The joint synovium undergoes profound changes during rheumatoid arthritis, resulting in the hyperplastic and invasive tissue known as pannus. The fibroblast-like cells within pannus have a persistently activated phenotype, show increased proliferation and decreased apoptosis, and increased growth factor and matrix-degrading enzyme release. Our work has emphasized the role of macrophage migration inhibitory factor (MIF) in this process. We reported on MIF's ability to induce sustained activation of the ERK1/2 MAP kinase pathway and to inhibit p53-dependent apoptosis. We also described functional polymorphisms in the MIF gene and their association with rheumatoid arthritis severity. These genetic results recently have been confirmed in a larger, multi-center European study. In the prior funding period, we cloned the two component MIF receptor and demonstrated the importance of the ERK1/2 and p53 regulatory pathways in cell-based and genetic-KO studies of MIF inflammatory function. In this competitive renewal, we seek to define the structural basis of MIF interaction with its receptor using biochemical and genetic means. We focus on MIF's N-terminal region and its enigmatic tautomerase activity, which we hypothesize has a role in engaging the MIF binding receptor (CD74). We also will define the inflammatory and activation properties of monocyte/macrophages and synovia! fibroblasts encoding high- versus low-expression MIF alleles. Our Specific Alms are to: 1. Define the Importance of the MIF N- terminal Domain In MIF Signal Transductlon and Pro-inflammatory Function. Our working hypothesis is that the MIF N-terminal region is essential for MIF inflammatory activity because it engages the MIF receptor. 2. Define the Inflammatory Phenotype of the P1G-MIF Knockln Mouse that Expresses a Tautornerase- null MIF Protein. We will induce arthritis in these mice and compare their phenotype with that of wild-type, MIF-KO, and MIF receptor-KO (CD74-KO) mice. We also will study arthritis development in wild-type mice treated with different anti-MIF mAbs, soluble MIF receptor (sCD74-Fc), and the small molecule MIF antagonist, ISO-1, which binds to the MIF N-terminal region and inhibits tautomerase activity. 3. Define the Role of High- and Low-expression MIF Alleles in MIF Production and Cellular Activation Events Relevant to Rheumatoid Pannus. MIF is produced both by monocytes/macrophages and by fibroblasts, and it exerts auto- crine/paracrine activation effects. Our working hypothesis is that human monocytes or synovial fibroblasts encoding high-expression MIF alleles will show enhanced MIF production, MIF-mediated signal transduction, and a more activated phenotype when compared to cells encoding low-expression MIF alleles. These results will be significant because they will provide a strong foundation for the design of MIF inhibitors - by monoclonal antibody, soluble receptor, or small molecule approaches. Moreover, elucidation of the mechanism(s) by which high expression MIF alleles contribute to joint damage may allow for the identification of patients with an MIF-dependent form of disease and guide the selection of patients in whom pharmacologic inhibition of MIF may offer greatest therapeutic benefit.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MOSS-C (02))
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Mao, Su-Yau
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Yale University
Internal Medicine/Medicine
Schools of Medicine
New Haven
United States
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Meza-Romero, Roberto; Benedek, Gil; Jordan, Kelley et al. (2016) Modeling of both shared and distinct interactions between MIF and its homologue D-DT with their common receptor CD74. Cytokine 88:62-70
Yao, Jie; Leng, Lin; Sauler, Maor et al. (2016) Transcription factor ICBP90 regulates the MIF promoter and immune susceptibility locus. J Clin Invest 126:732-44
Meza-Romero, Roberto; Benedek, Gil; Leng, Lin et al. (2016) Predicted structure of MIF/CD74 and RTL1000/CD74 complexes. Metab Brain Dis 31:249-55
Assis, David N; Takahashi, Hiroki; Leng, Lin et al. (2016) A Macrophage Migration Inhibitory Factor Polymorphism Is Associated with Autoimmune Hepatitis Severity in US and Japanese Patients. Dig Dis Sci 61:3506-3512
Rowe, Meredith A; Harper, Lindsey R; McNulty, Margaret A et al. (2016) Deletion of Macrophage Migration Inhibitory Factor Reduces Severity of Osteoarthritis in Aged Mice. Arthritis Rheumatol :
Galvão, Izabela; Dias, Ana Carolina Fialho; Tavares, Livia Duarte et al. (2016) Macrophage migration inhibitory factor drives neutrophil accumulation by facilitating IL-1β production in a murine model of acute gout. J Leukoc Biol 99:1035-43
Djudjaj, Sonja; Lue, Hongqi; Rong, Song et al. (2016) Macrophage Migration Inhibitory Factor Mediates Proliferative GN via CD74. J Am Soc Nephrol 27:1650-64
Yoo, Seung-Ah; Leng, Lin; Kim, Bum-Joon et al. (2016) MIF allele-dependent regulation of the MIF coreceptor CD44 and role in rheumatoid arthritis. Proc Natl Acad Sci U S A 113:E7917-E7926
Gu, Ran; Santos, Leilani L; Ngo, Devi et al. (2015) Macrophage migration inhibitory factor is essential for osteoclastogenic mechanisms in vitro and in vivo mouse model of arthritis. Cytokine 72:135-45
Hwang, Seong-Hye; Jung, Seung-Hyun; Lee, Saseong et al. (2015) Leukocyte-specific protein 1 regulates T-cell migration in rheumatoid arthritis. Proc Natl Acad Sci U S A 112:E6535-43

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