Expression of Immunomodulatory Genes in Human Monocytes Induced by Voriconazole in the Presence ofAspergillus fumigatus

Abstract

We assessed the effect of voriconazole (VRC) on the expression and release of selected cytokines and chemokines in the THP-1 human monocytic cell line in response toAspergillus fumigatushyphal fragments (HF) by cDNA microarray analysis, reverse transcriptase (RT) PCR, and enzyme-linked immunosorbent assay. Stimulation of THP-1 cells by HF alone caused a significant up-regulation ofCCL4(MIP1B) andCCL16, whileCCL2(MCP1) was down-regulated. By comparison, in the presence of VRC, a large number of genes such asCCL3(MIP1A),CCL4(MIP1B),CCL5(RANTES),CCL7(MCP3),CCL11(EOTAXIN),CCL15(MIP1Δ),CXCL6, andCXCL13were strongly up-regulated in THP-1 cells challenged by HF, whereasCCL20(MIP3A) andCCL21(MIP2) were down-regulated. Among five genes differentially expressed in THP-1 cells,IL12A,IL12B, andIL-16were down-regulated whereasIL-11andTGFB1were significantly up-regulated in the presence of VRC. The inflammation-related genesIFNγ,IL1R1, andTNFAwere also up-regulated in THP-1 cells exposed to HF only in the presence of VRC. RT-PCR of four selected genes validated the results of microarrays. The release of interleukin 1β (IL-1β) and IL-12 was significantly increased from monocytes stimulated either by HF alone (P< 0.05) or in the presence of VRC (P< 0.01 andP< 0.05, respectively). In contrast, tumor necrosis factor alpha release from monocytes was enhanced only in the presence of VRC (P< 0.01). The chemokines monocyte chemoattractant protein 1 and macrophage inflammatory protein 1β were decreased under both conditions (P< 0.01). These results demonstrate that in the presence of VRC, HF induces a more pronounced profile of gene expression in THP-1 cells than HF alone, potentially leading to more-efficient host resistance toA. fumigatus.