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.
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 DENVinfection.
Authors: Michelle A Josephson; Daniel Gillen; Basit Javaid; Pradeep Kadambi; Shane Meehan; Preston Foster; Robert Harland; Richard J Thistlethwaite; Marc Garfinkel; Walter Atwood; Joslynn Jordan; Molly Sadhu; Michael J Millis; James Williams Journal: Transplantation Date: 2006-03-15 Impact factor: 4.939
Authors: Ivonne Ceballos-Olvera; Salvador Chávez-Salinas; Fernando Medina; Juan E Ludert; Rosa M del Angel Journal: Virology Date: 2009-11-07 Impact factor: 3.616
Authors: Alfonso MartIn-Fontecha; Silvia Sebastiani; Uta E Höpken; Mariagrazia Uguccioni; Martin Lipp; Antonio Lanzavecchia; Federica Sallusto Journal: J Exp Med Date: 2003-08-18 Impact factor: 14.307