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

Abstract

SUMMARY(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 MIFdependent 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.

Regulation of p53 by macrophage migration inhibitory factor in inflammatory arthritis

“…The combination of effects on apoptosis and proliferation strongly suggest that MIF is a critical mediator of synovial hypercellularity in arthritis. Of note, MIF immunoneutralization in animal models of arthritis is associated with substantial reductions in synovial cellularity (11,12). In this study, very few proliferating cells were detected in mice with AIA synovitis, with no significant further reduction detectable in MIF -/-animals.…”

“…AIA was induced and assessed in male mice (6-8 weeks) as described previously (12). Briefly, mice were injected subcutaneously with 200 g of methylated BSA (mBSA)/200 l of Freund's complete adjuvant (Sigma) and Bordetella pertussis (0.4 ϫ 10 9 organisms/400 l of saline per mouse; Difco, Detroit, MI) and received a subcutaneous boost of 200 g of mBSA/200 l of Freund's complete adjuvant on day 7.…”

“…The proinflammatory cytokine MIF contributes to synovial hypercellularity in experimental models of RA (11,12). MIF is abundantly expressed in RA synovial cells and synovial tissue (13).…”

Macrophage migration inhibitory factor (MIF) gene polymorphism is associated with susceptibility to but not severity of inflammatory polyarthritis

“…Firstly, in experimental animal models of inflammatory arthritis, neutralisation of MIF markedly suppresses the inflammatory response. [5][6][7] Secondly, MIF protein within the synovial fluid of rheumatoid arthritis (RA) patients has been found to be elevated 5-to 10-fold higher than that seen in osteoarthritis patients and normal volunteers. 12 Thirdly, MIF is known to induce macrophage tumour necrosis factor a (TNFa) release and nitric oxide production, as well as being involved in T-cell activation, all of which play a role in RA pathogenesis.…”

“…Raised levels of MIF expression have been reported in RA serum and synovial fluid, and anti-MIF antibodies have been reported to delay the onset and severity of animal models of inflammatory arthritis. [5][6][7] Two functional promoter polymorphisms of the MIF gene have been described. Donn et al 8 identified a singlenucleotide polymorphism (SNP) in the 5' region of the MIF gene (MIF-173*G/C).…”