Osteopontin (OPN) is a multifunctional matricellular
protein produced by a broad range of cells including osteoclasts, macrophages, T cells, endothelial cells, and vascular smooth muscle cells. OPN modulates various physiological and pathological events such as
inflammation, wound healing, and bone formation and remodeling. Dengue virus (DENV)
infection causes an increase in plasma OPN levels, which is correlated with the severity of symptoms and coagulation abnormalities. DENV
infection also induces OPN gene expression in human macrophages. This study investigated the inhibitory effects of
brefelamide and its methyl
ether derivative on DENV-3 by measuring changes in OPN levels in human THP-1 and 293T cell lines infected at different multiplicities of
infection and post-
infection time points. OPN
mRNA expression and
viral RNA were detected by
reverse transcriptase quantitative real-time PCR, whereas
protein level was determined by
enzyme-linked
immunosorbent assay. We found that viral copy number was higher in 293T than in THP-1 cells. However, THP-1 constitutively expressed higher levels of OPN
mRNA and
protein, which were enhanced by DENV-3
infection.
Brefelamide and its derivative suppressed OPN production in DENV-3 infected THP-1 cells; the effective doses of these compounds had no effect on uninfected cells, indicating low cytotoxicity. These results suggest that
brefelamide and its methyl
ether derivative have
therapeutic effects in preventing
inflammation, coagulopathy, and fibrinolysis caused by OPN upregulation induced by DENV-3
infection.