近年來，登革病毒已然成為最常見的病蚊媒傳播的病毒，而患者感染登革病毒出現之病症嚴重度輕者可能為無症狀，但嚴重者可能會出現嚴重血管滲漏甚至死亡。除了病毒本身之外，登革病毒非結構性蛋白1也被認為在登革病毒所導致的細胞激素風暴或是血管滲漏等致病作用中扮演一個相當關鍵的角色。在已知會從被登革病毒非結構性蛋白1刺激的細胞所釋放出來的細胞激素中，屬於促發炎性細胞激素的巨噬細胞移動抑制因子被發現在登革病人血清中的濃度和病人的病症嚴重度有相關性。然而，登革病毒非結構性蛋白1刺激所誘導的巨噬細胞移動抑制因子釋放的機制目前仍不甚清楚。在本篇研究中，我們發現相較於其他免疫細胞株，受登革病毒非結構性蛋白1刺激所誘導巨噬細胞移動抑制因子釋放在人類嗜鹼性球細胞株KU812中有更顯著的上升。因而我們選擇使用登革病毒非結構性蛋白1刺激KU812的模式來探索巨噬細胞移動抑制因子之釋放機制。在登革病毒非結構性蛋白1的刺激下，我們發現會有細胞自噬現象增加的情況。已知細胞自噬作用可以參與到傳統型或非傳統型蛋白釋放機制，因此我們假設細胞自噬作用會參與到登革病毒非結構性蛋白1誘導巨噬細胞移動抑制因子釋放的機制。在確認登革病毒非結構性蛋白1所誘導之巨噬細胞移動抑制因子釋放和細胞自噬的增加的確是有相關性後，我們使用了小髮夾RNA和抑制劑(3-MA 和 Bafilomycin A1)來驗證這個假說，並且也發現在使用這些方法去抑制細胞自噬作用後巨噬細胞移動抑制因子的釋放都會有所下降。另外，我們也發現在登革病毒非結構性蛋白1的刺激下也可以看到缺氧誘導因子-1α在KU812中的表現量有明顯的上升。由於先前的研究指出缺氧誘導因子-1α可以調節細胞自噬作用的形成，因此我們進一步使用小髮夾RNA去分別抑制缺氧誘導因子-1α和細胞自噬作用後發現抑制缺氧誘導因子-1α也會影響登革病毒非結構性蛋白1所誘導的細胞自噬作用，因此我們認為缺氧誘導因子-1α可能是作為一個細胞自噬上游的調節因子去影響登革病毒非結構性蛋白1所誘導的巨噬細胞移動抑制因子釋放。最後，因為許多研究指出登革病毒非結構性蛋白1活化細胞可能可以透過不同的受體，因此我們也想知道登革病毒非結構性蛋白1是透過何種受體以活化細胞釋放噬細胞移動抑制因子。而我們的實驗結果發現使用Toll 樣受體4 訊號抑制劑(TAK242)和內吞作用抑制劑 (Dynasore) 都能使巨噬細胞移動抑制因子的釋放量下降。綜合上述，我們的實驗結果顯示登革病毒非結構性蛋白1可能通過 Toll 樣受體4和內吞作用來活化KU812，而後續登革病毒非結構性蛋白1誘導之缺氧誘導因子-1α的表現增加會調節細胞自噬的形成以促進巨噬細胞移動抑制因子的釋放。

Dengue virus (DENV) is one of the most common mosquito-borne viruses in the past decades. DENV infection can cause diverse symptoms range from asymptomatic to severe vascular leakage or even death. Aside from DENV virion, DENV nonstructural protein 1 (NS1) is believed to play a critical role in dengue-induced pathogenic effects such as cytokine storm and vascular leakage. Among the cytokines secreted from NS1-stimulated cells, macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine, the seral level of which is correlated with disease severity in dengue patients. However, the mechanisms of MIF secretion under DENV NS1 stimulation during dengue infection remain elusive. In this study, we found that MIF secretion was significantly increased in NS1-stimulated human basophil cell line, KU812, compared to other immune cells. Therefore, we used NS1-stimulated KU812 to study the underlying mechanisms of MIF secretion. Since autophagy is known to participate in both conventional and unconventional protein secretion and autophage is induced in NS1-stimulated cells, we proposed and tested the hypothesis that autophagy is involved in NS1-induced MIF secretion pathway. We found that NS1-induced MIF secretion was simultaneously associated with increase of autophagy induction; Furthermore, using shRNA and autophagy inhibitors (3-MA and Bafilomycin A1) could significantly block NS1-triggered MIF secretion. Besides, we also observed that hypoxia-inducible factor 1 α (HIF-1α) expression was significantly elevated after NS1 treatment in KU812 compared to control groups. Since several studies have demonstrated that HIF-1α could regulate autophagy formation, we further used shRNA to investigate if HIF-1α can regulate autophagy formation in NS1-stimulated KU812. We found that NS1-induced autophagy formation was decreased in shHIF-1α KU812. Based on our results, HIF-1α may be an upstream regulatory factor to control NS1-induced autophagy formation and MIF secretion. On the other hand, since studies had indicated that NS1 can active cell through different TLRs receptors, we also wanted to know TLR is involved in NS1 activation of KU812 to secret MIF. Our findings revealed MIF secretion was decreased by using TLR4 signaling inhibitor (TAK242) and endocytosis inhibitor (Dynasore). To sum up, our results indicate that NS1 may activate KU812 through TLR4 and endocytosis, followed by upregulation of autophagy formation to facilitate MIF secretion from cells.

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