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

Journal Article · Tue Jan 01 04:00:00 EST 2008 · Journal of Immunology

DOI:https://doi.org/10.4049/jimmunol.180.12.8250· OSTI ID:959595

Kamir, D; Zierow, S; Leng, L; Cho, Y; Diaz, Y; Griffith, J; McDonald, C; Merk, M; Mitchell, R

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.

• Research Organization: Brookhaven National Laboratory (BNL) National Synchrotron Light Source
• Sponsoring Organization: Doe - Office Of Science
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 959595
• Report Number(s): BNL--82581-2009-JA
• Journal Information: Journal of Immunology, Journal Name: Journal of Immunology Vol. 180; ISSN 0022-1767; ISSN JOIMA3
• Country of Publication: United States
• Language: English

Related Subjects

36 MATERIALS SCIENCE
APOPTOSIS
CRYSTAL STRUCTURE
MACROPHAGES
PHOSPHOTRANSFERASES
PROTEINS
TARGETS
national synchrotron light source