title: A critical role for the host mediator macrophage migration inhibitory factor in the pathogenesis of malarial anemia.
abstract: 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.
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. mmcdevi1@jhmi.edu
authors.forename: Michael A
authors.initials: MA
authors.lastname: McDevitt
authors.forename: Jianlin
authors.initials: J
authors.lastname: Xie
authors.forename: Shanmugasundaram
authors.initials: S
authors.lastname: Ganapathy-Kanniappan
authors.forename: Ganapathy
authors.initials: G
authors.lastname: Shanmugasundaram
authors.forename: Jason
authors.initials: J
authors.lastname: Griffith
authors.forename: Aihua
authors.initials: A
authors.lastname: Liu
authors.forename: Courtney
authors.initials: C
authors.lastname: McDonald
authors.forename: Philip
authors.initials: P
authors.lastname: Thuma
authors.forename: Victor R
authors.initials: VR
authors.lastname: Gordeuk
authors.forename: Christine N
authors.initials: CN
authors.lastname: Metz
authors.forename: Robert
authors.initials: R
authors.lastname: Mitchell
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Keefer
authors.forename: John
authors.initials: J
authors.lastname: David
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
mesh_terms: D000483:Alleles; D000740:Anemia / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines; D015672:Erythroid Precursor Cells / Q000276:immunology; D004920:Erythropoiesis / Q000187:drug effects / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006420:Hemeproteins / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D019746:Intramolecular Oxidoreductases; D008263:Macrophage Migration-Inhibitory Factors / Q000008:administration & dosage / Q000172:deficiency / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D008288:Malaria / Q000150:complications / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016788:Plasmodium chabaudi / Q000276:immunology*; D011110:Polymorphism, Genetic / Q000276:immunology; D040641:Quantitative Trait Loci / Q000235:genetics / Q000276:immunology
chemical_list: D016207:Cytokines; D006420:Hemeproteins; D008263:Macrophage Migration-Inhibitory Factors; C020753:hemozoin; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse