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Antimicrobial Agents and Chemotherapy, March 2007, p. 1048-1054, Vol. 51, No. 3
0066-4804/07/$08.00+0     doi:10.1128/AAC.01095-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Expression of Immunomodulatory Genes in Human Monocytes Induced by Voriconazole in the Presence of Aspergillus fumigatus{triangledown}

M. Simitsopoulou,1,2 E. Roilides,1,3 C. Likartsis,2 J. Ioannidis,2 A. Orfanou,2 F. Paliogianni,4 and T. J. Walsh3*

Laboratory of Infectious Diseases, 3rd Department of Pediatrics, School of Medicine, Aristotle University, Hippokration Hospital, Thessaloniki 54642, Greece,1 Laboratory of Medical Biotechnology, Department of Medical Laboratories, Technological Educational Institute of Thessaloniki, 57400 Thessaloniki, Greece,2 Immunocompromised Host Section, National Cancer Institute, Bethesda, Maryland 20892,3 Department of Microbiology, University of Patras Medical School, Patras 26500, Greece4

Received 30 August 2006/ Returned for modification 5 October 2006/ Accepted 8 December 2006

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{Delta}), 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{gamma}, 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 1ß (IL-1ß) 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 1ß 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.

* Corresponding author. Mailing address: Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, Bldg. 10, CRC 1-5750, Bethesda, MD 20892. Phone: (301) 402-0023. Fax: (301) 480-2308. E-mail: walsht{at}mail.nih.gov.

{triangledown} Published ahead of print on 18 December 2006.

Antimicrobial Agents and Chemotherapy, March 2007, p. 1048-1054, Vol. 51, No. 3
0066-4804/07/$08.00+0     doi:10.1128/AAC.01095-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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