title: The D-dopachrome tautomerase (DDT) gene product is a cytokine and functional homolog of macrophage migration inhibitory factor (MIF).
abstract: Macrophage migration inhibitory factor (MIF) is a pivotal regulator of the immune response. Neutralization or genetic deletion of MIF does not completely abrogate activation responses, however, and deletion of the MIF receptor, CD74, produces a more pronounced phenotype than MIF deficiency. We hypothesized that these observations may be explained by a second MIF-like ligand, and we considered a probable candidate to be the protein encoded by the homologous, D-dopachrome tautomerase (D-DT) gene. We show that recombinant D-DT protein binds CD74 with high affinity, leading to activation of ERK1/2 MAP kinase and downstream proinflammatory pathways. Circulating D-DT levels correlate with disease severity in sepsis or malignancy, and the specific immunoneutralization of D-DT protects mice from lethal endotoxemia by reducing the expression of downstream effector cytokines. These data indicate that D-DT is a MIF-like cytokine with an overlapping spectrum of activities that are important for our understanding of MIF-dependent physiology and pathology.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Merk
authors.forename: Swen
authors.initials: S
authors.lastname: Zierow
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.forename: Rituparna
authors.initials: R
authors.lastname: Das
authors.forename: Xin
authors.initials: X
authors.lastname: Du
authors.forename: Wibke
authors.initials: W
authors.lastname: Schulte
authors.forename: Juan
authors.initials: J
authors.lastname: Fan
authors.forename: Hongqi
authors.initials: H
authors.lastname: Lue
authors.forename: Yibang
authors.initials: Y
authors.lastname: Chen
authors.forename: Huabao
authors.initials: H
authors.lastname: Xiong
authors.forename: Frederic
authors.initials: F
authors.lastname: Chagnon
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bernhagen
authors.forename: Elias
authors.initials: E
authors.lastname: Lolis
authors.forename: Gil
authors.initials: G
authors.lastname: Mor
authors.forename: Olivier
authors.initials: O
authors.lastname: Lesur
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism; D000075686:COP9 Signalosome Complex; D002465:Cell Movement / Q000187:drug effects; D019446:Endotoxemia / Q000473:pathology / Q000517:prevention & control; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D016678:Genome / Q000235:genetics; D005938:Glucocorticoids / Q000494:pharmacology; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D007165:Immunosuppression Therapy; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000097:blood / Q000737:chemistry* / Q000235:genetics* / Q000302:isolation & purification; D008070:Lipopolysaccharides / Q000494:pharmacology; D008263:Macrophage Migration-Inhibitory Factors / Q000097:blood / Q000737:chemistry* / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D009500:Neutralization Tests; D010447:Peptide Hydrolases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D018805:Sepsis / Q000097:blood / Q000473:pathology; D017386:Sequence Homology, Amino Acid; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D005938:Glucocorticoids; D000949:Histocompatibility Antigens Class II; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D008263:Macrophage Migration-Inhibitory Factors; C045084:invariant chain; D048049:Extracellular Signal-Regulated MAP Kinases; D010447:Peptide Hydrolases; C501490:Cops5 protein, mouse; D000075686:COP9 Signalosome Complex; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase