Immunomodulatory Effects of Voriconazole on Monocytes Challenged withAspergillus fumigatus: Differential Role of Toll-Like Receptors

Abstract

Voriconazole (VRC) has activity againstAspergillus fumigatus, the most frequent cause of invasive aspergillosis in immunocompromised patients. The combination of VRC andA. fumigatushyphae induced a more pronounced profile of expression of genes encoding inflammatory molecules in human monocytes thanAspergillusalone did. Herein, we provide further evidence of the potential mechanism underlying this immunomodulatory effect of VRC on human monocytes in response toA. fumigatushyphae. A significant additive antifungal effect was shown when VRC was combined with monocytes againstA. fumigatushyphae. BothA. fumigatushyphae and VRC induced pronounced profiles of mRNA and protein expression of Toll-like receptor 2 (TLR2) as well as tumor necrosis factor alpha (TNF-α) in THP-1 monocytic cells compared to untreated cells. The VRC-induced increase was greater than that induced by hyphae. The combination of VRC and hyphae increased mRNA and protein expression of TLR2 and TNF-α to even higher levels than did either VRC or hyphae alone. In contrast, TLR4 expression, both at the mRNA and protein levels, was not increased by either VRC or hyphae or their combination. In addition, significantly more NF-κB was translocated to the nuclei of THP-1 cells treated with VRC than untreated cells. While VRC induced more NF-κB than hyphae did, treatment with the combination of the two factors induced the greatest NF-κB expression. The pronounced profile of TLR2 signaling, TNF-α expression, and NF-κB activation in the presence of VRC suggests an immunomodulatory effect leading to a more efficient response toA. fumigatus.