Differential expression of cytokines and chemokines in human monocytes induced by lipid formulations of amphotericin B.
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-1beta (IL-1beta), IL-1 receptor antagonist (IL-1ra), tumor necrosis factor alpha (TNF-alpha), monocyte chemotactic protein 1 (MCP-1), and macrophage inflammatory protein 1beta (MIP-1beta) 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-alpha) or 6 h (all the others). In the mRNA studies, DAMB resulted in an early increase of inflammatory cytokines or chemokines IL-1beta, TNF-alpha, MCP-1, and MIP-1beta (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-1beta and TNF-alpha, whereas ABLC additionally decreased MIP-1beta. In protein measurement studies, DAMB and ABCD up-regulated production of IL-1beta (P < 0.05), decreased the IL-1ra/IL-1beta ratio, and up-regulated the production of MCP-1 and MIP-1beta. 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-1beta 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.
Simitsopoulou
M
M
Laboratory of Infectious Diseases, 3rd Department of Pediatrics, School of Medicine, Aristotle University of Thessaloniki, Greece.
Roilides
E
E
Dotis
J
J
Dalakiouridou
M
M
Dudkova
F
F
Andreadou
E
E
Walsh
T J
TJ
D000666:Amphotericin B / Q000737:chemistry / Q000494:pharmacology*; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D003840:Deoxycholic Acid; D005786:Gene Expression Regulation; D006801:Humans; D008081:Liposomes; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D000935:Antifungal Agents; D018925:Chemokines; D016207:Cytokines; D008081:Liposomes; D012333:RNA, Messenger; D003840:Deoxycholic Acid; D000666:Amphotericin B