INHIBITION OF LPS-MEDIATED CELL ACTIVATION IN-VITRO AND IN-VIVO BY GANGLIOSIDES

Addition of purified GM1 gangliosides inhibited lipopolysaccharide (LP S)-stimulated proliferation of purified B cells by greater than 90%. A ddition of gangliosides to B cells as late as 120 min after the additi on of LPS still inhibited B-cell proliferation, suggesting that inhibi tion did not simply reflect direct binding of LPS to gangliosides. Gan gliosides also inhibited proliferation of B cells stimulated by anti-I g antibodies, albeit to a lesser degree than inhibition of the LPS-sti mulated 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 wit h binding of the B-cell stimuli to membrane receptors. The inhibitory effect of gangliosides was not restricted to B cells, since LPS-induce d TNF production by macrophages was also inhibited in vitro. The inhib itory activity of gangliosides was also seen in vivo, and mice injecte d with soluble gangliosides or implanted with slow-release pellets imp regnated with gangliosides showed reduced TNF production in vivo in re sponse to LPS. Mice that were implanted with these slow-release pellet s were also protected from LPS-induced lethality. Thus, while only 10% of control mice survived injection with LPS + galactosamine, the expe rimental group showed a 64% survival. It is likely that this protectiv e 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 ac tivation in vitro and in vivo. Furthermore, it suggests new approaches to suppress the toxic effects induced by LPS in vivo. (C) 1995 Wiley- Liss, Inc.