Hoi Alberta Y, Hickey Michael J, Hall Pamela, Yamana Jiro, O'Sullivan Kim M, Santos Leilani L, James Will G, Kitching A Richard, Morand Eric F
Department of Medicine, Centre for Inflammatory Diseases, Monash Institute of Medical Research, Monash University, Melbourne, Australia.
J Immunol. 2006 Oct 15;177(8):5687-96. doi: 10.4049/jimmunol.177.8.5687.
Systemic lupus erythematosus (SLE) is a serious systemic autoimmune disease of unknown etiology. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that is operative in innate and adaptive immunity and important in immune-mediated diseases such as rheumatoid arthritis and atherosclerosis. The functional relevance of MIF in systemic autoimmune diseases such as SLE is unknown. Using the lupus-prone MRL/lpr mice, we aim to examine the expression and function of MIF in this murine model of systemic autoimmune disease. These experiments revealed that renal MIF expression was significantly higher in MRL/lpr mice compared with nondiseased control mice (MRL/MpJ), and MIF was also markedly up-regulated in skin lesions of MRL/lpr mice. To examine the effect of MIF on development of systemic autoimmune disease, we generated MRL/lpr mice with a targeted disruption of the MIF gene (MIF(-/-)MRL/lpr), and compared their disease manifestations to MIF(+/+)MRL/lpr littermates. MIF(-/-)MRL/lpr mice exhibited significantly prolonged survival, and reduced renal and skin manifestations of SLE. These effects occurred in the absence of major changes in T and B cell markers or alterations in autoantibody production. In contrast, renal macrophage recruitment and glomerular injury were significantly reduced in MIF(-/-)MRL/lpr mice, and this was associated with reduction in the monocyte chemokine MCP-1. Taken together, these data suggest MIF as a critical effector of organ injury in SLE.
系统性红斑狼疮（SLE）是一种病因不明的严重全身性自身免疫性疾病。巨噬细胞移动抑制因子（MIF）是一种促炎细胞因子，在先天性和适应性免疫中起作用，在类风湿性关节炎和动脉粥样硬化等免疫介导疾病中具有重要作用。MIF在系统性自身免疫性疾病如SLE中的功能相关性尚不清楚。我们利用易患狼疮的MRL/lpr小鼠，旨在研究MIF在这种系统性自身免疫性疾病小鼠模型中的表达和功能。这些实验表明，与未患病的对照小鼠（MRL/MpJ）相比，MRL/lpr小鼠肾脏中MIF的表达显著更高，并且MRL/lpr小鼠皮肤病变中MIF也明显上调。为了研究MIF对系统性自身免疫性疾病发展的影响，我们构建了MIF基因靶向敲除的MRL/lpr小鼠（MIF(-/-)MRL/lpr），并将它们的疾病表现与MIF(+/+)MRL/lpr同窝小鼠进行比较。MIF(-/-)MRL/lpr小鼠的生存期显著延长，SLE的肾脏和皮肤表现减轻。这些效应在T和B细胞标志物没有重大变化或自身抗体产生没有改变的情况下出现。相反，MIF(-/-)MRL/lpr小鼠肾脏中的巨噬细胞募集和肾小球损伤显著减少，这与单核细胞趋化因子MCP-1的减少有关。综上所述，这些数据表明MIF是SLE中器官损伤的关键效应因子。
