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J. Biol. Chem., Vol. 277, Issue 46, 44261-44267, November 15, 2002

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Homologues of Human Macrophage Migration Inhibitory Factor from a Parasitic Nematode
GENE CLONING, PROTEIN ACTIVITY, AND CRYSTAL STRUCTURE^*

Xingxing Zang^§, Paul Taylor^¶, Ji Ming Wang, David J. Meyer^**, Alan L. Scott, Malcolm D. Walkinshaw^¶, and Rick M. Maizels^§§

From the  Institute of Cell, Animal & Population Biology, University of Edinburgh, Edinburgh EH9 3JT, United Kingdom, ^¶ Institute of Cell and Molecular Biology, University of Edinburgh, Edinburgh EH9 3JT, United Kingdom,  Laboratory of Molecular Immunoregulation, NCI, National Institutes of Health, Frederick Cancer Research and Development Center, Bethesda, Maryland 21702-1201, ^** Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom, and  Department of Molecular Microbiology and Immunology, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland 21205

Cytokines are the molecular messengers of the vertebrate immune system, coordinating the local and systemic immune responses to infective organisms. We report here functional and structural data on cytokine-like proteins from a eukaryotic pathogen. Two homologues of the human cytokine macrophage migration inhibitory factor (MIF) have been isolated from the parasitic nematode Brugia malayi. Both molecules (Bm-MIF-1 and Bm-MIF-2) show parallel functions to human MIF. They are chemotactic for human monocytes and activate them to produce IL-8, TNF-, and endogenous MIF. The human and nematode MIF homologues share a tautomerase enzyme activity, which is in each case abolished by the mutation of the N-terminal proline residue. The crystal structure of Bm-MIF-2 at 1.8-Å resolution has been determined, revealing a trimeric assembly with an inner pore created by -stranded sheets from each subunit. Both biological activity and crystal structure reveal remarkable conservation between a human cytokine and its parasite counterpart despite the considerable phylogenetic divide among these organisms. The strength of the similarity implies that MIF-mediated pathways play an important role in nematode immune evasion strategies.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY004865.

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