D-dopachrome tautomerase (DDT) gene product is a cytokine and functional homolog of macrophage migration inhibitory factor (MIF)

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-08, Vol.108 (34), p.E577-E585
• Main Authors: Merk, Melanie, Zierow, Swen, Leng, Lin, Das, Rituparna, Du, Xin, Schulte, Wibke, Fan, Juan, Lue, Hongqi, Chen, Yibang, Xiong, Huabao, Chagnon, Frederic, Bernhagen, Jürgen, Lolis, Elias, Mor, Gil, Lesur, Olivier, Bucala, Richard
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antigens, Differentiation, B-Lymphocyte - metabolism; Biological Sciences; Cell adhesion & migration; Cell Movement - drug effects; COP9 Signalosome Complex; Cytokines; Data processing; DDT; disease severity; Endotoxemia; Endotoxemia - pathology; Endotoxemia - prevention & control; Enzymes; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; genes; Genome - genetics; Genotype & phenotype; Glucocorticoids - pharmacology; Histocompatibility Antigens Class II - metabolism; Humans; Immune response; Immunosuppression; Inflammation; Intracellular Signaling Peptides and Proteins - metabolism; Intracellular Space - metabolism; Intramolecular Oxidoreductases - blood; Intramolecular Oxidoreductases - chemistry; Intramolecular Oxidoreductases - genetics; Intramolecular Oxidoreductases - isolation & purification; Lipopolysaccharides - pharmacology; Macrophage migration inhibitory factor; Macrophage Migration-Inhibitory Factors - blood; Macrophage Migration-Inhibitory Factors - chemistry; Macrophage Migration-Inhibitory Factors - metabolism; macrophages; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Malignancy; MAP kinase; Mice; mitogen-activated protein kinase; Molecular Sequence Data; Molecules; Neoplasm Invasiveness; neutralization; Neutralization Tests; Peptide Hydrolases - metabolism; Phosphorylation - drug effects; physiology; PNAS Plus; Protein Binding - drug effects; Sepsis; Sepsis - blood; Sepsis - pathology; Sequence Homology, Amino Acid; Up-Regulation - drug effects
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1102941108

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.