Background/Purpose:

Macrophage migration inhibitory factor (MIF) plays a pivotal role in promotion of inflammatory diseases such as rheumatoid arthritis (RA). MIF has previously been shown to oppose the action of glucocorticoids, by regulating the expression of dual-specificity phosphatase (DUSP)-1 (syn. MAPK phosphatase-1 (MKP-1)) and thereby to amplify MAP kinase signalling and up-regulate multiple cytokines and chemokines. Glucocorticoids also act by regulation of glucocorticoid induced leucine zipper (GILZ). Whether MIF opposition of glucocorticoid actions involves modulation of other DUSPs or GILZ is unknown. Therefore, the aim of this study was to examine the effects of MIF on the expression of DUSPs and GILZ.

Methods:

Bone marrow derived macrophages and dermal fibroblasts were isolated from WT, MIF^-/- and GILZ^-/- mice. The expression of a panel of DUSPs and GILZ, and TNF and IL-6, were investigated by real time RT-PCR, Western blotting and ELISA. 

Results:

In MIF^-/- macrophages, multiple DUSPs, including DUSP1/MKP-1, but also DUSP 2, 5, 6, 8, 9, 10, 16, and 19, were significantly increased. GILZ mRNA and protein were significantly increased in MIF^-/- macrophages and fibroblasts, and GILZ expression induced by Dex was also significantly greater in MIF^-/- cells. Correspondingly, recombinant MIF inhibited GILZ expression, MIF inhibited the expression and nuclear translocation of the transcription factor FoxO3a, and FoxO3a silencing reversed the effect of MIF deletion on GILZ. The basal and Dex-induced expression of the panel of MIF-regulated DUSPs was significantly reduced in GILZ^-/- cells, and accordingly, LPS-induced TNF and IL-6 were significantly increased in GILZ^-/- cells. 

Conclusion:

These studies indicate a previously unsuspected broad regulatory effect of MIF on multiple DUSPs. Moreover, we identify FoxO3a-dependent regulation of GILZ by MIF, and a corresponding regulatory effect of GILZ on DUSPs and cytokine expression. The results suggest that GILZ-mediated regulation of DUSP expression mediates the antagonistic effect of MIF on glucocorticoid actions.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/macrophage-migration-inhibitory-factor-regulates-dual-specificity-phosphatases-via-glucocorticoid-induced-leucine-zipper/