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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Antigens, Differentiation, B-Lymphocyte / metabolism
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COP9 Signalosome Complex
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Cell Movement / drug effects
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Endotoxemia / pathology
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Endotoxemia / prevention & control
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Female
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Genome / genetics
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Glucocorticoids / pharmacology
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Histocompatibility Antigens Class II / metabolism
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Humans
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Immunosuppression Therapy
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Intracellular Signaling Peptides and Proteins / metabolism
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Intracellular Space / metabolism
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Intramolecular Oxidoreductases / blood
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Intramolecular Oxidoreductases / chemistry*
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Intramolecular Oxidoreductases / genetics*
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Intramolecular Oxidoreductases / isolation & purification
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Lipopolysaccharides / pharmacology
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Macrophage Migration-Inhibitory Factors / blood
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Macrophage Migration-Inhibitory Factors / chemistry*
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Macrophage Migration-Inhibitory Factors / metabolism*
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Macrophages / cytology
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Macrophages / drug effects
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Macrophages / metabolism
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Mice
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Molecular Sequence Data
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Neoplasm Invasiveness
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Neutralization Tests
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Peptide Hydrolases / metabolism
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Phosphorylation / drug effects
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Protein Binding / drug effects
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Sepsis / blood
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Sepsis / pathology
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Sequence Homology, Amino Acid*
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Up-Regulation / drug effects
Substances
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Antigens, Differentiation, B-Lymphocyte
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Glucocorticoids
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Histocompatibility Antigens Class II
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Intracellular Signaling Peptides and Proteins
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Lipopolysaccharides
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Macrophage Migration-Inhibitory Factors
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invariant chain
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Extracellular Signal-Regulated MAP Kinases
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Peptide Hydrolases
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Cops5 protein, mouse
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COP9 Signalosome Complex
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Intramolecular Oxidoreductases
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dopachrome isomerase