title: Immunosuppressive effects and mechanisms of leflunomide in dengue virus infection of human dendritic cells.
abstract: BACKGROUND
  Dengue virus (DENV) infection is a serious public health issue without specific treatment. We examined the potential immunomodulatory effects of leflunomide, a dihydroorotate dehydrogenase inhibitor commonly prescribed for arthritis, in DENV-stimulated monocyte-derived dendritic cells (mo-DCs).
  
  
  METHODS
  mo-DCs were prepared from purified monocytes. Cytokine and chemokine concentrations were determined by enzyme-linked immunosorbent assay. Expression of cell surface markers or viral E protein was measured by flow cytometry. The activation of transcription factors and kinases was determined by electrophoretic mobility shift assays, Western blotting, or immunoprecipitation kinase assays. Chemotaxis assays were used to determine cell migration.
  
  
  RESULTS
  Leflunomide at therapeutic concentrations inhibited cytokine and chemokine production from DENV-infected mo-DCs. Leflunomide suppressed mo-DC maturation by downregulating the expression of both CD80 and CD86. In addition, leflunomide inhibited DENV-induced mo-DC migration and mo-DC response to chemoattractants CCL19 and CCL21. Inhibition of mo-DC migration was likely due to the suppression of CCR7 expression on mo-DCs. These events were associated with the suppression of nuclear factor kappa B and activator protein-1 signaling pathways by leflunomide.
  
  
  CONCLUSIONS
  Leflunomide preserves immunosuppressive effects, inhibiting activation of DENV-stimulated mo-DCs. Leflunomide may be helpful in the development of therapeutics for DENV infection.
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Miaoli County, 350, Taiwan, Republic of China.
authors.forename: Wan-Lin
authors.initials: WL
authors.lastname: Wu
authors.forename: Ling-Jun
authors.initials: LJ
authors.lastname: Ho
authors.forename: Pei-Chih
authors.initials: PC
authors.lastname: Chen
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Tsai
authors.forename: Seng-Ting
authors.initials: ST
authors.lastname: Hsu
authors.forename: Deh-Ming
authors.initials: DM
authors.lastname: Chang
authors.forename: Jenn-Haung
authors.initials: JH
authors.lastname: Lai
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D054415:Chemokine CCL19 / Q000235:genetics / Q000378:metabolism; D054421:Chemokine CCL21 / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003715:Dengue / Q000188:drug therapy* / Q000276:immunology*; D003716:Dengue Virus / Q000276:immunology / Q000472:pathogenicity; D000090722:Dihydroorotate Dehydrogenase; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007555:Isoxazoles / Q000494:pharmacology*; D000077339:Leflunomide; D009000:Monocytes / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors; D054400:Receptors, CCR7 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000276:immunology
chemical_list: C515370:CCR7 protein, human; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D000090722:Dihydroorotate Dehydrogenase; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D016328:NF-kappa B; D054400:Receptors, CCR7; D018808:Transcription Factor AP-1; D014759:Viral Envelope Proteins; C072281:E protein TH Sman, Dengue virus; D044925:Oxidoreductases Acting on CH-CH Group Donors; D000077339:Leflunomide