Structural Requirements of Lipid A Responsible for the Functions: A Study with Chemically Synthesized Lipid A and Its Analogues1

Jy, Homma; Matsuura, Motohiro; Kanegasaki, Shiro; Kawakubo, Yasuaki; Kojima, Yasuhiko; Shibukawa, Nobuyuki; Kumazawa, Yoshio; Yamamoto, Akihiro; Tanamoto, Ken‐ichi; Yasuda, Tatsuji; Imoto, Masahiro; Yoshimura, Hidetoshi; Kusumoto, Shoichi; Shiba, Tetsuo

doi:10.1093/oxfordjournals.jbchem.a135294

Cited by 135 publications

(77 citation statements)

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“…Both of these lipid As, the Salmonella-type heptaacylated and E. coli-type hexaacylated forms, had been successfully synthesized chemically in the past (12)(13)(14), and their biological properties had been carefully tested by many investigators (15)(16)(17)(18)(19)(20). The Salmonella-type lipid A had been demonstrated to be very active in mice and rabbits and subsequently had been thought to be a typical lipid A (18 -20) along with that from E. coli.…”

Section: Discussionmentioning

confidence: 99%

“…Escherichia coli-and Salmonella-type lipid A have the most typical lipid A structures so far defined, and both have been synthesized chemically (12)(13)(14) and well characterized biologically by many investigators (15)(16)(17)(18)(19)(20). The chemical structure of these lipid As consists of a hexa-and heptaacylated diglucosamine bearing six and seven fatty acids, respectively, as shown in Fig.…”

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confidence: 99%

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Salmonella-Type Heptaacylated Lipid A Is Inactive and Acts as an Antagonist of Lipopolysaccharide Action on Human Line Cells

Tanamoto

Azumi

2000

The Journal of Immunology

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The stimulation of both THP-1 and U937 human-derived cells by Salmonella lipid A preparations from various strains, as assessed by TNF-α induction and NF-κB activation, was found to be very low (almost inactive) compared with Escherichia coli lipid A, but all of the lipid As exerted strong activity on mouse cells and on Limulus gelation activity. Experiments using chemically synthesized E. coli-type hexaacylated lipid A (506) and Salmonella-type heptaacylated lipid A (516) yielded clearer results. Both lipid A preparations strongly induced TNF-α release and activated NF-κB in mouse peritoneal macrophages and mouse macrophage-like cell line J774-1 and induced Limulus gelation activity, although the activity of the latter was slightly weaker than that of the former. However, 516 was completely inactive on both THP-1 and U937 cells in terms of both induction of TNF-α and NF-κB activation, whereas 506 displayed strong activity on both cells, the same as natural E. coli LPS. In contrast to the action of the lipid A preparations, all the Salmonella LPSs also exhibited full activity on human cells. However, the polysaccharide portion of the LPS neither exhibited TNF-α induction activity on the cells when administered alone or together with lipid A nor inhibited the activity of the LPS. These results suggest that the mechanism of activation by LPS or the recognition of lipid A structure by human and mouse cells may differ. In addition, both 516 and lipid A from Salmonella were found to antagonize the 506 and E. coli LPS action that induced TNF-α release and NF-κB activation in THP-1 cells.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Salmonella-Type Heptaacylated Lipid A Is Inactive and Acts as an Antagonist of Lipopolysaccharide Action on Human Line Cells

Tanamoto

Azumi

2000

The Journal of Immunology

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“…the preparations with the disaccharide backbone exhibit higher activity than those with the monosaccharide backbone, especially in toxicity. Both of the two phosphates in positions 1 and 4' play an important role in the manifestation of the full activity [3,4]. Fatty acids especially play an essential role in the activity.…”

Section: Introductionmentioning

confidence: 99%

Predominant role of the substituents on the hydroxyl groups of 3‐hydroxy fatty acids of non‐reducing glucosamine in lipid A for the endotoxic and antagonistic activity

Tanamoto

1994

FEBS Letters

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The synthetic disaccharide precursor of lipid A (406: identical to lipid IVA) was found to reduce its endotoxic activity in mice by an order of 105 or more, by replacing the hydroxyl groups with succinyl or acetyl residues. Both the succinylated and acetylated 406 were also found to antagonize the endotoxic mitogenicity on murine splenocytes. Previous studies demonstrated that the succinylated or acetylated synthetic complete lipid A preparations retained the whole endotoxic activity , Infect, Immunol. 62, 1705. The drastic contrast in all of these results suggests the importance of the substituents on the hydroxyl groups of 3-hydroxy fatty acids of non-reducing glucosamine of lipid A for the activity and for transformation to the antagonistic structure.

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“…Activation of the TLR4/MD-2 complex leads to a downstream signaling cascade and eventually to increased production of proinflammatory cytokines, such as interleukin-6 (IL-6) (reviewed in reference 39). The endotoxic activity of LPS is determined entirely by the composition of the lipid A moiety (23). Previous studies have shown that the phosphate groups as well as the number and length of the acyl chains are critical determinants of the endotoxic activity of lipid A (31,44,54).…”

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Expression of the Lipopolysaccharide-Modifying Enzymes PagP and PagL Modulates the Endotoxic Activity ofBordetella pertussis

Geurtsen¹,

Steeghs

Hamstra³

et al. 2006

Infect Immun

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Lipopolysaccharide (LPS) is one of the major constituents of the gram-negative bacterial cell envelope. Its endotoxic activity causes the relatively high reactogenicity of whole-cell vaccines. Several bacteria harbor LPS-modifying enzymes that modulate the endotoxic activity of the LPS. Here we evaluated whether two such enzymes, i.e., PagP and PagL, could be useful tools for the development of an improved and less reactogenic whole-cell pertussis vaccine. We showed that expression of PagP and PagL in Bordetella pertussis leads to increased and decreased endotoxic activity of the LPS, respectively. As expected, PagP activity also resulted in increased endotoxic activity of whole bacterial cells. However, more unexpectedly, this was also the case for PagL. This paradoxical result may be explained, in part, by an increased release of LPS, which we observed in the PagL-expressing cells.

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Structural Requirements of Lipid A Responsible for the Functions: A Study with Chemically Synthesized Lipid A and Its Analogues1

Cited by 135 publications

References 0 publications

Salmonella-Type Heptaacylated Lipid A Is Inactive and Acts as an Antagonist of Lipopolysaccharide Action on Human Line Cells

Salmonella-Type Heptaacylated Lipid A Is Inactive and Acts as an Antagonist of Lipopolysaccharide Action on Human Line Cells

Predominant role of the substituents on the hydroxyl groups of 3‐hydroxy fatty acids of non‐reducing glucosamine in lipid A for the endotoxic and antagonistic activity

Expression of the Lipopolysaccharide-Modifying Enzymes PagP and PagL Modulates the Endotoxic Activity ofBordetella pertussis

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