Stosic-Grujicic Stanislava, Stojanovic Ivana, Maksimovic-Ivanic Danijela, Momcilovic Miljana, Popadic Dusan, Harhaji Ljubica, Miljkovic Djordje, Metz Christine, Mangano Katia, Papaccio Gianpaolo, Al-Abed Yousef, Nicoletti Ferdinando
Department of Immunology, Institute for Biological Research Sinisa Stankovic, Belgrade, Serbia.
J Cell Physiol. 2008 Jun;215(3):665-75. doi: 10.1002/jcp.21346.
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine of the innate immune system that plays a major role in the induction of immunoinflammatory responses. To examine the role of endogenous MIF in the pathogenesis of type 1 diabetes (TID) we evaluated the effects of administration of neutralizing anti-MIF antibodies to NOD mice with accelerated forms of diabetes induced by injection of cyclophosphamide or by transfer of diabetogenic spleen cells. Both accelerated forms of diabetes were markedly reduced by anti-MIF antibody. Furthermore, MIF-deficient (MIF(-/-)) mice were less susceptible to the induction of immunoinflammatory diabetes, insulitis and apoptosis within the endocrine pancreas by multiple low doses of streptozotocin (MLD-STZ) than genetically matched wild type (WT) mice. MIF deficiency resulted in lower proliferation and lymphocyte adhesion, as well as reduced production from the spleens and peritoneal cells of a variety of inflammatory mediators typically associated with development of the disease including IL-12, IL-23, TNF-alpha, and IL-1beta. Furthermore, MIF deletion affected the production of IL-18, TNF-alpha, IL-1beta, and iNOS in the islets of Langerhans. These data, along with the higher expression of IL-4 and TGF-beta observed in the periphery and in the pancreas of MLD-STZ-challenged MIF(-/-) mice as compared to WT controls suggest that MIF deficiency has induced an immune deviation towards protective type 2/3 response. These results suggest that MIF participates in T1D by controlling the functional activity of monocytes/macrophages and T cells and modulating their secretory capacity of pro- and anti-inflammatory molecules.
巨噬细胞移动抑制因子（MIF）是先天性免疫系统的一种促炎细胞因子，在免疫炎症反应的诱导中起主要作用。为了研究内源性MIF在1型糖尿病（TID）发病机制中的作用，我们评估了向注射环磷酰胺或转移致糖尿病脾细胞诱导出加速型糖尿病的NOD小鼠体内注射中和性抗MIF抗体的效果。两种加速型糖尿病均因抗MIF抗体而显著减轻。此外，与基因匹配的野生型（WT）小鼠相比，MIF缺陷（MIF(-/-)）小鼠对多次低剂量链脲佐菌素（MLD-STZ）诱导的免疫炎症性糖尿病、内分泌胰腺内的胰岛炎和细胞凋亡的易感性较低。MIF缺陷导致增殖和淋巴细胞黏附降低，以及脾脏和腹膜细胞产生的多种通常与疾病发展相关的炎症介质减少，包括IL-12、IL-23、TNF-α和IL-1β。此外，MIF缺失影响了胰岛中IL-18、TNF-α、IL-1β和诱导型一氧化氮合酶的产生。这些数据，以及与WT对照相比，在MLD-STZ攻击的MIF(-/-)小鼠的外周和胰腺中观察到的IL-4和TGF-β的更高表达，表明MIF缺陷已诱导出向保护性2/3型反应的免疫偏差。这些结果表明，MIF通过控制单核细胞/巨噬细胞和T细胞的功能活性以及调节它们的促炎和抗炎分子分泌能力来参与T1D。
