Inhibition of LPS-mediated cell activation in vitro and in vivo by gangliosides.
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.
Mond
J J
JJ
Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
Witherspoon
K
K
Yu
R K
RK
Perera
P Y
PY
Vogel
S N
SN
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005732:Gangliosides / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D019158:N-Acetylneuraminic Acid; D012794:Sialic Acids / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
D005732:Gangliosides; D008070:Lipopolysaccharides; D012794:Sialic Acids; D014409:Tumor Necrosis Factor-alpha; D019158:N-Acetylneuraminic Acid