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

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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.