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HAE-RIM KIM, MI-KYUNG PARK, MI-LA CHO, CHONG-HYEON YOON, SANG-HEON LEE, SUNG-HWAN PARK, LIN LENG, RICHARD BUCALA, INSOO KANG, JONGSEON CHOE, and HO-YOUN KIM ABSTRACT. 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. (First Release April 1 2007; J Rheumatol 2007:34:927-36) Key Indexing Terms:
MACROPHAGE MIGRATION
INHIBITORY FACTOR From the Department of Internal Medicine, School of Medicine, Konkuk University; Rheumatism Research Center, Catholic Research Institute of Medical Science, Catholic University of Korea, Seoul; Department of Microbiology and Immunology, Kangwon National University School of Medicine, Chunchon, Korea; and the Department of Internal Medicine, School of Medicine, Yale University, New Haven, Connecticut, USA. Supported by grant R11-2002-098-05001-0 from the Korea Science and Engineering Foundation through the Rheumatism Research Center at Catholic University of Korea, grants from the National Institutes of Health (to LL, RB, IK), and a Vascular System Research Center grant from the Korea Science and Engineering Foundation (to JC). H-R. Kim, MD; S-H. Lee, MD, Department of Internal Medicine, School of Medicine, Konkuk University; M-K. Park, MS; M-L. Cho, PhD; C-H. Yoon, MD; S-H. Park, MD; H-Y. Kim, MD, Rheumatism Research Center, Catholic Research Institute of Medical Science, Catholic University of Korea; L. Leng, MD; R. Bucala, MD; I. Kang, MD, Department of Internal Medicine, School of Medicine, Yale University; J. Choe, PhD, Department of Microbiology and Immunology, Kangwon National University School of Medicine. Address reprint requests to Dr. S-H. Park, Department of Internal Medicine, Kangnam St. Mary's Hospital, The Catholic University of Korea, 505 Banpo-dong Seocho-ku, Seoul, 137-040, Korea. E-mail : rapark@catholic.ac.kr. Accepted for publication January 12, 2007. All rights reserved. |
