Differential effects of triptolide and tetrandrine on activation of COX-2, NF-κB, and AP-1 and virus production in dengue virus-infected human lung cells

Most virus infections induce cycloxygenase-2 (COX-2) expression and subsequent prostaglandin E-2 (PGE(2)) production in cells, an inflammatory response that might be detrimental to virus replication and pathogenesis. This response in dengue virus infection remains to be elucidated. Triptolide and tetrandrine, compounds derived from two commonly used Chinese herbs, both demonstrate anti-inflammatory and immunosuppressive effects partly through modulation of COX-2 expression and, hence, may have antiviral effects. In this study. we examined, firstly, the immune response to dengue virus infection with respect to COX-2 expression and PGE2 production in human lung cells (A549), liver cells (HepG2) and dendritic cells. Secondly, we assessed the potential antiviral effects of triptolide and tetrandrine on dengue virus infection vis-A-vis expression of COX-2, PGE2, transcription factors, as well as virus production. We found that dengue virus infection enhanced COX-2 expression and PGE2 production in A549 cells, similarly to the response in dendritic cells, but not in HepG2 cells. In dengue virus-infected A549 cells, nuclear factor kappa B (NF-kappa B) and activator protein 1 (AP-1) were also activated, and both were dose-dependently inhibited by triptolide (0.5-4 ng/ml). Tetrandrine (1-10 mu M) had no similar immunosuppressive effects and, moreover, at higher concentrations, enhanced NF-kappa B and AP-1 activity, COX-2 expression and PGE2 production. However, unexpectedly, tetrandrine, but not triptolide, dose-dependently suppressed dengue virus production in A549 cells, independent of PGE(2) level. Our findings imply that triptolide and tetrandrine may attenuate dengue virus infection in human lung cells, but through distinct pathways. (c) 2008 Elsevier B.V. All rights reserved.