Macrophage migration inhibitory factor inhibits the antiinflammatory effects of glucocorticoids via glucocorticoid-induced leucine zipper

Huapeng Fan, Wenping Kao, Yuan Hang Yang, Ran Gu, James Harris, Gunter Fingerle-Rowson, Richard Bucala, Devi Ngo, Elaine Vicky Beaulieu, Eric Francis Morand

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)2059 - 2070
Number of pages12
JournalArthritis and Rheumatology
Volume66
Issue number8
DOIs
Publication statusPublished - 2014

Cite this

Fan, Huapeng ; Kao, Wenping ; Yang, Yuan Hang ; Gu, Ran ; Harris, James ; Fingerle-Rowson, Gunter ; Bucala, Richard ; Ngo, Devi ; Beaulieu, Elaine Vicky ; Morand, Eric Francis. / Macrophage migration inhibitory factor inhibits the antiinflammatory effects of glucocorticoids via glucocorticoid-induced leucine zipper. In: Arthritis and Rheumatology. 2014 ; Vol. 66, No. 8. pp. 2059 - 2070.
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title = "Macrophage migration inhibitory factor inhibits the antiinflammatory effects of glucocorticoids via glucocorticoid-induced leucine zipper",
abstract = "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.",
author = "Huapeng Fan and Wenping Kao and Yang, {Yuan Hang} and Ran Gu and James Harris and Gunter Fingerle-Rowson and Richard Bucala and Devi Ngo and Beaulieu, {Elaine Vicky} and Morand, {Eric Francis}",
year = "2014",
doi = "10.1002/art.38689",
language = "English",
volume = "66",
pages = "2059 -- 2070",
journal = "Arthritis and Rheumatology",
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publisher = "Wiley-Blackwell",
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Macrophage migration inhibitory factor inhibits the antiinflammatory effects of glucocorticoids via glucocorticoid-induced leucine zipper. / Fan, Huapeng; Kao, Wenping; Yang, Yuan Hang; Gu, Ran; Harris, James; Fingerle-Rowson, Gunter; Bucala, Richard; Ngo, Devi; Beaulieu, Elaine Vicky; Morand, Eric Francis.

In: Arthritis and Rheumatology, Vol. 66, No. 8, 2014, p. 2059 - 2070.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Macrophage migration inhibitory factor inhibits the antiinflammatory effects of glucocorticoids via glucocorticoid-induced leucine zipper

AU - Fan, Huapeng

AU - Kao, Wenping

AU - Yang, Yuan Hang

AU - Gu, Ran

AU - Harris, James

AU - Fingerle-Rowson, Gunter

AU - Bucala, Richard

AU - Ngo, Devi

AU - Beaulieu, Elaine Vicky

AU - Morand, Eric Francis

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

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U2 - 10.1002/art.38689

DO - 10.1002/art.38689

M3 - Article

VL - 66

SP - 2059

EP - 2070

JO - Arthritis and Rheumatology

JF - Arthritis and Rheumatology

SN - 2326-5191

IS - 8

ER -