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* Yale University School of Medicine, New Haven, CT 06520;
Centro Internacional de Entrenamiento e Investigaciones Médicas, Cali, Colombia;
University of Louisville, Louisville, KY 40202;
Mt. Sinai School of Medicine, New York, NY 10029; and
¶ Institute of Biochemistry, University Hospital Rheinisch-Westfaelische Technische Hochschule, Aachen, Germany
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 Å). 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 (Kd = 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.
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1 This work was supported by National Institutes of Health Grants AI051306 and AI042310 (to R.B.), U19 AI65866-01 (to D.Mc.-P. and R.B.), and AI065029 (to E.L.); Deutsche Forschungsgemeinschaft Grant SFB542/A7 (to J.B.); and fellowships from the Marianne und Dr. Fritz Walter Fischer-foundation im Stifterverband der Deutschen Wissenschaft (to D.K.), the German Academic Exchange Service (to S.Z.), and the Studienstiftung des deutschen Volkes (to M.M.).
2 D.K. and S.Z. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Richard Bucala, Yale University School of Medicine, TAC S525, P.O. Box 208031, 300 Cedar Street, New Haven, CT 06520. E-mail address: Richard.Bucala{at}Yale.edu or Dr. Elias Lolis, Yale University School of Medicine, SHM B345, P.O. Box 208066, 333 Cedar Street New Haven, CT 06520-8066. E-mail address: Elias.Lolis{at}Yale.edu
4 Abbreviations used in this paper: MIF, macrophage migration inhibitory factor; BMM, bone marrow-derived macrophage; ISO-1, (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester; 4-IPP, 4-iodo-phenyl-pyrimidine; Lm1740MIF, Leishmania major MIF ortholog 1740; Lm1750MIF, L. major MIF ortholog 1750; qPCR, quantitative PCR; sCD74, soluble CD74; SNP, sodium nitroprusside; FWD, forward; BWD, backward.
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