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 rheumatoid arthritis. The synthesis of MIF by synovial cells is stimulated by glucocorticoids, 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 reverse the anti-inflammatory effects of glucocorticoids in murine antigen-induced arthritis (AIA). Cutaneous DTH reactions and AIA were induced by intradermal injection and intra-articular injection, respectively, of methylated bovine serum albumin in presensitized mice. Animals were treated with anti-MIF MoAbs, recombinant MIF, and/or dexamethasone (DEX). Skin thickness of DTH reactions was measured with callipers and arthritis severity was measured by blinded quantitative histological assessment of synovial cellularity. Cutaneous DTH to the disease-initiating antigen was significantly inhibited by anti-MIF MoAb treatment (P < 0.001). AIA was also significantly inhibited by anti-MIF MoAb (P < 0.02). DEX treatment induced a dose-dependent inhibition of AIA, which was significant at 0.2 mg/kg (P < 0.05). MIF treatment reversed the effect of therapeutic DEX on AIA (P < 0.001). DEX also significantly inhibited DTH reactions (P < 0.05) but rMIF had no effect on this effect of DEX. DTH and AIA are MIF-dependent models of inflammation and arthritis. The reversal of glucocorticoid suppression of AIA by MIF supports the concept that MIF is a counter-regulator of glucocorticoid control of synovial inflammation. Although DTH was observed to be MIF-dependent and glucocorticoid-sensitive, rMIF had no reversing effect on the suppression of DTH by glucocorticoids. This suggests that inflammatory processes in specific tissues may respond differently to MIF in the presence of glucocorticoids.
Santos
L
L
Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Melbourne, Australia.
Hall
P
P
Metz
C
C
Bucala
R
R
Morand
E F
EF
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D001168:Arthritis / Q000276:immunology*; D002417:Cattle; D004195:Disease Models, Animal; D005938:Glucocorticoids / Q000276:immunology*; D006801:Humans; D008263:Macrophage Migration-Inhibitory Factors / Q000276:immunology*; D051379:Mice; D011994:Recombinant Proteins / Q000276:immunology; D012710:Serum Albumin, Bovine / Q000276:immunology / Q000633:toxicity
D000906:Antibodies; D005938:Glucocorticoids; D008263:Macrophage Migration-Inhibitory Factors; D011994:Recombinant Proteins; D012710:Serum Albumin, Bovine