Document Detail

Macrophage migration inhibitory factor in rheumatoid arthritis: evidence of proinflammatory function and regulation by glucocorticoids.
MedLine Citation:
PMID:  10446857     Owner:  NLM     Status:  MEDLINE    
OBJECTIVE: Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine whose involvement in tumor necrosis factor alpha (TNFalpha) synthesis and T cell activation suggests a role in the pathogenesis of rheumatoid arthritis (RA). Antagonism of MIF is associated with marked inhibition of animal models of RA. Uniquely, MIF is inducible by low concentrations of glucocorticoids. We sought to investigate the expression of MIF in RA synovial tissue. METHODS: MIF was demonstrated in human RA synovium by immunohistochemistry, flow cytometry, enzyme-linked immunosorbent assay (ELISA), and reverse transcription-polymerase chain reaction (RT-PCR). Regulation of MIF expression was investigated by treatment of cultured fibroblast-like synoviocytes (FLS) with interleukin-1beta (IL-1beta), TNFalpha, or interferon-gamma (IFNgamma), and dexamethasone (DEX). Mononuclear cell TNFalpha release after exposure to FLS-conditioned medium was measured by ELISA. RESULTS: MIF was present in RA synovial lining CD14+ macrophages and FLS. Constitutive MIF messenger RNA (mRNA) expression was demonstrated by RT-PCR of RNA from unstimulated cultured RA FLS, which also released abundant MIF. Serum, synovial fluid, and FLS intracellular MIF were significantly higher in RA patients than in controls. Synoviocyte MIF was not increased by IL-1beta, TNFalpha, or IFNgamma. In contrast, DEX 10(-7)M significantly reduced synoviocyte MIF, while DEX 10(-10)-10(-12)M induced a significant increase in MIF and MIF mRNA. Peripheral blood mononuclear cell TNFalpha release was induced by culture in RA FLS-conditioned medium, and this induction was significantly abrogated by monoclonal anti-MIF antibody, suggesting that MIF is an upstream regulator of TNFalpha release. CONCLUSION: These data represent the first demonstration of the cytokine MIF in human autoimmune disease and suggest MIF as a potential therapeutic target in RA.
M Leech; C Metz; P Hall; P Hutchinson; K Gianis; M Smith; H Weedon; S R Holdsworth; R Bucala; E F Morand
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Arthritis and rheumatism     Volume:  42     ISSN:  0004-3591     ISO Abbreviation:  Arthritis Rheum.     Publication Date:  1999 Aug 
Date Detail:
Created Date:  1999-08-19     Completed Date:  1999-08-19     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  0370605     Medline TA:  Arthritis Rheum     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1601-8     Citation Subset:  AIM; IM    
Monash Medical Centre, Melbourne, Australia.
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MeSH Terms
Arthritis, Rheumatoid / metabolism*
Cells, Cultured
Cytokines / pharmacology
Glucocorticoids / pharmacology
Interferon-gamma / pharmacology
Lymphocyte Activation
Macrophage Migration-Inhibitory Factors / analysis*,  genetics
Macrophages / metabolism
Monocytes / secretion
RNA, Messenger / analysis,  drug effects
Reverse Transcriptase Polymerase Chain Reaction
Synovial Membrane / chemistry,  cytology
T-Lymphocytes / immunology
Tumor Necrosis Factor-alpha / biosynthesis,  metabolism
Reg. No./Substance:
0/Cytokines; 0/Glucocorticoids; 0/Macrophage Migration-Inhibitory Factors; 0/RNA, Messenger; 0/Tumor Necrosis Factor-alpha; 82115-62-6/Interferon-gamma

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