登革病毒的感染可造成登革熱 (DF) 或嚴重的登革出血熱 (DHF) 及登革休克症候群 (DSS) 等病症。細胞激素被認為參與了登革感染致病的機制，然而發炎性細胞激素巨噬細胞移動抑制因子 (MIF)在登革感染的角色則尚不清楚。在我們的研究中，將不同疾病嚴重度的登革病人血清中的MIF與其他細胞激素如TNF-α, IL-6, IL-10 及 IFN-γ 做比較。發現除了 IFN-γ 及 TNF-α 外，DHF/DSS 死亡病患血清中的 MIF, IL-6 及 IL-10 皆要比 DHF 存活病患及 DF 的病人高。所以除了 IL-6 及 IL-10外，MIF 的量對於登革病人的疾病嚴重度及臨床結果也可以為一個預測指標。為了進一步瞭解登革病毒感染對細胞激素 MIF 產生的影響，我們已建立 登革病毒第二型 (DV2, PL046株) 感染免疫細胞、內皮細胞及 A549 肺內皮細胞的系統。以 anti-pr M 抗體去加強登革病毒感染 PBMC 及 THP-1 細胞，其結果發現登革病毒感染可以刺激有大量 MIF 產生。另以雙染方式可證實 DV2 感染表皮細胞亦可引起大量 MIF 產生。如果用類固醇（dexamethasone）及薑黃素（curcumin）處理細胞再感染 DV2 則並沒有引起大量的 MIF，因此推測 DV2 可能是透過活化 NF-kB 路徑而引起 MIF 產生。另外由臨床病人血清發現 DHF 病人有大量 MIF 及凝血酶調節素上升，蛋白C及蛋白S則有下降的現象，我們推論 MIF 或 DV2 對凝血酶調節素（thrombomodulin）、蛋白C及蛋白S的表現量可能有所影響。因此構築人類基因重組 MIF 蛋白（rMIF），此 rMIF 其功能如之前報告一樣可引起 ICAM-1 產生。利用 rMIF 處理內皮細胞、THP-1 細胞及 HepG2 細胞以了解凝血因子及抗凝血因子的產生是否受 MIF 影響。利用 RT-PCR, IFA 螢光染色及流式細胞儀分析方法證實 rMIF 在內皮細胞及 THP-1 細胞可引起大量的凝血酶調節素的表現。加入 anti-MIF 中和抗體處理則內皮細胞凝血酶調節素的表現量會減少，證實 rMIF 的確可引起凝血酶調節素產生。以 rMIF 處理 HepG2 細胞則可抑制凝血酶原、蛋白C及蛋白S RNA 的產生。另外我們也發現 DV2 可在內皮細胞引起MIF及凝血酶調節素基因的表現；而DV2透過何種途徑引起凝血酶調節素的產生其機制亦尚不清楚。綜合這些研究證明MIF 在 DHF 的致病機制中所扮演重要的角色。阻擋MIF的產生或其功能將可能對DHF的治療及預防提供更有效的幫助。

Dengue virus infection can cause mild dengue fever (DF) or severe dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS). Cytokines are believed to be involved in the pathogenesis of dengue infection. However, the role of a pro-inflammatory cytokine, macrophage migration inhibitory factor (MIF), in dengue infection remains unclear. In this study, serum levels of MIF in dengue patients with different disease severity and clinical outcome were determined and compared with the levels of other cytokines such as tumor necrosis factor alpha (TNF-), interleukin-6 (IL-6), IL-10, and interferon gamma (IFN-) of the same patients. Serum levels of MIF, IL-6, and IL-10 but not IFN- or TNF-, were higher in all DHF/DSS nonsurvivors than in DHF survivors and DF patients. We conclude that in addition to IL-6 and IL-10, elevated serum MIF is a potential indicator of disease severity and clinical outcome in dengue patients. Thus, we have set up an in vitro cell culture system (including human immune cells, endothelial cells and A549 lung epithelial cells) to understand the effects of Dengue virus serotype 2 ( DV2, PL046 strain) infection on the production of MIF. We found in the presence of anti-pr M Ab to enhance dengue virus infection, MIF production of human DV2 infected PBMC and THP-1 cells were all increased. Double immunofluorescent staining showed that DV2 infection of epithelial cells leads to MIF production. DV-induced MIF production was inhibited in the presence of dexamethasone and curcumin which indicated MIF production induced by DV may involve the activation of NF-kB pathway. In addition, to MIF, thrombomodulin was also increased while protein C and protein S were decreased in serum of DHF patients. Therefore, it is speculated that MIF or DV2 infection may influence the expression of thrombomodulin, protein C and protein S. Recombinant human MIF (rMIF) protein was expressed and purified which was able to induce the production of ICAM-1 as previous report. Furthermore, to understand whether the production of coagulation and anticoagulation factors is affected by MIF, endothelial cells, THP-1 cells and HepG2 cells were treated with rMIF. RT-PCR, IFA staining and flow cytometric methods demonstrate that rMIF induced thrombomodulin protein expression in endothelial cells and THP-1 cells which was blocked in the presence of neutralizing anti-MIF Ab. Furthermore, MIF treatment in HepG2 cells results in the suppression of prothrombin, protein C and protein S RNA expression. Since DV2 infection of endothelial cells induced the expression of MIF and thrombomodulin, it remains unclear the precise mechanism to induce thrombomodulin by DV2. Taken together, this study demonstrated the potential important roles of MIF in the pathogenesis of DHF. Blocking MIF production or its function may provide solutions in the treatment and prevention of DHF.

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