• 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, and Richard Bucala.
• Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
• Proc. Natl. Acad. Sci. U.S.A. 2011 Aug 23; 108 (34): E577-85.

AbstractMacrophage 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.

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