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

Melanie Merk, Swen Zierow, Lin Leng, Rituparna Das, Xin Du, Wibke Schulte, Juan Fan, Hongqi Lue, Yibang Chen, Huabao Xiong, Frederic Chagnon, Jürgen Bernhagen, Elias Lolis, Gil Mor, Olivier Lesur, Richard Bucala

Research output: Contribution to journalArticlepeer-review

176 Scopus citations

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.

Original languageEnglish
Pages (from-to)E577-E585
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number34
DOIs
StatePublished - 23 Aug 2011

Keywords

  • Inflammation
  • Lipopolysaccharide
  • Septic shock

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