of GILZ has also been shown to enhance extracellularsignal regulated kinase (ERK) signaling in murine bone marrow-derived macrophages (20). Therefore, we examined LPSinduced ERK activation in curcumin-treated WT and GILZ KO BMMs.…”

“…6, C-F). Both ERK and NF-B are involved in LPS-induced TNF-␣ production in murine BMMs (20). Thus, we also examined the inhibitory effects of curcumin on TNF-␣ secretion in WT and GILZ KO cells.…”