Multistep regulation mechanisms for tolerance induction to lipopolysaccharide lethality in the tumor-necrosis-factor-alpha-mediated pathway. Application of non-toxic monosaccharide lipid A analogues for elucidation of mechanisms.
Lipid A is the active principle of lipopolysaccharide (LPS). Synthetic lipid A analogues with monosaccharide backbones, GLA-60, GLA-69 and GLA-58, which exhibit potent, weak and scarce agonistic activities of LPS, respectively, induced tolerance against LPS lethality in galactosamine-(GalN)-sensitized mice while none of them were pyrogenic in rabbits. The tolerance-inducing mechanisms were investigated focusing on the regulation of tumor-necrosis-factor-alpha(TNF-alpha)-mediated lethal pathway of LPS. Induction of serum TNF-alpha in LPS-challenged mice was suppressed by prior administration of these analogues as well as LPS. Prior treatment of murine macrophages with the substances suppressed LPS-stimulated TNF-alpha production in the culture supernatant and TNF-alpha mRNA expression in the cells as well. Lethal toxicity of TNF-alpha in GalN-sensitized mice was effectively suppressed by prior treatment with LPS, GLA-60 and GLA-69 but not by GLA-58. This protective effect was suggested to be mediated by endogenous TNF-alpha, which was induced by prior treatment with the effective substances, because either neutralization of endogenously induced TNF-alpha activity with an antibody or deletion of its induction by using LPS-resistant C3H/HeJ mice reduced the protective effect, and a detectable amount of TNF-alpha was produced by stimulating macrophages with the effective substances but not with GLA-58. These results indicated that multiple regulation steps (one is prior to and the others are following TNF-alpha production) are participating in the tolerance induction by LPS and some lipid A analogues and that GLA-58 is a characteristic compound which induces the tolerance by only blocking the step prior to TNF-alpha production.
Matsuura
M
M
Department of Microbiology, Jichi Medical School, Tochigi, Japan.
Kiso
M
M
Hasegawa
A
A
Nakano
M
M
D000818:Animals; D004361:Drug Tolerance; D005334:Fever / Q000139:chemically induced; D005688:Galactosamine / Q000494:pharmacology; D008050:Lipid A / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity*; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D012475:Salmonella; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*
D008050:Lipid A; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine