A Leishmania Ortholog of Macrophage Migration Inhibitory Factor Modulates Host Macrophage Responses

• Published in: The Journal of immunology (1950) 2008-06, Vol.180 (12), p.8250-8261
• Main Authors: Kamir, Daniela, Zierow, Swen, Leng, Lin, Cho, Yoonsang, Diaz, Yira, Griffith, Jason, McDonald, Courtney, Merk, Melanie, Mitchell, Robert A, Trent, John, Chen, Yibang, Kwong, Yuen-Kwan Amy, Xiong, Huabao, Vermeire, Jon, Cappello, Michael, McMahon-Pratt, Diane, Walker, John, Bernhagen, Jurgen, Lolis, Elias, Bucala, Richard
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antigens, Differentiation, B-Lymphocyte - genetics; Antigens, Differentiation, B-Lymphocyte - metabolism; Antigens, Differentiation, B-Lymphocyte - physiology; APOPTOSIS; Apoptosis Regulatory Proteins - chemistry; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Apoptosis Regulatory Proteins - physiology; Cell Line; Cells, Cultured; CRYSTAL STRUCTURE; Crystallography, X-Ray; Histocompatibility Antigens Class II - genetics; Histocompatibility Antigens Class II - metabolism; Histocompatibility Antigens Class II - physiology; Humans; Intramolecular Oxidoreductases - chemistry; Intramolecular Oxidoreductases - genetics; Intramolecular Oxidoreductases - metabolism; Intramolecular Oxidoreductases - physiology; Leishmania major; Leishmania major - chemistry; Leishmania major - immunology; Leishmania major - metabolism; Macrophage Migration-Inhibitory Factors - chemistry; Macrophage Migration-Inhibitory Factors - genetics; Macrophage Migration-Inhibitory Factors - metabolism; Macrophage Migration-Inhibitory Factors - physiology; MACROPHAGES; Macrophages, Peritoneal - enzymology; Macrophages, Peritoneal - immunology; Macrophages, Peritoneal - parasitology; MATERIALS SCIENCE; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Knockout; Molecular Sequence Data; national synchrotron light source; PHOSPHOTRANSFERASES; PROTEINS; Recombinant Proteins - biosynthesis; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Recombinant Proteins - pharmacology; Structural Homology, Protein; TARGETS
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.180.12.8250

Parasitic organisms have evolved specialized strategies to evade immune defense mechanisms. We describe herein an ortholog of the cytokine, macrophage migration inhibitory factor (MIF), which is produced by the obligate intracellular parasite, Leishmania major. The Leishmania MIF protein, Lm1740MIF, shows significant structural homology with human MIF as revealed by a high-resolution x-ray crystal structure (1.03 A). Differences between the two proteins in the N-terminal tautomerization site are evident, and we provide evidence for the selective, species-specific inhibition of MIF by small-molecule antagonists that target this site. Lm1740MIF shows significant binding interaction with the MIF receptor, CD74 (K(d) = 2.9 x 10(-8) M). Like its mammalian counterpart, Lm1740MIF induces ERK1/2 MAP kinase activation in a CD74-dependent manner and inhibits the activation-induced apoptosis of macrophages. The ability of Lm1740MIF to inhibit apoptosis may facilitate the persistence of Leishmania within the macrophage and contribute to its evasion from immune destruction.