title: Dengue virus enhances thrombomodulin and ICAM-1 expression through the macrophage migration inhibitory factor induction of the MAPK and PI3K signaling pathways.
abstract: Dengue virus (DV) infections cause mild dengue fever (DF) or severe life-threatening dengue hemorrhagic fever (DHF). The mechanisms that cause hemorrhage in DV infections remain poorly understood. Thrombomodulin (TM) is a glycoprotein expressed on the surface of vascular endothelial cells that plays an important role in the thrombin-mediated activation of protein C. Prior studies have shown that the serum levels of soluble TM (sTM) and macrophage migration inhibitory factor (MIF) are significantly increased in DHF patients compared to levels in DF patients or normal controls. In this study, we investigated how MIF and sTM concentrations are enhanced in the plasma of DHF patients and the potential effect of MIF on coagulation through its influence on two factors: thrombomodulin (TM) and intercellular adhesion molecule-1 (ICAM-1) in endothelial cells and monocytes. Recombinant human macrophage migration inhibitory factor (rMIF) was used to treat monocytic THP-1 cells and endothelial HMEC-1 cells or primary HUVEC cells. The subsequent expression of TM and ICAM-1 was assessed by immunofluorescent staining and flow cytometry analysis. Additionally, the co-incubation of THP-1 cells with various cell signaling pathway inhibitors was used to determine the pathways through which MIF mediated its effect. The data provided evidence that severe DV infections induce MIF expression, which in turn stimulates monocytes or endothelial cells to express TM and ICAM-1 via the Erk, JNK MAPK and the PI3K signaling pathways, supporting the idea that MIF may play an important role as a regulator of coagulation.
authors: Department of Medical Technology, National Cheng Kung University, Taiwan, Republic of China.
authors: Trai-Ming
authors: TM
authors: Yeh
authors: Shu-Hsiang
authors: SH
authors: Liu
authors: Kao-Chang
authors: KC
authors: Lin
authors: Chieh
authors: C
authors: Kuo
authors: Shu-Yun
authors: SY
authors: Kuo
authors: Tzuu-Yuan
authors: TY
authors: Huang
authors: Yong-Ren
authors: YR
authors: Yen
authors: Rong-Kun
authors: RK
authors: Wen
authors: Lien-Cheng
authors: LC
authors: Chen
authors: Tsai-Feng
authors: TF
authors: Fu
mesh_terms: D002460:Cell Line; D003716:Dengue Virus / Q000502:physiology*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism / Q000821:virology; D005786:Gene Expression Regulation; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D020935:MAP Kinase Signaling System; D008263:Macrophage Migration-Inhibitory Factors / Q000097:blood / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000378:metabolism / Q000821:virology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011486:Protein C / Q000378:metabolism; D019595:Severe Dengue / Q000097:blood / Q000378:metabolism / Q000473:pathology; D012995:Solubility; D018180:Thrombomodulin / Q000097:blood / Q000737:chemistry / Q000235:genetics*
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D011486:Protein C; D018180:Thrombomodulin; D018799:Intercellular Adhesion Molecule-1; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases
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