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Antimicrobial Agents and Chemotherapy, April 2005, p. 1397-1403, Vol. 49, No. 4
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.4.1397-1403.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Differential Expression of Cytokines and Chemokines in Human Monocytes Induced by Lipid Formulations of Amphotericin B

M. Simitsopoulou,^1,2 E. Roilides,^1,3 J. Dotis,¹ M. Dalakiouridou,¹ F. Dudkova,^1, E. Andreadou,² and T. J. Walsh^3*

Laboratory of Infectious Diseases, 3rd Department of Pediatrics, School of Medicine, Aristotle University of Thessaloniki,¹ Laboratory of Medical Biotechnology, Department of Medical Laboratories, Technological Educational Institute, Thessaloniki, Greece,² Immunocompromised Host Section, National Cancer Institute, Bethesda, Maryland³

Received 8 August 2004/ Returned for modification 11 October 2004/ Accepted 24 December 2004

The immunomodulatory effects of liposomal amphotericin B (LAMB), amphotericin B lipid complex (ABLC), and amphotericin B colloidal dispersion (ABCD) on mRNA and protein profiles of five cytokines and chemokines expressed by human monocyte-enriched mononuclear leukocytes (MNCs) were comprehensively evaluated by semiquantitative reverse transcription-PCR and enzyme-linked immunosorbent assays; they were compared to those of deoxycholate amphotericin B (DAMB). mRNAs of interleukin-1ß (IL-1ß), IL-1 receptor antagonist (IL-1ra), tumor necrosis factor alpha (TNF-), monocyte chemotactic protein 1 (MCP-1), and macrophage inflammatory protein 1ß (MIP-1ß) were assessed after treatment of MNCs with each drug for 0.5, 2, 6, and 22 h. The cytokine protein profiles were obtained after incubation of MNCs with the drugs for 2 h (TNF-) or 6 h (all the others). In the mRNA studies, DAMB resulted in an early increase of inflammatory cytokines or chemokines IL-1ß, TNF-, MCP-1, and MIP-1ß (2 to 6 h) and in a late increase of anti-inflammatory IL-1ra (22 h). ABCD showed a general similar trend of inflammatory gene up-regulation. LAMB and ABLC decreased or did not affect IL-1ß and TNF-, whereas ABLC additionally decreased MIP-1ß. In protein measurement studies, DAMB and ABCD up-regulated production of IL-1ß (P < 0.05), decreased the IL-1ra/IL-1ß ratio, and up-regulated the production of MCP-1 and MIP-1ß. In comparison, LAMB and ABLC down-regulated or did not affect the production of these cytokines/chemokines compared to untreated MNCs; furthermore, ABLC tended to increase the IL-1ra/IL-1ß ratio. These studies demonstrate that amphotericin B formulations differentially affect gene expression and release of an array of proinflammatory and anti-inflammatory cytokines that potentially may explain the differences in infusion-related reactions and dose-dependent nephrotoxicity as well as modulation of the host immune response to invasive fungal infections.

Present address: Department of Medical and Biological Sciences, Pharmaceutical Faculty, Heyrovskeho, Hradec Kralove, Czech Republic.

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