The Journal of Experimental Medicine
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Published online 24 April 2006 doi:10.1084/jem.20052398
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 5, 1185-1196
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ARTICLE

 A critical role for the host mediator macrophage migration inhibitory factor in the pathogenesis of malarial anemia

Michael A. McDevitt1, Jianlin Xie3, Ganapathy Shanmugasundaram1, Jason Griffith4,5, Aihua Liu4,5, Courtney McDonald4,5, Philip Thuma6, Victor R. Gordeuk7,8, Christine N. Metz3, Robert Mitchell9, Jeffrey Keefer2, John David10, Lin Leng4,5, and Richard Bucala4,5

1 Department of Medicine and 2 Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205
3 The Feinstein Institute for Medical Research, North Shore–Long Island Jewish Health Systems, Manhasset, NY 11030
4 Department of Medicine and 5 Department of Pathology, Yale University School of Medicine, New Haven, CT 06520
6 Macha Malaria Research Institute, Choma, Zambia
7 Department of Medicine and 8 Center for Sickle Cell Disease, Howard University, Washington, DC 20059
9 James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202
10 Harvard School of Public Health, Boston, MA 02115

CORRESPONDENCE Richard Bucala: richard.bucala{at}yale.edu OR Michael A. McDevitt: mmcdevi1{at}jhmi.edu

The pathogenesis of malarial anemia is multifactorial, and the mechanisms responsible for its high mortality are poorly understood. Studies indicate that host mediators produced during malaria infection may suppress erythroid progenitor development (Miller, K.L., J.C. Schooley, K.L. Smith, B. Kullgren, L.J. Mahlmann, and P.H. Silverman. 1989. Exp. Hematol. 17:379–385; Yap, G.S., and M.M. Stevenson. 1991. Ann. NY Acad. Sci. 628:279–281). We describe an intrinsic role for macrophage migration inhibitory factor (MIF) in the development of the anemic complications and bone marrow suppression that are associated with malaria infection. At concentrations found in the circulation of malaria-infected patients, MIF suppressed erythropoietin-dependent erythroid colony formation. MIF synergized with tumor necrosis factor and {gamma} interferon, which are known antagonists of hematopoiesis, even when these cytokines were present in subinhibitory concentrations. MIF inhibited erythroid differentiation and hemoglobin production, and it antagonized the pattern of mitogen-activated protein kinase phosphorylation that normally occurs during erythroid progenitor differentiation. Infection of MIF knockout mice with Plasmodium chabaudi resulted in less severe anemia, improved erythroid progenitor development, and increased survival compared with wild-type controls. We also found that human mononuclear cells carrying highly expressed MIF alleles produced more MIF when stimulated with the malarial product hemozoin compared with cells carrying low expression MIF alleles. These data suggest that polymorphisms at the MIF locus may influence the levels of MIF produced in the innate response to malaria infection and the likelihood of anemic complications.

Abbreviations used: BFU-E, burst-forming unit erythroid; CFU-E, CFU erythroid; DAF, diaminofluorene; ERK, extracellular signal-related kinase; JNK, c-Jun NH2-terminal kinase; MAP, mitogen-activated protein; MEL, mouse erythroleukemia; MIF, macrophage migration inhibitory factor.

M.A. McDevitt, J. Xie, and G. Shanmugasundaram contributed equally to this paper.

J. Xie's present address is Department of Medicine, The University of Chicago Pritzker School of Medicine, Chicago, IL 60637.


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