Relationship of Structure and Biological Activity of Monosaccharide Lipid A Analogues to Induction of Nitric Oxide Production by Murine Macrophage RAW264.7 Cells

Funatogawa, Keiji; Matsuura, Motohiro; Nakano, Masayasu; Kiso, Makoto; Hasegawa, Akira

doi:10.1128/iai.66.12.5792-5798.1998

Cited by 29 publications

(22 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4) (9,20,23). The monosaccharide lipid A analogue GLA-58, which has been found to be an LPS antagonist in murine cells (6,27), also exhibited antagonistic activity in human cells (Fig. 5).…”

Section: Fig 4 Inhibitory Effect Of Synthetic Lipid a Analogues On mentioning

confidence: 94%

“…release. GLA-58 is a monosaccharide lipid A analogue which has been found to act as an LPS antagonist in murine cells (6,27). The activity of this analogue as an LPS antagonist or agonist in human U937 cells was examined.…”

Section: Antagonistic Effect Of Monosaccharide Lipid a Analogue Gla-5mentioning

confidence: 99%

“…The above-mentioned ratio is also important for activation of murine cells, since 506 exhibits the strongest activity in murine cells of the disaccharide analogues (33) and GLA-60 exhibits the strongest activity in murine cells of the monosaccharide analogues (6,11). However, a clear difference between the activation of murine cells and human cells by 406 was observed.…”

Section: Fig 4 Inhibitory Effect Of Synthetic Lipid a Analogues On mentioning

confidence: 99%

“…We have been studying the biological activities of monosaccharide-type lipid A analogues and have shown that these analogues are nonpyrogenic but that some of them preserve LPS-mimetic activities such as induction of cytokines from murine macrophages (6,21,28) and induction of resistance to microbial infections and tumors in animal models (13,14,25,31). In these monosaccharide lipid A analogues, acylation patterns as well as phosphorylation patterns were revealed to play an important role in the expression of biological activities, as was observed for disaccharide lipid A analogues (34).…”

mentioning

confidence: 99%

See 3 more Smart Citations

Activity of Monosaccharide Lipid A Analogues in Human Monocytic Cells as Agonists or Antagonists of Bacterial Lipopolysaccharide

1999

Self Cite

View full text Add to dashboard Cite

The lipid A portion of bacterial lipopolysaccharide (LPS) plays a central role in the production of endotoxic mediators. Different responses between human and murine macrophages to lipid A-like structures have been indicated. We investigated a series of structurally related monosaccharide lipid A analogues for their potency to activate human macrophage U937 cells and peripheral blood mononuclear cells for production of tumor necrosis factor-␣ and interleukin-6 compared with their potency to activate murine macrophage RAW264.7 cells. Two of the analogues were found to have sufficient potency to activate the human cells as well as the murine cells. These analogues comprise D-glucosamine, phosphoryl groups, and acyl groups of defined carbon chain lengths (C 14 and C 12 ) in a ratio of 1:1:3. This ratio of molecular constituents is proportional to that of the complete disaccharide structure of lipid A (2:2:6). Other analogues with two or four C 14 acyl groups and with three acyl groups but including a C 10 or a C 16 acyl group, which are active to murine cells, showed no LPS-agonistic activity, but did show LPS-antagonistic activity, to human cells. An LPS-antagonistic analogue in the murine cells also showed antagonistic activity in human cells. These results reveal that lipid A analogues recognized as being LPS agonists by human macrophages have common structural features in monosaccharide and disaccharide structures which are more strict than those required for recognition by murine macrophages and that broad lipid A-like structures are recognized as being LPS antagonists by human cells but are recognized by murine cells as being either LPS agonists or antagonists. by guest http://iai.asm.org/ Downloaded from FIG. 6. Structures of synthetic lipid A analogues in relation to their LPS-agonistic and -antagonistic actions in murine and human macrophages (M).

show abstract

Section: Fig 4 Inhibitory Effect Of Synthetic Lipid a Analogues On mentioning

confidence: 94%

Section: Antagonistic Effect Of Monosaccharide Lipid a Analogue Gla-5mentioning

confidence: 99%

Section: Fig 4 Inhibitory Effect Of Synthetic Lipid a Analogues On mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Activity of Monosaccharide Lipid A Analogues in Human Monocytic Cells as Agonists or Antagonists of Bacterial Lipopolysaccharide

1999

Self Cite

View full text Add to dashboard Cite

show abstract

“…Some synthetic monosaccharide lipid A analogues are known to activate both human and murine cells, while others activate only murine cells and function as an LPS antagonist to human cells 10,22 . In the present study, we attempted to determine which TLR is utilized by monosaccharide lipid A analogues for cellular signalling, to clarify the relationship between the chemical structures of lipid A and TLRs.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2003

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Modulation of CD14 and TLR4⋅MD‐2 Activities by a Synthetic Lipid A Mimetic

et al. 2013

View full text Add to dashboard Cite

Monosaccharide lipid A mimetics composed by a glucosamine core linked to two fatty acid chains and bearing one or two phosphates have been synthesized. While compounds 1 and 2, with one phosphate group, were practically inactive in inhibiting LPS-induced TLR4 signaling and cytokine production in HEK-blue™ cells and murine macrophages, compound 3 with two phosphates was found to be active in efficiently inhibiting TLR4 signal in both cell types. The direct interaction of molecule 3 with MD-2 co-receptor has been investigated by means of NMR and molecular modeling/docking analysis. This compound also interacts directly with CD14 receptor, stimulating its internalization by endocytosis. Experiments on macrophages show that the effect on CD14 reinforces the activity on MD-2.TLR4, because compound 3 activity is higher when CD14 is important for TLR4 signaling i,e, at low LPS concentration. The dual MD-2 and CD14 targeting, accompanied by good solubility in water and lack of toxicity, suggests the use of monosaccharide 3 as a lead compound to develop drugs directed against TLR4-related syndromes.

show abstract

Relationship of Structure and Biological Activity of Monosaccharide Lipid A Analogues to Induction of Nitric Oxide Production by Murine Macrophage RAW264.7 Cells

Cited by 29 publications

References 24 publications

Activity of Monosaccharide Lipid A Analogues in Human Monocytic Cells as Agonists or Antagonists of Bacterial Lipopolysaccharide

Activity of Monosaccharide Lipid A Analogues in Human Monocytic Cells as Agonists or Antagonists of Bacterial Lipopolysaccharide

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

Modulation of CD14 and TLR4⋅MD‐2 Activities by a Synthetic Lipid A Mimetic

Contact Info

Product

Resources

About