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

Proc Natl Acad Sci U S A. 2011 Aug 23;108(34):E577-85. doi: 10.1073/pnas.1102941108. Epub 2011 Aug 4.


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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antigens, Differentiation, B-Lymphocyte / metabolism
  • COP9 Signalosome Complex
  • Cell Movement / drug effects
  • Endotoxemia / pathology
  • Endotoxemia / prevention & control
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Genome / genetics
  • Glucocorticoids / pharmacology
  • Histocompatibility Antigens Class II / metabolism
  • Humans
  • Immunosuppression Therapy
  • 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 Factors / blood
  • Macrophage Migration-Inhibitory Factors / chemistry*
  • Macrophage Migration-Inhibitory Factors / metabolism*
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Molecular Sequence Data
  • Neoplasm Invasiveness
  • Neutralization Tests
  • Peptide Hydrolases / metabolism
  • Phosphorylation / drug effects
  • Protein Binding / drug effects
  • Sepsis / blood
  • Sepsis / pathology
  • Sequence Homology, Amino Acid*
  • Up-Regulation / drug effects


  • Antigens, Differentiation, B-Lymphocyte
  • Glucocorticoids
  • Histocompatibility Antigens Class II
  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharides
  • Macrophage Migration-Inhibitory Factors
  • invariant chain
  • Extracellular Signal-Regulated MAP Kinases
  • Peptide Hydrolases
  • Cops5 protein, mouse
  • COP9 Signalosome Complex
  • Intramolecular Oxidoreductases
  • dopachrome isomerase