Role of macrophage migration inhibitory factor (MIF) in murine antigen-induced arthritis: interaction with glucocorticoids

(MIF) is a broad-spectrum proinflammatory cytokine implicated in human rheu matoid arthritis. The synthesis of MIF by synovial cells is stimulated by g lucocorticoids, and previous studies suggest that MIF antagonizes the anti- inflammatory effects of glucocorticoids. This has not been established in a model of arthritis. We wished to test the hypothesis that MIF can act to r everse the anti-inflammatory effects of glucocorticoids in murine antigen-i nduced arthritis (AIA). Cutaneous DTH reactions and AIA were induced by int radermal injection and intra-articular injection, respectively, of methylat ed bovine serum albumin in presensitized mice. Animals were treated with an ti-MIF MoAbs, recombinant MIF, and/or dexamethasone (DEX). Skin thickness o f DTH reactions was measured with callipers and arthritis severity was meas ured by blinded quantitative histological assessment of synovial cellularit y. Cutaneous DTH to the disease-initiating antigen was significantly inhibi ted by anti-MIF MoAb treatment (P < 0.001). AIA was also significantly inhi bited by anti-MIF MoAb (P < 0.02). DEX treatment induced a dose-dependent i nhibition of AIA, which was significant at 0.2 mg/kg (P < 0.05). MIF treatm ent reversed the effect of therapeutic DEX on AIA (P < 0.001). DEX also sig nificantly inhibited DTH reactions (P < 0.05) but rMIF had no effect on thi s effect of DEX. DTH and AIA are MIF-dependent models of inflammation and a rthritis. The reversal of glucocorticoid suppression of AIA by MIF supports the concept that MIF is a counter-regulator of glucocorticoid control of s ynovial inflammation. Although DTH was observed to be MIF-dependent and glu cocorticoid-sensitive, rMIF had no reversing effect on the suppression of D TH by glucocorticoids. This suggests that inflammatory processes in specifi c tissues may respond differently to MIF in the presence of glucocorticoids .