title: Macrophage migration inhibitory factor deficiency enhances immune response to Nippostrongylus brasiliensis.
abstract: Infections with helminth parasites are endemic in the developing world and are a target for intervention with new therapies. Macrophage migration inhibitory factor (MIF) is a cytokine with pleiotropic effects in inflammation and immune responses. We investigated the role of MIF in a naturally cleared model of helminth infection in rodents, Nippostrongylus brasiliensis. At day 7 postinfection, MIF-deficient (MIF-/-) mice had reduced parasite burden and mounted an enhanced type 2 immune response (Th2), including increased Gata3 expression and interleukin-13 (IL-13) production in the mesenteric lymph nodes (MLNs). Bone marrow reconstitution demonstrated that MIF produced from hematopoietic cells was crucial and Rag1-/-reconstitution provided direct evidence that MIF-/-CD4+T cells were responsible for the augmented parasite clearance. MIF-/-CD4+T cells produced less IL-6 postinfection, which correlated with enhanced Th2 responses. MIF-/-CD4+T cells exhibited lower nuclear factor-κB activation, potentially explaining the reduction in IL-6. Finally, we demonstrated enhanced clearance of the parasite and Th2 response in wild-type mice treated with the MIF tautomerase inhibitor, sulforaphane, a compound found naturally found in cruciferous vegetables. These results are the first to describe the importance of the tautomerase enzyme activity in MIF function in N. brasiliensis infection.
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Sheela R
authors.initials: SR
authors.lastname: Damle
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Rebecca K
authors.initials: RK
authors.lastname: Martin
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, VA 22904.
authors.forename: Janet V
authors.initials: JV
authors.lastname: Cross
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Conrad
mesh_terms: D000818:Animals; D000947:Antigens, Helminth / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D007109:Immunity; D018793:Interleukin-13 / Q000378:metabolism*; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017879:Isothiocyanates / Q000627:therapeutic use; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology* / Q000469:parasitology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009559:Nippostrongylus / Q000276:immunology*; D059208:Parasite Load; D017206:Strongylida Infections / Q000188:drug therapy / Q000276:immunology*; D013454:Sulfoxides; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology* / Q000469:parasitology
chemical_list: D000947:Antigens, Helminth; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D018793:Interleukin-13; D017879:Isothiocyanates; D008263:Macrophage Migration-Inhibitory Factors; D013454:Sulfoxides; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse; C042501:dopachrome isomerase; C016766:sulforaphane