上海士锋生物关于金属蛋白酶组织抑制因子3又有新效用

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。

Regulation of Th1/Th2 polarization by tissue inhibitor of metalloproteinase-3 via modulating dendritic cells

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 plaet 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.