title: Expression of immunomodulatory genes in human monocytes induced by voriconazole in the presence of Aspergillus 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 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 (MIP1Delta), 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 IFNgamma, 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 1beta (IL-1beta) 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 and P < 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 1beta 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 to A. fumigatus.
authors.affiliation: Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, Bldg. 10, CRC 1-5750, Bethesda, MD 20892, USA.
authors.forename: M
authors.initials: M
authors.lastname: Simitsopoulou
authors.forename: E
authors.initials: E
authors.lastname: Roilides
authors.forename: C
authors.initials: C
authors.lastname: Likartsis
authors.forename: J
authors.initials: J
authors.lastname: Ioannidis
authors.forename: A
authors.initials: A
authors.lastname: Orfanou
authors.forename: F
authors.initials: F
authors.lastname: Paliogianni
authors.forename: T J
authors.initials: TJ
authors.lastname: Walsh
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000276:immunology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D025301:Hyphae / Q000276:immunology; D007113:Immunity, Innate / Q000187:drug effects* / Q000235:genetics*; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D011743:Pyrimidines / Q000494:pharmacology*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014230:Triazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018076:DNA, Complementary; D053583:Interleukin-1beta; D019402:Macrophage Inflammatory Proteins; D011743:Pyrimidines; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D012313:RNA; D065819:Voriconazole