Release of TNF-α and IL-1β from porcine brain endothelium corresponds to the pyrogenic potential of three marketed formulations of amphotericin

Background: Formulations of amphotericin include a deoxycholate suspension (d-Amph), an amphotericin-B lipid complex (Ablc), and a liposomal product (L-Amph). Fever is most frequent with d-Amph, intermediate with Ablc, and lowest with L-Amph. Objective: To determine if the release of tumor necrosis factor-alpha (TNF-α) and interleukin-1-beta (IL-1) from brain endothelium corresponds to the incidence of amphotericin fever. Results: Release of TNF-α and IL-1β after L-Amph treatment was similar to negative controls while after d-Amph treatment release was similar to lipopolysaccharide. Ablc treatment produced intermediate pyrogen release. NF-κB expression, a transcriptional regulator for TNF-α and IL-1β genes, corresponded to this secretion pattern. TNF-α release was elevated 2 hours (p = 0.0021) after treatment while significant elevations in IL-1β required 6 hours (p = 0.0009). Conclusion: Results from this in vitro study suggest that amphotericin fever may be directly mediated by brain endothelium. These experiments also suggest that amphotericin fever is initially mediated by TNF-α.