A Leishmania ortholog of macrophage migration inhibitory factor modulates host macrophage responses.
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.
Kamir
Daniela
D
Yale University School of Medicine, New Haven, CT 06520, USA.
Zierow
Swen
S
Leng
Lin
L
Cho
Yoonsang
Y
Diaz
Yira
Y
Griffith
Jason
J
McDonald
Courtney
C
Merk
Melanie
M
Mitchell
Robert A
RA
Trent
John
J
Chen
Yibang
Y
Kwong
Yuen-Kwan Amy
YK
Xiong
Huabao
H
Vermeire
Jon
J
Cappello
Michael
M
McMahon-Pratt
Diane
D
Walker
John
J
Bernhagen
Jurgen
J
Lolis
Elias
E
Bucala
Richard
R
D000595:Amino Acid Sequence; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018320:Leishmania major / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000276:immunology* / Q000469:parasitology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D040681:Structural Homology, Protein
D000944:Antigens, Differentiation, B-Lymphocyte; D051017:Apoptosis Regulatory Proteins; D000949:Histocompatibility Antigens Class II; D008263:Macrophage Migration-Inhibitory Factors; D011994:Recombinant Proteins; C045084:invariant chain; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse