Institute of Basic Medical Sciences and Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital, Shandong University, Jinan, China.
Blood. 2012 May 17;119(20):4636-44. doi: 10.1182/blood-2011-08-376418. Epub 2012 Mar 13.
Tissue inhibitor of metalloproteinase-3 (TIMP-3) is one of a family of proteins inhibiting matrix metalloproteinases, which has also been identified as a mediator for checking inflammation. Meanwhile, it is well known that inflammation causes the activation of the immune response. However, it is not clear whether TIMP-3 plays a role in the immune system. In the present study, we demonstrated a novel function of TIMP-3 in Th1/Th2 polarization through its influence on the antigen-presenting cells. First, TIMP-3 was found strikingly up-regulated by IL-4 during the differentiation of human dendritic cells via the p38MAPK pathway. Second, the expression of costimulatory molecule-CD86 was repressed by TIMP-3. Besides, the induction of IL-12 in matured dendritic cells was significantly inhibited in a PI3K-dependent manner. Furthermore, dendritic cells matured in the presence of TIMP-3 could stimulate allogeneic naive T helper (Th) cells to display a prominent Th2 polarization. Importantly, in an autoimmune disorder-primary immune thrombocytopenia, TIMP-3 showed a statistically positive correlation with IL-4 and platelet count, but a negative correlation with IFN-γ in patient blood samples. Collectively, these in vitro and in vivo data clearly suggested a novel role of TIMP-3 in Th1/Th2 balance in humans.
组织金属蛋白酶抑制剂 3（TIMP-3）是抑制基质金属蛋白酶家族的一种蛋白质，它也被鉴定为一种控制炎症的介质。同时，众所周知，炎症会引发免疫反应的激活。然而，目前尚不清楚 TIMP-3 是否在免疫系统中发挥作用。在本研究中，我们通过其对抗原呈递细胞的影响，证明了 TIMP-3 在 Th1/Th2 极化中的新功能。首先，通过 p38MAPK 途径发现 TIMP-3 在人类树突状细胞的分化过程中被 IL-4 显著上调。其次，共刺激分子-CD86 的表达受 TIMP-3 抑制。此外，TIMP-3 以 PI3K 依赖的方式显著抑制成熟树突状细胞中 IL-12 的诱导。此外，在 TIMP-3 存在下成熟的树突状细胞可以刺激同种异体幼稚 T 辅助（Th）细胞表现出明显的 Th2 极化。重要的是，在自身免疫性疾病——原发性免疫性血小板减少症中，TIMP-3 在患者血液样本中与 IL-4 和血小板计数呈正相关，与 IFN-γ 呈负相关。总的来说，这些体外和体内数据清楚地表明 TIMP-3 在人类 Th1/Th2 平衡中具有新的作用。
