Cell activation by monosaccharide lipid A analogues utilizing Toll-like receptor 4.
Lipid A is the bioactive centre of lipopolysaccharide (LPS), and its properties exhibit various endotoxic and biological effects toward host cells. We examined whether Toll-like receptors (TLRs) are mediated by the signals from various synthetic acylated derivatives of d-glucosamine monophosphate. All test synthetic monosaccharide lipid A analogues similar to acylated beta-(1-6)-d-glucosamine disaccharide bisphosphates, such as Escherichia coli-type lipid A (compound 506) and its precursor (compound 406), clearly induced nuclear factor (NF)-kappaB activation in Ba/F3 cells expressing murine TLR4 and its accessory protein MD-2 (Ba/mTLR4/mMD-2), but no induction was found in those expressing murine TLR2 (Ba/mTLR2). Compound 411, the non-reducing sugar moiety of compound 506, exhibited interleukin-8 (IL-8) and tumour necrosis factor-alpha (TNF-alpha)-producing activities in human peripheral blood mononuclear cells (PBMC), whereas compound 401, the reducing moiety of compounds 506 and 406, and Gifu lipid A-46 (GLA-46), the non-reducing moiety of compound 406, induced no production of IL-8 and TNF-alpha, which was similar to the findings for compound 406. Among the synthetic triacylated monosaccharide lipid A analogues, some compounds with three tetradecanoyl (C14) groups or that included a dodecanoyl (C12) group were more active toward murine and human cells than were other analogues with a decanoyl (C10) or hexadecanoyl (C16) group. Furthermore, IL-8 production in PBMC stimulated with the active monosaccharide lipid A analogues as well as compound 506 was clearly inhibited by the monoclonal antibody to human TLR4. These findings suggest that monosaccharide lipid A analogues similar to disaccharide lipid As are capable of activating both murine and human cells through TLR4.
Tamai
Riyoko
R
Department of Oral Microbiology, Asahi University School of Dentistry, Gifu, Japan.
Asai
Yasuyuki
Y
Hashimoto
Masahito
M
Fukase
Koichi
K
Kusumoto
Shoichi
S
Ishida
Hideharu
H
Kiso
Makoto
M
Ogawa
Tomohiko
T
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002460:Cell Line; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D008050:Lipid A / Q000031:analogs & derivatives* / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D016328:NF-kappa B / Q000276:immunology; D011956:Receptors, Cell Surface / Q000276:immunology*; D013329:Structure-Activity Relationship; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000911:Antibodies, Monoclonal; D016209:Interleukin-8; D008050:Lipid A; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha