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but Not IFN-
Antiviral Effect via Down-Regulating Tyk2-STAT Signaling in the Human Dendritic Cell1
* Division of Gerontology Research, National Health Research Institute, Rheumatology/Immunology and Allergy, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, and Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
The immunopathogenesis mechanism of dengue virus (DV) infection remains elusive. We previously showed that the target of DV in humans is dendritic cells (DCs), the primary sentinels of immune system. We also observed that despite the significant amount of IFN-
induced; DV particles remain massively produced from infected DCs. It suggests that DV may antagonize the antiviral effect of IFN-. Recent work in animal studies demonstrated the differential critical roles of antiviral cytokines, namely IFN-/IFN-
and IFN-
, in blocking early viral production and in preventing viral-mediated disease, respectively. In this study, we examined the effects of IFN- and IFN- in DV infection of monocyte-derived DCs. We showed that the preinfection treatment with either IFN- or IFN- effectively armed DCs and limited viral production in infected cells. However, after infection, DV developed mechanisms to counteract the protection from lately added IFN-, but not IFN-. Such a selective antagonism on antiviral effect of IFN-, but not IFN-, correlated with down-regulated tyrosine-phosphorylation and DNA-binding activities of STAT1 and STAT3 transcription factors by DV. Furthermore, subsequent studies into the underlying mechanisms revealed that DV attenuated IFN--induced tyrosine-phosphorylation of Tyk2, an upstream molecule of STAT activation, but had no effect on expression of both IFN- receptor 1 and IFN- receptor 2. Moreover, DV infection by itself could activate STAT1 and STAT3 through IFN--dependent and both IFN--dependent and IFN--independent mechanisms, respectively. These observations provide very useful messages with physiological significance in investigation of the pathogenesis, the defense mechanisms of human hosts and the therapeutic considerations in DV infection.
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