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. 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.
巨噬细胞移动抑制因子 (MIF) 是免疫反应的关键调节因子。然而，中和或基因缺失 MIF 并不能完全消除激活反应，而缺失 MIF 受体 CD74 会产生比 MIF 缺乏更为明显的表型。我们假设这些观察结果可能可以通过第二种类似 MIF 的配体来解释，我们考虑了同源的 D-多巴胺色烯互变异构酶 (D-DT) 基因编码的蛋白质作为可能的候选物。我们表明，重组 D-DT 蛋白与 CD74 具有高亲和力结合，导致 ERK1/2 MAP 激酶和下游促炎途径的激活。循环 D-DT 水平与败血症或恶性肿瘤的疾病严重程度相关，特异性免疫中和 D-DT 通过降低下游效应细胞因子的表达来保护小鼠免于致死性内毒素血症。这些数据表明 D-DT 是一种类似 MIF 的细胞因子，具有重叠的活性谱，对于我们理解 MIF 依赖性生理学和病理学非常重要。
