Open AccessRegulation of synoviocyte phospholipase A 2 and cyclooxygenase 2 by macrophage migration inhibitory factor
Author(s) -
Sampey Annaleise V.,
Hall Pamela H.,
Mitchell Robert A.,
Metz Christine N.,
Morand Eric F.
Publication year - 2001
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/1529-0131(200106)44:6<1273::aid-art219>3.0.co;2-8
Subject(s) - macrophage migration inhibitory factor , phospholipase a2 , proinflammatory cytokine , cytokine , tumor necrosis factor alpha , cyclooxygenase , monocyte , chemistry , microbiology and biotechnology , biology , endocrinology , medicine , immunology , inflammation , enzyme , biochemistry
Objective Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with known actions in macrophage and T cell activation. MIF also has the unique capacity to reverse the inhibitory effects of glucocorticoids on these cells. We have recently demonstrated MIF expression in human rheumatoid arthritis (RA) synovium and cultured fibroblast‐like synoviocytes (FLS), as well as the ability of FLS‐derived MIF to induce monocyte release of tumor necrosis factor α. We investigated the effects of MIF on aspects of RA FLS activation, including the induction of phospholipase A 2 (PLA 2 ) and cyclooxygenase (COX). Methods PLA 2 activity was measured by 3 H–arachidonic acid released from treated FLS supernatants. COX activity was measured by prostaglandin E 2 enzyme‐linked immunosorbent assay. Cytosolic PLA 2 (cPLA 2 ) and COX‐2 messenger RNA (mRNA) were determined using semiquantitative reverse transcriptase–polymerase chain reaction. Results Constitutive PLA 2 activity was detected in RA FLS. Recombinant human MIF up‐regulated PLA 2 activity ( P < 0.01) and cPLA 2 mRNA expression, but had no effect on secretory PLA 2 . Recombinant human MIF up‐regulated COX activity ( P < 0.05) and COX‐2 mRNA, but had no observable effect on COX‐1. Interleukin‐1β (IL‐1β) significantly up‐regulated PLA 2 activity ( P < 0.005) and cPLA 2 mRNA expression while anti‐MIF monoclonal antibody (mAb) significantly inhibited this IL‐1β–induced PLA 2 activity ( P < 0.02). Anti‐MIF mAb significantly reduced IL‐1β–induced COX activity ( P < 0.05) and COX‐2 mRNA expression. Conclusion MIF exerts a proinflammatory effect on key aspects of RA FLS activation. That anti‐MIF mAb inhibited IL‐1β up‐regulation of FLS indicates an additional cofactor role for MIF in IL‐1β–induced FLS activation. These data suggest that MIF antagonism has important therapeutic potential in RA.