Expression of Immunomodulatory Genes in Human Monocytes Induced by Voriconazole in the Presence of<i>Aspergillus fumigatus</i>

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 to Aspergillus fumigatus hyphal 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 of CCL4 ( MIP1B ) and CCL16 , while CCL2 ( MCP1 ) was down-regulated. By comparison, in the presence of VRC, a large number of genes such as CCL3 ( MIP1A ), CCL4 ( MIP1B ), CCL5 ( RANTES ), CCL7 ( MCP3 ), CCL11 ( EOTAXIN ), CCL15 ( MIP1 Δ), CXCL6 , and CXCL13 were strongly up-regulated in THP-1 cells challenged by HF, whereas CCL20 ( MIP3A ) and CCL21 ( MIP2 ) were down-regulated. Among five genes differentially expressed in THP-1 cells, IL12A , IL12B , and IL-16 were down-regulated whereas IL-11 and TGFB1 were significantly up-regulated in the presence of VRC. The inflammation-related genes IFN γ, IL1R1 , and TNFA were 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 &lt; 0.05) or in the presence of VRC ( P &lt; 0.01 and P &lt; 0.05, respectively). In contrast, tumor necrosis factor alpha release from monocytes was enhanced only in the presence of VRC ( P &lt; 0.01). The chemokines monocyte chemoattractant protein 1 and macrophage inflammatory protein 1β were decreased under both conditions ( P &lt; 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 to A. fumigatus .