A Leishmania ortholog of macrophage migration inhibitory factor modulates host macrophage responses

J Immunol. 2008 Jun 15;180(12):8250-61. doi: 10.4049/jimmunol.180.12.8250.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antigens, Differentiation, B-Lymphocyte / genetics
  • Antigens, Differentiation, B-Lymphocyte / metabolism
  • Antigens, Differentiation, B-Lymphocyte / physiology
  • Apoptosis Regulatory Proteins / chemistry
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Apoptosis Regulatory Proteins / physiology
  • Cell Line
  • Cells, Cultured
  • 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 / 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, Peritoneal / enzymology
  • Macrophages, Peritoneal / immunology*
  • Macrophages, Peritoneal / parasitology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C3H
  • Mice, Knockout
  • Molecular Sequence Data
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / pharmacology
  • Structural Homology, Protein*

Substances

  • Antigens, Differentiation, B-Lymphocyte
  • Apoptosis Regulatory Proteins
  • Histocompatibility Antigens Class II
  • Macrophage Migration-Inhibitory Factors
  • Recombinant Proteins
  • invariant chain
  • Intramolecular Oxidoreductases
  • Mif protein, mouse

Associated data

  • PDB/3B64