Study on the roles of macrophage migration inhibitory factor (MIF) in the pathogenesis of dengue virus infection
| Autor: | Lien-cheng Chen, 陳連城 |
|---|---|
| Rok vydání: | 2007 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 95 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. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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