Fungal beta-glucans modulate macrophage release of tumor necrosis factor-alpha in response to bacterial...

Tumor necrosis factor-alpha (TNF alpha) is a potent cytokine believed to participate in the development of endotoxin-induced shock and the adult respiratory distress syndrome. Treatment of animals with beta-glucan prior to bacterial challenge reduces TNF alpha release and prevents death. We therefore hypothesized that beta-glucan might regulate TNF alpha secretion from macrophages in response to lipopolysaccharide (LPS). Rat alveolar macrophages were cultured in the presence of beta-glucan alone and the TNF alpha secretion quantified using an L929 cytotoxicity assay. Concentrations of beta-glucan less than 500 micrograms/ml were found to stimulate TNF alpha release from macrophages. However, concentrations of beta-glucan greater than 500 micrograms/ml resulted in suppression of the TNF alpha activity released. This reduction in TNF alpha release was not mediated by a toxic effect of beta-glucan, as large concentrations of beta-glucan had no effect on macrophage viability. We further observed that the incubation of macrophages with large concentrations of beta-glucan (500 micrograms/ml) also inhibited the secretion of TNF alpha induced by bacterial LPS. Furthermore, interferon-gamma (IFN gamma), a potent activator of TNF alpha expression, failed to overcome the inhibition of TNF alpha caused by beta-glucan. These data suggest an immunomodulatory role for beta-glucan which may explain both the TNF alpha-stimulating and -inhibiting effects of fungal beta-glucans during infection.