研究DUSP1在巨噬細胞中參與細胞自噬調控的角色

Abstract

細胞自噬（autophagy）是細胞在演化上具高度保守性的分解系統，可增進細胞在特定壓力環境（如飢餓、細菌感染等）下之存活。當細胞受到壓力時會做出適當的反應，以提高細胞或個體之存活。而在細胞中有相當多訊息傳遞路徑負責調控壓力下細胞的反應。其中在受病原菌感染時，細胞中有絲分裂原活化蛋白激酶（mitogen-activated protein kinases, MAPK）會活化，促使細胞分泌促發炎細胞激素（pro-inflammatory cytokine）來活化免疫系統。而有絲分裂原活化蛋白激酶活化後，則會促使細胞表現雙特異性磷酸酶1（dual-specificity phosphatase 1, DUSP1），進而降低有絲分裂原活化蛋白激酶之活性，形成負回饋調控，以維持免疫反應之恆定。本篇研究發現雙特異性磷酸酶1會藉由調控有絲分裂原活化蛋白激酶，進而調節細胞自噬之活性。在小鼠巨噬細胞株（raw 264.7）當中，抑制雙特異性磷酸酶1會促使細胞自噬之活性上升，並且此現象不涉及調控飢餓引起之細胞自噬的哺乳類雷怕霉素標靶（mammalian target of rapamycin, mTOR）活性之改變。反之抑制有絲分裂原活化蛋白激酶活性，則可阻斷因抑制雙特異性磷酸酶1之活性所引起之細胞自噬活性的改變。除此之外，本研究亦發現加入細胞自噬抑制劑會降低介白素6之分泌及調控雙特異性磷酸酶1之訊息核醣核酸的表現。綜合以上研究結果，顯示雙特異性磷酸酶1及細胞自噬的活性彼此密切相關，以達到調整細胞生理功能之目的。

Autophagy, a degradation system conserved from yeast to human, helps cells survive many stress conditions, such as starvation and pathogen infection. Under stress conditions, cells react and perform appropriate stress responses in order to increase the survival rates of cells or an individual. To best response to different stress conditions, there are many pathways reacting to different stresses. The mitogen-activated protein kinases (MAPK) cascade, which is activated after the stimulation of Toll-like receptors (TLR), responds to pathogen infection, and plays an important role in innate immunity. After MAPK activation, DUal Specificity Phosphatase 1 (DUSP1) is up-regulated, and it will down-regulate MAPK activities to decrease the immune responses. This negative feedback loop could maintain the activities of immune responses within a suitable level. Because autophagy is also correlated to the control of immune responses, it is of interests to know if DUSP1 affect autophagy activity. In this study, I found that DUSP1 regulated autophagy via controlling MAPKs activities. Inhibiting DUSP1 in raw 264.7 cells up regulated the activities of autophagy and two subsets of MAPKs (ERK and p38), and this activation of autophagy was not related to the change of the activity of mammalian target of rapamycin (mTOR) complex, which is the main regulator of starvation-induced autophagy. Furthermore, inhibiting ERK activity could block inhibiting DUSP1-induced autophagy. I also found that an autophagy inhibitor regulated IL-6 secretion and DUSP1 mRNA expression after TLR stimulation. Overall, these results suggest that DUSP1 and autophagy may mutually affect each other to maintain cellular physical homeostasis.