Universität zu Köln

Fan, Huapeng ORCID: 0000-0001-5635-2353, Kao, Wenping, Yang, Yuan H., Gu, Ran, Harris, James ORCID: 0000-0002-5634-9637, Fingerle-Rowson, Guenter, Bucala, Richard, Ngo, Devi, Beaulieu, Elaine ORCID: 0000-0002-9529-9943 and Morand, Eric F. (2014). Macrophage Migration Inhibitory Factor Inhibits the Antiinflammatory Effects of Glucocorticoids via Glucocorticoid-Induced Leucine Zipper. Arthritis Rheumatol., 66 (8). S. 2059 - 2071. HOBOKEN: WILEY. ISSN 2326-5205

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Abstract

Objective. Glucocorticoids remain a mainstay in the treatment of rheumatoid arthritis (RA). Dose-dependent adverse effects highlight the need for therapies that regulate glucocorticoid sensitivity to enable dosage reduction. Macrophage migration inhibitory factor (MIF) is a proinflammatory protein that has been implicated in the pathogenesis of RA; it impairs glucocorticoid sensitivity via MAPK phosphatase 1 (MKP-1) inhibition. 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 undertook this study to investigate whether GILZ is involved in the 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 MKP-1 was 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 MAPK phosphorylation and cytokine release. Conclusion. MIF exerts its effects on MKP-1 expression and MAPK activity through inhibitory effects on GILZ. These findings suggest a previously unsuspected interaction between MIF and GILZ and identify GILZ as a potential target for the therapeutic regulation of glucocorticoid sensitivity.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Fan, Huapeng UNSPECIFIED orcid.org/0000-0001-5635-2353 UNSPECIFIED Kao, Wenping UNSPECIFIED UNSPECIFIED UNSPECIFIED Yang, Yuan H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gu, Ran UNSPECIFIED UNSPECIFIED UNSPECIFIED Harris, James UNSPECIFIED orcid.org/0000-0002-5634-9637 UNSPECIFIED Fingerle-Rowson, Guenter UNSPECIFIED UNSPECIFIED UNSPECIFIED Bucala, Richard UNSPECIFIED UNSPECIFIED UNSPECIFIED Ngo, Devi UNSPECIFIED UNSPECIFIED UNSPECIFIED Beaulieu, Elaine UNSPECIFIED orcid.org/0000-0002-9529-9943 UNSPECIFIED Morand, Eric F. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-432485
DOI:	10.1002/art.38689
Journal or Publication Title:	Arthritis Rheumatol.
Volume:	66
Number:	8
Page Range:	S. 2059 - 2071
Date:	2014
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	2326-5205
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INNATE IMMUNE-RESPONSES; ACTIVATED PROTEIN-KINASE; NF-KAPPA-B; RHEUMATOID-ARTHRITIS; MAP KINASE; ENDOGENOUS GLUCOCORTICOIDS; DEFICIENT MICE; PHOSPHATASE-1; EXPRESSION; GILZ Multiple languages Rheumatology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/43248