Inhibition of LPS-mediated cell activation in vitro and in vivo by gangliosides.

Abstract

Addition of purified GM1 gangliosides inhibited lipopolysaccharide (LPS)-stimulated proliferation of purified B cells by greater than 90%. Addition of gangliosides to B cells as late as 120 min after the addition of LPS still inhibited B-cell proliferation, suggesting that inhibition did not simply reflect direct binding of LPS to gangliosides. Gangliosides also inhibited proliferation of B cells stimulated by anti-Ig antibodies, albeit to a lesser degree than inhibition of the LPS-stimulated response. The finding that B-cell proliferation stimulated by the combination of PMA+ionomycin was also inhibited by gangliosides suggests that its inhibitory activity did not reflect interference with binding of the B-cell stimuli to membrane receptors. The inhibitory effect of gangliosides was not restricted to B cells, since LPS-induced TNF production by macrophages was also inhibited in vitro. The inhibitory activity of gangliosides was also seen in vivo, and mice injected with soluble gangliosides or implanted with slow-release pellets impregnated with gangliosides showed reduced TNF production in vivo in response to LPS. Mice that were implanted with these slow-release pellets were also protected from LPS-induced lethality. Thus, while only 10% of control mice survived injection with LPS+galactosamine, the experimental group showed a 64% survival. It is likely that this protective effect reflects the ability of gangliosides to suppress LPS-mediated TNF production. This model provides a basis for studying a regulatory role for gangliosides in B-cell activation in vitro and macrophage activation in vitro and in vivo. Furthermore, it suggests new approaches to suppress the toxic effects induced by LPS in vivo.