Identification of NURR1 as a mediator of MIF signaling during chronic arthritis: effects on glucocorticoid-induced MKP1

Jennifer Ralph, Afsar Ahmed, Leilani Santos, Andrew Clark, Jason McMorrow, Evelyn Murphy, Eric Morand

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Elucidation of factors regulating glucocorticoid (GC) sensitivity is required for the development of steroid-sparing therapies for chronic inflammatory diseases, including rheumatoid arthritis (RA). Accumulating evidence suggests that macrophage migration inhibitory factor (MIF) counterregulates the GC-induction of anti-inflammatory mediators, including mitogen-activated protein kinase phosphatase 1 (MKP1), a critical mitogen-activated protein kinase signaling inhibitor. This observation has yet to be extended to human disease; the molecular mechanisms remain unknown. We investigated NURR1, a GC-responsive transcription factor overexpressed in RA, as a MIF signaling target. We reveal abrogation by recombinant MIF (rMIF) of GC-induced MKP1 expression in RA fibroblast-like synoviocytes (FLS). rMIF enhanced NURR1 expression, artificial NBRE (orphan receptor DNA-binding site) reporter transactivation, and reversed GC-inhibition of NURR1. NURR1 expression was reduced during experimental arthritis in MIF-/- synovium, and silencing MIF reduced RA FLS NURR1 mRNA. Consistent with NBRE identification on the MKP1 gene, MKP1 mRNA was reduced in FLS that ectopically express NURR1, and silencing NURR1 enhanced MKP1 mRNA in RA FLS. rMIF enhanced NBRE binding on the MKP1 gene, and the absence of the NBRE prevented NURR1-repressive effects on basal and GC-induced MKP1 transactivation. This study defines NURR1 as a novel MIF target in chronic inflammation and demonstrates a role for NURR1 in regulating the anti-inflammatory mediator, MKP1. We propose a MIF-NURR1 signaling axis as a regulator of the GC sensitivity of MKP1.
Original languageEnglish
Pages (from-to)2366 - 2378
Number of pages13
JournalAmerican Journal of Pathology
Volume177
Issue number5
DOIs
Publication statusPublished - 2010

Cite this

Ralph, Jennifer ; Ahmed, Afsar ; Santos, Leilani ; Clark, Andrew ; McMorrow, Jason ; Murphy, Evelyn ; Morand, Eric. / Identification of NURR1 as a mediator of MIF signaling during chronic arthritis: effects on glucocorticoid-induced MKP1. In: American Journal of Pathology. 2010 ; Vol. 177, No. 5. pp. 2366 - 2378.
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abstract = "Elucidation of factors regulating glucocorticoid (GC) sensitivity is required for the development of steroid-sparing therapies for chronic inflammatory diseases, including rheumatoid arthritis (RA). Accumulating evidence suggests that macrophage migration inhibitory factor (MIF) counterregulates the GC-induction of anti-inflammatory mediators, including mitogen-activated protein kinase phosphatase 1 (MKP1), a critical mitogen-activated protein kinase signaling inhibitor. This observation has yet to be extended to human disease; the molecular mechanisms remain unknown. We investigated NURR1, a GC-responsive transcription factor overexpressed in RA, as a MIF signaling target. We reveal abrogation by recombinant MIF (rMIF) of GC-induced MKP1 expression in RA fibroblast-like synoviocytes (FLS). rMIF enhanced NURR1 expression, artificial NBRE (orphan receptor DNA-binding site) reporter transactivation, and reversed GC-inhibition of NURR1. NURR1 expression was reduced during experimental arthritis in MIF-/- synovium, and silencing MIF reduced RA FLS NURR1 mRNA. Consistent with NBRE identification on the MKP1 gene, MKP1 mRNA was reduced in FLS that ectopically express NURR1, and silencing NURR1 enhanced MKP1 mRNA in RA FLS. rMIF enhanced NBRE binding on the MKP1 gene, and the absence of the NBRE prevented NURR1-repressive effects on basal and GC-induced MKP1 transactivation. This study defines NURR1 as a novel MIF target in chronic inflammation and demonstrates a role for NURR1 in regulating the anti-inflammatory mediator, MKP1. We propose a MIF-NURR1 signaling axis as a regulator of the GC sensitivity of MKP1.",
author = "Jennifer Ralph and Afsar Ahmed and Leilani Santos and Andrew Clark and Jason McMorrow and Evelyn Murphy and Eric Morand",
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Identification of NURR1 as a mediator of MIF signaling during chronic arthritis: effects on glucocorticoid-induced MKP1. / Ralph, Jennifer; Ahmed, Afsar; Santos, Leilani; Clark, Andrew; McMorrow, Jason; Murphy, Evelyn; Morand, Eric.

In: American Journal of Pathology, Vol. 177, No. 5, 2010, p. 2366 - 2378.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Identification of NURR1 as a mediator of MIF signaling during chronic arthritis: effects on glucocorticoid-induced MKP1

AU - Ralph, Jennifer

AU - Ahmed, Afsar

AU - Santos, Leilani

AU - Clark, Andrew

AU - McMorrow, Jason

AU - Murphy, Evelyn

AU - Morand, Eric

PY - 2010

Y1 - 2010

N2 - Elucidation of factors regulating glucocorticoid (GC) sensitivity is required for the development of steroid-sparing therapies for chronic inflammatory diseases, including rheumatoid arthritis (RA). Accumulating evidence suggests that macrophage migration inhibitory factor (MIF) counterregulates the GC-induction of anti-inflammatory mediators, including mitogen-activated protein kinase phosphatase 1 (MKP1), a critical mitogen-activated protein kinase signaling inhibitor. This observation has yet to be extended to human disease; the molecular mechanisms remain unknown. We investigated NURR1, a GC-responsive transcription factor overexpressed in RA, as a MIF signaling target. We reveal abrogation by recombinant MIF (rMIF) of GC-induced MKP1 expression in RA fibroblast-like synoviocytes (FLS). rMIF enhanced NURR1 expression, artificial NBRE (orphan receptor DNA-binding site) reporter transactivation, and reversed GC-inhibition of NURR1. NURR1 expression was reduced during experimental arthritis in MIF-/- synovium, and silencing MIF reduced RA FLS NURR1 mRNA. Consistent with NBRE identification on the MKP1 gene, MKP1 mRNA was reduced in FLS that ectopically express NURR1, and silencing NURR1 enhanced MKP1 mRNA in RA FLS. rMIF enhanced NBRE binding on the MKP1 gene, and the absence of the NBRE prevented NURR1-repressive effects on basal and GC-induced MKP1 transactivation. This study defines NURR1 as a novel MIF target in chronic inflammation and demonstrates a role for NURR1 in regulating the anti-inflammatory mediator, MKP1. We propose a MIF-NURR1 signaling axis as a regulator of the GC sensitivity of MKP1.

AB - Elucidation of factors regulating glucocorticoid (GC) sensitivity is required for the development of steroid-sparing therapies for chronic inflammatory diseases, including rheumatoid arthritis (RA). Accumulating evidence suggests that macrophage migration inhibitory factor (MIF) counterregulates the GC-induction of anti-inflammatory mediators, including mitogen-activated protein kinase phosphatase 1 (MKP1), a critical mitogen-activated protein kinase signaling inhibitor. This observation has yet to be extended to human disease; the molecular mechanisms remain unknown. We investigated NURR1, a GC-responsive transcription factor overexpressed in RA, as a MIF signaling target. We reveal abrogation by recombinant MIF (rMIF) of GC-induced MKP1 expression in RA fibroblast-like synoviocytes (FLS). rMIF enhanced NURR1 expression, artificial NBRE (orphan receptor DNA-binding site) reporter transactivation, and reversed GC-inhibition of NURR1. NURR1 expression was reduced during experimental arthritis in MIF-/- synovium, and silencing MIF reduced RA FLS NURR1 mRNA. Consistent with NBRE identification on the MKP1 gene, MKP1 mRNA was reduced in FLS that ectopically express NURR1, and silencing NURR1 enhanced MKP1 mRNA in RA FLS. rMIF enhanced NBRE binding on the MKP1 gene, and the absence of the NBRE prevented NURR1-repressive effects on basal and GC-induced MKP1 transactivation. This study defines NURR1 as a novel MIF target in chronic inflammation and demonstrates a role for NURR1 in regulating the anti-inflammatory mediator, MKP1. We propose a MIF-NURR1 signaling axis as a regulator of the GC sensitivity of MKP1.

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U2 - 10.2353/ajpath.2010.091204

DO - 10.2353/ajpath.2010.091204

M3 - Article

VL - 177

SP - 2366

EP - 2378

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 5

ER -