TIFA蛋白在血管內皮細胞先天性免疫反應中之角色

The role of TIFA in endothelial innate immunity

林庭揚(Ting-Yang Lin)

指導教授 ： 蔡明道

共同指導教授 ： 史允中(John Y-J. Shyy)

國立臺灣大學/生命科學院/生化科學研究所/博士(2016年)

https://doi.org/10.6342/NTU201602215

摘要

類鐸受體所介導的NF-kappaB的激活是響應於助氧化和促炎性刺激的血管內皮細胞的一個主要的先天免疫反義。 我們確定了TIFA [TNFalpha receptor-associated factor（TRAF) interacting protein with a FHA damain]在血管內皮細胞中不但參與引發NLRP3炎症小體的誘導（信號1) 也參與了其活化（信號2)。我們首先發現氧化和炎性壓力如atheroprone流和高脂血症在in vitro及 in vivo實驗中皆能誘發與活化TIFA。接著，對於信號1的起動，固醇調節元件結合蛋白2（SREBP2)此一轉錄因子能上調TIFA的信使RNA表現，藉此誘導NF-kappaB和增強NLRP3炎症小體成員的轉錄。然而對於信號2的活化，我們實驗室發現Akt參與了TIFA Thr9的磷酸化，此磷酸畫的作用使TIFA-TIFA嗜同聚合體形成。 Thr9磷酸依賴性TIFA聚合體能夠促使NLRP3炎症小體的具合與活化，而此聚合作用是透過在活化的內皮細胞中TIFA和caspase-1之間的相互作用所達成的。另外， 當TIFA被過度表達時，我們發現我們發現細胞的自噬作用， 單核細胞的黏附作用，以及細胞焦亡反應皆細胞焦亡反應皆上升了。綜合以上結果，我們發現TIFA是透過誘導與加強NLRP3炎症小體活化之信號1和2的內皮先天免疫反應的關鍵介體。

關鍵字

TIFA ； 血管內皮細胞 ； 先天性免疫 ； 發炎體 ； 剪切應力

並列摘要

Toll-like receptor-mediated NF-κB activation is a major innate immune reaction of vascular endothelial cells (ECs) in response to pro-oxidative and pro-inflammatory stimuli. We identified that TIFA [abbreviated from TNFα receptor-associated factor (TRAF)-interacting protein with a forkhead-associated (FHA) domain] is a novel regulator of both priming (Signal 1) and activating (Signal 2) signals of NLRP3 inflammasome in ECs. Oxidative and inflammatory stresses such as atheroprone flow and hyperlipidemia induce and activate TIFA in vitro and in vivo. For the priming of Signal 1, sterol regulatory element-binding protein 2 (SREBP2) transactivates TIFA, which in turn induces NF-κB and augments the transcription of NLRP3 inflammasome components. For the activation of Signal 2, our lab has found that Akt is involved in TIFA Thr9 phosphorylation, which is essential for TIFA-TIFA homophilic oligomerization. Thr9 phosphorylation-dependent TIFA oligomerization facilitates the higher-order assembly of NLRP3 inflammasome, as indicated by the interactions between TIFA and caspase-1 in the activated ECs. Furthermore, we revealed that overexpression of TIFA leads to increased autophagy, monocyte adhesion and pyroptosis, indicationg. Our results suggest that TIFA is a crucial mediator in the endothelial innate immune response by potentiating and amplifying NLRP3 inflammasome via augmenting Signals 1 and 2.

並列關鍵字

TIFA ； endothelial cells ； innate immunity ； NLRP3 inflammasome ； shear stress

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