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. (c) 2014 American College of Rheumatology.