Macrophage Migration Inhibitory Factor Inhibits the Antiinflammatory Effects of Glucocorticoids via Glucocorticoid‐Induced Leucine Zipper

Abstract

Objectives Glucocorticoids remain a mainstay of the treatment of rheumatoid arthritis (RA). Dose-dependent adverse effects highlight the potential for therapies that regulate glucocorticoid sensitivity to enable glucocorticoid dose reduction. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory protein implicated in the pathogenesis of RA, which also impairs glucocorticoid sensitivity via inhibition of the MAP kinase phosphatase, MKP-1. The intracellular protein glucocorticoid-induced leucine zipper (GILZ) mimics the effects of glucocorticoids in models of RA, but whether it represents a target for the modulation of glucocorticoid sensitivity remains unknown. We therefore investigated whether GILZ is implicated in regulation of glucocorticoid sensitivity by MIF. Methods GILZ expression was studied in the presence and absence of MIF, and the role of GILZ in the MIF-dependent regulation of the glucocorticoid sensitivity mediator MAP kinase phosphatase-1 (MKP-1) studied at the level of expression and function. Results GILZ expression was significantly inhibited by endogenous MIF, both basally and during responses to glucocorticoid treatment. The effects of MIF on GILZ were dependent on the expression and Akt-induced nuclear translocation of the transcription factor FoxO3a. GILZ was shown to regulate the expression of MKP-1, and consequent MAP kinase phosphorylation and cytokine release. Conclusions MIF exerts its effects on MKP-1 expression and MAP kinase activity through inhibitory effects on GILZ. These findings suggest a previously unsuspected intersection between these two molecules and identify GILZ as a potential target for the therapeutic regulation of glucocorticoid sensitivity.

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

“…In our experimental setting, MKP-1 expression and p38 as well as JNK activation were not affected by GILZ depletion, indicating that the absence of GILZ modulates ERK activity mainly via increased Raf1 phosphorylation in an MKP-1-independent manner. A recent report by Fan et al (30) contrasts our observations by showing that GILZ KO increases both ERK and p38 activation even in nonactivated BMMs, most likely via reduced MKP-1 expression. However, these results may not be directly comparable with this study, because cell culture protocols and treatment schemes were distinctly different.…”

“…In addition to its ability to bind to NF-kB and AP-1, GILZ has also been reported to interfere with MAPK signaling (3,7,8,23,30,31). MAPKs modulate various physiological cell processes, such as proliferation and apoptosis.…”

“…GILZ has recently been implicated in GC-dependent upregulation of MKP-1 expression in endothelial cells (7) and has been suggested to regulate the expression of MKP-1 and MAPK phosphorylation in macrophages (30). MKP-1 was initially identified as an in vitro ERKspecific phosphatase, but depending on the cell type it can also dephosphorylate other members of the MAPK family, such as JNK and p38, and thus suppress signaling downstream of these kinases (39,(41)(42)(43)(44).…”

“…Studies showing that TAT-GILZ fusion protein protects against LPS-induced endotoxemia in mice (10) and that LPS resistance in the inbred mouse strain SPRET/Ei is due to GILZ expression (45) further underline the central role of GILZ in the LPS response. Although the regulation and functional significance of GILZ expression in activated macrophages has been addressed previously (4,14,30), the contribution of endogenous GILZ to macrophage deactivation is largely unknown. Therefore, we examined the regulation and functional significance of GILZ in LPS tolerance.…”

“…GILZ has been suggested to modulate MAPK signaling in various cell types (3,7,8,23,30,31). Therefore, we examined LPS-induced p38, JNK, and ERK activation in WT and GILZ KO cells.…”