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 A₂ (PLA₂) and cyclooxygenase (COX).

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.

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‐1β (IL‐1β) significantly up‐regulated PLA₂ activity (P < 0.005) and cPLA₂ mRNA expression while anti‐MIF monoclonal antibody (mAb) significantly inhibited this IL‐1β–induced PLA₂ activity (P < 0.02). Anti‐MIF mAb significantly reduced IL‐1β–induced COX activity (P < 0.05) and COX‐2 mRNA expression.

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.