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

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
Proceedings of the National Academy of Sciences of the United States of America 2011 v.108 no.34 pp. E577
cytokines, disease severity, endotoxemia, genes, immune response, macrophages, mice, mitogen-activated protein kinase, neutralization, physiology
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.