Amphotericin B up-regulates lipid a-induced IL-6 production via caspase-8

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. © 2012 international & american associations for dental research.