title: Dengue virus serotype 2 blocks extracellular signal-regulated kinase and nuclear factor-κB activation to downregulate cytokine production.
abstract: BACKGROUND
  Dengue virus (DENV) infection is the most common mosquito-borne viral disease threatening human health around the world. Type I interferon (IFN) and cytokine production are crucial in the innate immune system. We previously reported that DENV serotype 2 (DENV-2) induced low levels of interferon regulatory factor 3 and NF-κB activation, thus leading to reduced production of IFN-β in the early phase of infection. Here, we determined whether DENV infection not only hampers type I IFN activation but also cytokine production triggered by Toll-like receptor (TLR) signaling.
  
  
  RESULTS
  We used quantitative RT-PCR and found that only low levels of IFN-β and inflammatory cytokines such as interleukin 10 (IL-10), IL-12 and tumor necrosis factor α (TNFα) mRNA were detected in DENV-2-infected bone-marrow-derived dendritic cells. Furthermore, DENV-2 infection repressed cytokine production triggered by TLR signaling. To elucidate the molecular mechanisms underlying this suppression event, we measured NF-κB activation by p65 nuclear translocation and luciferase reporter assay and found that NF-κB activation triggered by TLR ligands was blocked by DENV-2 infection. As well, extracellular signal-regulated kinase (ERK) activity was suppressed by DENV-2 infection.
  
  
  CONCLUSIONS
  To downregulate the host innate immunity, DENV-2 by itself is a weak inducer of type I IFN and cytokines, furthermore DENV-2 can also block the TLR-triggered ERK-NF-κB activation and cytokine production.
authors.affiliation: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan. changth@vghks.gov.tw
authors.forename: Tsung-Hsien
authors.initials: TH
authors.lastname: Chang
authors.forename: Siang-Ru
authors.initials: SR
authors.lastname: Chen
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Yu
authors.forename: You-Sheng
authors.initials: YS
authors.lastname: Lin
authors.forename: Yao-Shen
authors.initials: YS
authors.lastname: Chen
authors.forename: Toru
authors.initials: T
authors.lastname: Kubota
authors.forename: Mayumi
authors.initials: M
authors.lastname: Matsuoka
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Lin
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D016207:Cytokines / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism / Q000821:virology; D003716:Dengue Virus / Q000502:physiology*; D015536:Down-Regulation; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D016899:Interferon-beta / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D008024:Ligands; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000096:biosynthesis* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000096:biosynthesis* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D016207:Cytokines; D008024:Ligands; D016328:NF-kappa B; D051193:Toll-Like Receptors; D016753:Interleukin-10; D016899:Interferon-beta; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3