Signaling pathways involved in dengue-2 virus infection induced RANTES overexpression

Dengue viruses participate in liver inflammation by inducting the expression of various chemokines including Regulated on Activation Normal T-cell Expressed and Secreted (RANTES). However, the underlying signaling remains unknown. Here, we reveal that Ras, Raf-1 and three mitogen-activated protein kinases (MAPKs) p38, extracellular signal-regulated kinase (Erk), and c-jun-NH₂-terminal kinase (JNK) can be activated or phosphorylated in dengue-2 virus infected hepatocyte and epithelial cells by western blotting and confirmed by dominant negative mutants of ras, raf-1, p38, Erk, and JNK. The Tet-off inducible plasmids harboring dengue-2 virus prM, core, E or NS1 gene were utilized to reveal their role in RANTES activation. However, no effect was detected among the genes tested indicating that they are either dispensable or not sufficient for RANTES activation. Taken-together, Ras, Raf-1, JNK, Erk and p38 related signaling pathways are essential for the activation of RANTES by dengue-2 virus. The knowledge gathered will shed light on developing a novel therapeutic approach to block inflammatory infiltrates through decreasing RANTES expression.