title: Macrophage migration inhibitory factor deficiency is associated with impaired killing of gram-negative bacteria by macrophages and increased susceptibility to Klebsiella pneumoniae sepsis.
abstract: The cytokine macrophage migration inhibitory factor (MIF) is an important component of the early proinflammatory response of the innate immune system. However, the antimicrobial defense mechanisms mediated by MIF remain fairly mysterious. In the present study, we examined whether MIF controls bacterial uptake and clearance by professional phagocytes, using wild-type and MIF-deficient macrophages. MIF deficiency did not affect bacterial phagocytosis, but it strongly impaired the killing of gram-negative bacteria by macrophages and host defenses against gram-negative bacterial infection, as shown by increased mortality in a Klebsiella pneumonia model. Consistent with MIF's regulatory role of Toll-like 4 expression in macrophages, MIF-deficient cells stimulated with lipopolysaccharide or Escherichia coli exhibited reduced nuclear factor κB activity and tumor necrosis factor (TNF) production. Addition of recombinant MIF or TNF corrected the killing defect of MIF-deficient macrophages. Together, these data show that MIF is a key mediator of host responses against gram-negative bacteria, acting in part via a modulation of bacterial killing by macrophages.
authors.affiliation: Infectious Diseases Service, Department of Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Switzerland.
authors.forename: Thierry
authors.initials: T
authors.lastname: Roger
authors.forename: Julie
authors.initials: J
authors.lastname: Delaloye
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Chanson
authors.forename: Marlyse
authors.initials: M
authors.lastname: Giddey
authors.forename: Didier
authors.initials: D
authors.lastname: Le Roy
authors.forename: Thierry
authors.initials: T
authors.lastname: Calandra
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D006090:Gram-Negative Bacteria / Q000276:immunology*; D006801:Humans; D007710:Klebsiella Infections / Q000276:immunology* / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000276:immunology / Q000472:pathogenicity*; D008263:Macrophage Migration-Inhibitory Factors / Q000172:deficiency* / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D010587:Phagocytosis / Q000276:immunology
chemical_list: D008263:Macrophage Migration-Inhibitory Factors