Macrophage migration inhibitory factor in rheumatoid arthritis - Evidence of proinflammatory function and regulation by glucocorticoids

Objective. Macrophage migration inhibitory factor (MIF) is a proinflammator y cytokine whose involvement in tumor necrosis factor alpha (TNF alpha) syn thesis and T cell activation suggests a role in the pathogenesis of rheumat oid arthritis (RA), Antagonism of MIF is associated with marked inhibition of animal models of RA, Uniquely, MIF is inducible by low concentrations of glucocorticoids, We sought to investigate the expression of MIF in RA syno vial tissue, Methods, MIF was demonstrated in human RA synovium by immunohistochemistry, flow cytometry, enzyme-linked immunosorbent assay (ELISA), and reverse tra nscription-polymerase chain reaction (RT-PCR), Regulation of MIF expression was investigated by treatment of cultured fibroblast-like synoviocytes (FL S) with interleukin-1 beta (IL-1 beta), TNF alpha, or interferon-gamma (IFN gamma), and dexamethasone (DEX), Mononuclear cell TNF alpha release after exposure to FLS-conditioned medium was measured by ELISA, Results. MIF was present in RA synovial lining CD14+ macrophages and FLS, C onstitutive MIF messenger RNA (mRNA) expression was demonstrated by RT-PCR of RNA from unstimulated cultured RA FLS, which also released abundant MIF, Serum, synovial fluid, and FLS intracellular MIF were significantly higher in RA patients than in controls. Synoviocyte MIF was not increased by IL-1 beta, TNF alpha, or IFN gamma. In contrast, DEX 10(-7) M significantly red uced synoviocyte MIF, while DEX 10(-10)-10(-12) M induced a significant inc rease in MIF and MIF mRNA, Peripheral blood mononuclear cell TNF alpha rele ase was induced by culture in RA FLS-conditioned medium, and this induction was significantly abrogated by monoclonal anti-MIF antibody, suggesting th at MIF is an upstream regulator of TNF alpha release, Conclusion. These data represent the first demonstration of the cytokine MI F in human autoimmune disease and suggest MIF as a potential therapeutic ta rget in RA.