title: Amphotericin B up-regulates lipid A-induced IL-6 production via caspase-8.
abstract: Amphotericin B, an antifungal drug used to treat candidiasis, has been reported to induce pro-inflammatory cytokine production in cultured cells. This study investigated the effects of amphotericin B on pro-inflammatory cytokine production in response to lipid A, the bioactive component of lipopolysaccharide (LPS) in the cell walls of Gram-negative bacteria. Amphotericin B alone elicited a slight increase in interleukin (IL)-6 and IL-8 production by human gingival fibroblasts. However, amphotericin B synergistically up-regulated lipid A-induced production of IL-6 and IL-8. While amphotericin B minimally activated nuclear factor (NF)-κB, it synergistically increased lipid A-induced NF-κB activation. Pre-treatment with methyl-β-cyclodextrin (MβCD), a cholesterol-binding agent, reduced IL-6 and IL-8 production in human gingival fibroblasts. Cholesterol-saturated MβCD also reversed cytokine production, suggesting that the synergistic production of cytokines by amphotericin B and lipid A is dependent on cholesterol-rich microdomains. Amphotericin B activated caspase-8. In addition, a caspase-8 inhibitor inhibited IL-6 production by amphotericin B and lipid A. This suggests that caspase-8 is required for the synergistic production of IL-6 by amphotericin B and lipid A. Collectively, our results suggest that periodontal treatment carried out before amphotericin B treatment may protect against lipid A-induced pro-inflammatory cytokine production.
authors.affiliation: Department of Oral Medical Science, Ohu University School of Dentistry, 31-1 Misumido, Tomitamachi, Koriyama, Fukushima 963-8611, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Tamai
authors.forename: M
authors.initials: M
authors.lastname: Sugamata
authors.forename: Y
authors.initials: Y
authors.lastname: Kiyoura
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D053181:Caspase 8 / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D055113:Chronic Periodontitis / Q000378:metabolism; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005881:Gingiva / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis*; D016209:Interleukin-8 / Q000096:biosynthesis; D008050:Lipid A / Q000494:pharmacology*; D021962:Membrane Microdomains / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D015533:Transcriptional Activation; D015854:Up-Regulation; D047392:beta-Cyclodextrins / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D015850:Interleukin-6; D016209:Interleukin-8; D008050:Lipid A; D016328:NF-kappa B; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D000666:Amphotericin B; D002784:Cholesterol; D053181:Caspase 8