Macrophage migration inhibitory factor: a mediator of matrix metalloproteinase-2 production in rheumatoid arthritis.
Macrophage migration inhibitory factor: a mediator of matrix metalloproteinase-2 production in rheumatoid arthritis.
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DOI：
10.1186/ar2021
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发表时间：
2006
影响因子：
4.9
通讯作者：
Koch, Alisa E
中科院分区：
文献类型：
--
作者：
Pakozdi, Angela;Amin, Mohammad A;Haas, Christian S;Martinez, Rita J;Haines, G Kenneth 3rd;Santos, Lanie L;Morand, Eric F;David, John R;Koch, Alisa E
类风湿性关节炎（RA）是一种以骨和软骨破坏为特征的慢性炎症性疾病，其部分由滑膜成纤维细胞介导。基质金属蛋白酶（MMP）是一个负责基质降解的蛋白水解酶大家族。巨噬细胞移动抑制因子（macrophage migration inhibitory factor，MIF）是一种诱导大量促炎分子产生的细胞因子，通过促进炎症和血管生成在RA的发病机制中发挥重要作用。在本研究中，我们确定了MIF在RA滑膜成纤维细胞MMP产生中的作用及其潜在的信号传导机制。我们发现，MIF诱导RA滑膜成纤维细胞MMP-2表达的时间依赖性和浓度依赖性的方式。为了阐明MIF在MMP-2产生中的作用，我们在MIF基因缺陷和野生型小鼠中产生酵母多糖诱导的关节炎（ZIA）。我们发现，与野生型小鼠关节匀浆相比，MIF基因缺陷小鼠关节匀浆中MMP-2蛋白水平显著降低。免疫组化法检测MMP-2在ZIA中的表达。免疫组化结果显示，与MIF基因缺陷小鼠相比，野生型小鼠ZIA关节中MMP-2的表达量较高。有趣的是，滑膜衬里细胞，内皮细胞，和sublining非淋巴单核细胞表达MMP-2在ZIA滑膜。与这些结果一致，在甲基化BSA（mBSA）抗原诱导的关节炎（AIA），RA模型，增强MMP-2的表达也观察到野生型与MIF基因缺陷小鼠关节。为了阐明MIF诱导MMP-2上调的信号机制，在信号抑制剂存在下用MIF刺激RA滑膜成纤维细胞。我们发现MIF诱导的RA滑膜成纤维细胞MMP-2上调需要蛋白激酶C（PKC），c-jun N-末端激酶（JNK）和Src信号通路。我们研究了在PKC亚型特异性抑制剂存在下MMP-2的表达，发现PKC δ抑制剂rottlerin抑制MIF诱导的RA滑膜成纤维细胞MMP-2的产生。与上述结果一致，MIF可诱导JNK、PKC δ和c-jun磷酸化，提示MIF在RA组织破坏中可能具有新的作用。
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by destruction of bone and cartilage, which is mediated, in part, by synovial fibroblasts. Matrix metalloproteinases (MMPs) are a large family of proteolytic enzymes responsible for matrix degradation. Macrophage migration inhibitory factor (MIF) is a cytokine that induces the production of a large number of proinflammatory molecules and has an important role in the pathogenesis of RA by promoting inflammation and angiogenesis. In the present study, we determined the role of MIF in RA synovial fibroblast MMP production and the underlying signaling mechanisms. We found that MIF induces RA synovial fibroblast MMP-2 expression in a time-dependent and concentration-dependent manner. To elucidate the role of MIF in MMP-2 production, we produced zymosan-induced arthritis (ZIA) in MIF gene-deficient and wild-type mice. We found that MMP-2 protein levels were significantly decreased in MIF gene-deficient compared with wild-type mice joint homogenates. The expression of MMP-2 in ZIA was evaluated by immunohistochemistry (IHC). IHC revealed that MMP-2 is highly expressed in wild-type compared with MIF gene-deficient mice ZIA joints. Interestingly, synovial lining cells, endothelial cells, and sublining nonlymphoid mononuclear cells expressed MMP-2 in the ZIA synovium. Consistent with these results, in methylated BSA (mBSA) antigen-induced arthritis (AIA), a model of RA, enhanced MMP-2 expression was also observed in wild-type compared with MIF gene-deficient mice joints. To elucidate the signaling mechanisms in MIF-induced MMP-2 upregulation, RA synovial fibroblasts were stimulated with MIF in the presence of signaling inhibitors. We found that MIF-induced RA synovial fibroblast MMP-2 upregulation required the protein kinase C (PKC), c-jun N-terminal kinase (JNK), and Src signaling pathways. We studied the expression of MMP-2 in the presence of PKC isoform-specific inhibitors and found that the PKCδ inhibitor rottlerin inhibits MIF-induced RA synovial fibroblast MMP-2 production. Consistent with these results, MIF induced phosphorylation of JNK, PKCδ, and c-jun. These results indicate a potential novel role for MIF in tissue destruction in RA.