Macrophage migration inhibitory factor upregulates angiogenic factors and correlates with clinical measures in rheumatoid arthritis

Objective. To investigate the relationship between macrophage migration inhibitory factor (MIF) levels and clinical measures in rheumatoid arthritis (RA), and the potential for regulation of angiogenesis in RA. Methods. Serum and synovial fluid (SF) levels of MIF and vascular endothelial growth factor (VEGF) in patients with RA were determined by sandwich ELISA, and the relationships among MIF, VEGF, and RA clinical measures were analyzed. RA synovial fibroblasts were cultured with recombinant human MIF (rhMIF) and the production of VEGF and interleukin 8 (IL-8) were measured in the conditioned media. The angiogenic effect of MIF was examined using established measures of angiogenesis in vitro. Results. Erythrocyte sedimentation rate, C-reactive protein, and the daily dosage of oral prednisolone were correlated with SF levels of MIF. The SF levels of MIF were found to be higher in patients with bony erosion than in those without (69.2 ± 11.4 ng/ml vs 44.0 ± 6.2 ng/ml; p = 0.045). MIF levels had good correlation with VEGF levels (r = 0.52, p < 0.001 in sera, and r = 0.6, p < 0.001 in SF). Production of the angiogenic factors VEGF and IL-8 was enhanced in cultured RA synovial fibroblasts stimulated by rhMIF. Endothelial tube formation was augmented when the endothelial cells were cultured with the conditioned media from rhMIF-pretreated SF mononuclear cells, and this phenomenon was reversed by anti-VEGF antibody. Conclusion. SF MIF may reflect the clinical activity in patients with RA, and rhMIF induces the angiogenic factors in RA synovial fibroblasts. These results suggest that MIF may be an important cytokine in the perpetuation of the angiogenic and inflammatory processes in patients with RA.