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上海士鋒生物關(guān)于金屬蛋白酶組織抑制因子3又有新效用
點(diǎn)擊次數(shù)：803 發(fā)布時(shí)間：2013-6-22
Th1、Th2細(xì)胞是Th前體細(xì)胞 （pTh ）在特定抗原刺激及多種因素綜合作用下，發(fā)生功能性極化的結(jié)果。越來(lái)越多的證據(jù)表明，Th1/Th2極化是免疫應(yīng)答調(diào)節(jié)中的關(guān)鍵環(huán)節(jié)。已有的研究表明，細(xì)胞因子、抗原、抗原遞呈細(xì)胞（APC ）、共刺激信號(hào)及一些基因調(diào)控因子均為Th1/Th2極化提供了重要信號(hào)。
金屬蛋白酶組織抑制因子3（TIMP-3）是能夠抑制基質(zhì)金屬蛋白酶的蛋白家族中的一種，已經(jīng)發(fā)現(xiàn)它能夠作為一種炎癥檢查的介質(zhì)。
總所周知，炎癥引起了免疫反應(yīng)的激活，然而，TIMP-3是否也作用于免疫系統(tǒng)目前還不明確。在該研究中，研究人員發(fā)現(xiàn)了TIMP-3新的功能：通過(guò)影響抗原呈遞細(xì)胞，影響了Th1/Th2的極化。
首先，在人樹突細(xì)胞通過(guò)p38MAPK通路發(fā)生分化的時(shí)候，TIMP-3被發(fā)現(xiàn)通過(guò)IL-4而顯著上調(diào)。其次，共刺激分子CD86的表達(dá)能夠被TIMP-3所抑制。而且，在樹突細(xì)胞中，IL-12的誘導(dǎo)以PI3K依賴的方式被顯著的抑制。
此外，在TIMP-3存在下，樹突細(xì)胞的成熟能夠刺激同種異體初始T輔助（Th）細(xì)胞表現(xiàn)出顯著的Th2極化。重要的是，在自體免疫疾病原發(fā)免疫性血小板減少癥患者的血液樣品里，研究發(fā)現(xiàn)TIMP-3與IL-4及血小板數(shù)目表現(xiàn)出正相關(guān)關(guān)系，但是與IFN-γ卻表現(xiàn)出一個(gè)負(fù)相關(guān)關(guān)系。
總的來(lái)說(shuō)，該研究闡明了人體內(nèi)TIMP-3對(duì)Th1/Th2極化的新功能。
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.