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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, JÃ¼rgen, 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.