Regulation of synoviocyte phospholipase A2 and cyclooxygenase 2 by macrophage migration inhibitory factor.

  • Sampey A
  • Hall P
  • Mitchell R
 et al. 
  • 17

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Abstract

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 alpha. We investigated the effects of MIF on aspects of RA FLS activation, including the induction of phospholipase A2 (PLA2) and cyclooxygenase (COX).

METHODS: PLA2 activity was measured by 3H-arachidonic acid released from treated FLS supernatants. COX activity was measured by prostaglandin E2 enzyme-linked immunosorbent assay. Cytosolic PLA2 (cPLA2) and COX-2 messenger RNA (mRNA) were determined using semiquantitative reverse transcriptase-polymerase chain reaction.

RESULTS: Constitutive PLA2 activity was detected in RA FLS. Recombinant human MIF up-regulated PLA2 activity (P < 0.01) and cPLA2 mRNA expression, but had no effect on secretory PLA2. Recombinant human MIF up-regulated COX activity (P < 0.05) and COX-2 mRNA, but had no observable effect on COX-1. Interleukin-1beta (IL-1beta) significantly up-regulated PLA2 activity (P < 0.005) and cPLA2 mRNA expression while anti-MIF monoclonal antibody (mAb) significantly inhibited this IL-1beta-induced PLA2 activity (P < 0.02). Anti-MIF mAb significantly reduced IL-1beta-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-1beta up-regulation of FLS indicates an additional cofactor role for MIF in IL-1beta-induced FLS activation. These data suggest that MIF antagonism has important therapeutic potential in RA.

Author-supplied keywords

  • Antibodies, Blocking
  • Antibodies, Blocking: pharmacology
  • Arthritis, Rheumatoid
  • Arthritis, Rheumatoid: enzymology
  • Cells, Cultured
  • Cyclooxygenase 2
  • Cytosol
  • Cytosol: enzymology
  • DNA Primers
  • DNA Primers: chemistry
  • Dose-Response Relationship, Drug
  • Enzyme Induction
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Humans
  • Isoenzymes
  • Isoenzymes: genetics
  • Isoenzymes: metabolism
  • Macrophage Migration-Inhibitory Factors
  • Macrophage Migration-Inhibitory Factors: immunolog
  • Macrophage Migration-Inhibitory Factors: pharmacol
  • Membrane Proteins
  • Phospholipases A
  • Phospholipases A2
  • Phospholipases A: genetics
  • Phospholipases A: metabolism
  • Prostaglandin-Endoperoxide Synthases
  • Prostaglandin-Endoperoxide Synthases: genetics
  • Prostaglandin-Endoperoxide Synthases: metabolism
  • Recombinant Proteins
  • Reverse Transcriptase Polymerase Chain Reaction
  • Synovial Membrane
  • Synovial Membrane: drug effects
  • Synovial Membrane: enzymology
  • Synovial Membrane: pathology
  • Up-Regulation

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Authors

  • a V Sampey

  • P H Hall

  • R a Mitchell

  • C N Metz

  • E F Morand

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