Cell activation by monosaccharide lipid A analogues utilizing Toll-like receptor 4.

Abstract

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.

• Authors: Riyoko Tamai, Yasuyuki Asai, Masahito Hashimoto, Koichi Fukase, Shoichi Kusumoto, Hideharu Ishida, Makoto Kiso, Tomohiko Ogawa
• Journal: Immunology (Immunology) Vol. 110 Issue 1 Pg. 66-72 (Sep 2003) ISSN: 0019-2805 [Print] England
• PMID: 12941142 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Interleukin-8
• Lipid A
• Membrane Glycoproteins
• NF-kappa B
• Receptors, Cell Surface
• TLR2 protein, human
• TLR4 protein, human
• Toll-Like Receptor 2
• Toll-Like Receptor 4
• Toll-Like Receptors
• Tumor Necrosis Factor-alpha

Topics

• Animals
• Antibodies, Monoclonal (immunology)
• Cell Line
• Dose-Response Relationship, Immunologic
• Humans
• Interleukin-8 (biosynthesis)
• Lipid A (analogs & derivatives, immunology)
• Lymphocyte Activation (immunology)
• Membrane Glycoproteins (immunology)
• Mice
• NF-kappa B (immunology)
• Receptors, Cell Surface (immunology)
• Structure-Activity Relationship
• Toll-Like Receptor 2
• Toll-Like Receptor 4
• Toll-Like Receptors
• Tumor Necrosis Factor-alpha (biosynthesis)