Blood：发现金属蛋白酶组织抑制因子3的新功能

近日，来自山东省医学科学院基础医学研究所的邵倩倩等人发现，金属蛋白酶组织抑制因子3通过调节树突细胞，影响了Th1/Th2的平衡。相关研究成果发表于5月17日发表在Blood上。

Th1、Th2细胞是Th前体细胞 (pTh )在特定抗原刺激及多种因素综合作用下，发生功能性极化的结果。越来越多的证据表明，Th1/Th2极化是免疫应答调节中的关键环节。已有的研究表明，细胞因子、抗原、抗原递呈细胞(APC )、共刺激信号及一些基因调控因子均为Th1/Th2极化提供了重要信号。

金属蛋白酶组织抑制因子3(TIMP-3)是能够抑制基质金属蛋白酶的蛋白家族中的一种，已经发现它能够作为一种炎症检查的介质。

总所周知，炎症引起了免疫反应的激活，然而，TIMP-3是否也作用于免疫系统目前还不明确。在该研究中，研究人员发现了TIMP-3新的功能：通过影响抗原呈递细胞，影响了Th1/Th2的极化。

首先，在人树突细胞通过p38MAPK通路发生分化的时候，TIMP-3被发现通过IL-4而显著上调。其次，共刺激分子CD86的表达能够被TIMP-3所抑制。而且，在树突细胞中，IL-12的诱导以PI3K依赖的方式被显著的抑制。

此外，在TIMP-3存在下，树突细胞的成熟能够刺激同种异体初始T辅助(Th)细胞表现出显著的Th2极化。重要的是，在自体免疫疾病原发免疫性血小板减少症患者的血液样品里，研究发现TIMP-3与IL-4及血小板数目表现出正相关关系，但是与IFN-γ却表现出一个负相关关系。

总的来说，该研究阐明了人体内TIMP-3对Th1/Th2极化的新功能。

doi: 10.1182/blood-2011-08-376418
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Regulation of Th1/Th2 polarization by tissue inhibitor of metalloproteinase-3 via modulating dendritic cells

Qianqian Shao*, Hao Ning*, Jiaju Lv*, Yanguo Liu, Xin Zhao, Guangwen Ren, Alei Feng, Qi Xie, Jintang Sun, Bingfeng Song, Yongmei Yang, Wenjuan Gao, Kejia Ding, Meixiang Yang, Ming Hou, Jun Peng, and Xun Qu

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.