Dengue Virus Infection Induced NF-κB-dependent Macrophage Migration Inhibitory Factor Production

Huey-Wen Shyu,Huan-Yao Lei,Yee-Shin Lin,Hsiao-Sheng Liu,Lien-Cheng Chen,Shun-Hua Chen,Trai-Ming Yeh

doi:10.3844/ajidsp.2008.22.31

Abstract

Dengue virus (DV) infection can cause mild dengue fever or severe dengue hemorrhage fever and dengue shock syndrome. Macrophage migration inhibitory factor (MIF) is a cytokine that plays an important role in the modulation of inflammatory and immune responses and serum levels of MIF are correlated with disease severity in dengue patients. However, the mechanism that induces MIF production during DV infection is unclear. In this study, we showed that DV infection, but not UVinactivated DV stimulation, dose-and time-dependently induced MIF secretion in human A649 epithelial cells. MIF promoter assays and RT-PCR demonstrated that MIF gene transcription was activated during DV infection. Furthermore, DV infection induced NF-IoB activation, and the NF-IoB inhibitors dexamethasone and curcumin inhibited DV-induced MIF production. Finally, we found that different cells have different abilities to release MIF after DV infection. Interestingly, DV infection and MIF production in the human monocytic cell line THP-1 and peripheral blood mononuclear cells increased in the presence of antibodies against DV. Taken together, these results suggest that DV infection of human cells induces NF-IoB activation and MIF production, which can be increased in the presence of pre-existing antibodies.

Highlights

Dengue viruses (DV) are mosquito-borne flaviviruses subgrouped into four antigenically related serotypes: DV types 1, 2, 3, and 4[1]
No significant increase of migration inhibitory factor (MIF) release was found in DV2-infected A549 cells than in mockinfected cells after 24 h of infection (Figure 2A); after 48 h of infection, the MIF concentration were significantly elevated in the supernatants of the DV2-infected cells but not in the mock-infected cells
NF-κB was activated after DV infection of A549 cells: Because NF-κB activation is implicated in activating many pro-inflammatory cytokines, we examined whether NF-κB was activated after A549

Summary

Introduction

Dengue viruses (DV) are mosquito-borne flaviviruses subgrouped into four antigenically related serotypes: DV types 1, 2, 3, and 4[1]. Especially during secondary infection with a different serotype of DV, the infection may progress to dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS)[3]. DHF is a severe febrile disease characterized by abnormalities in homeostasis and increased capillary leakage that can progress to hypovolemic shock (DSS)[4]. Even though the process leading to DHF/DSS is not fully understood, antibody-dependent enhancement (ADE) has been proposed to explain the mechanisms by which heterogeneous serotype DV infection can induce DHF/DSS in secondary infection[5, 6]. According to the ADE hypothesis, the antibody generated during primary dengue infection can neutralize only DV with the same serotype but not those with different serotypes during secondary infection. The non-neutralizing antibodies may increase the virus uptake by macrophages through

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Conclusion