B-lymphocyte mitogenicity and adjuvanticity of an ornithine-containing lipid or a serine-containing lipid

Kawai, Yohko; Kamoshita, Katsuzo; Akagawa, Kiyoko S.

doi:10.1111/j.1574-6968.1988.tb02705.x-i1

Cited by 9 publications

(16 citation statements)

References 9 publications

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“…events by which flavolipin induces the production of inflammatory cytokines are suggested to be shared, at least in part, by that of LPS because flavolipin does not induce cytokine production by macrophages derived from LPShyporesponsive C3H/HeJ mice. 18 In this study, we show that the flavolipin signal is mediated by the TLR4/MD-2 complex. In addition, we show that the (R)-configuration of the lipid moiety in flavolipin is essential for induction of the signals mediated by the TLR4/MD-2 complex.…”

Section: Introductionmentioning

confidence: 58%

“…18 It has remained undetermined if TLR4 directly mediates flavolipin-induced signaling, and if MD-2, which associates with the extracellular portion of TLR4, is involved in the signaling.…”

Section: The Tlr4/md-2 Complex Mediates Signal Transduction Induced Bmentioning

confidence: 99%

“…11,17 Flavolipin has been shown to induce inflammatory immune responses, such as PGE 2 , IL-1b and TNF-a production by macrophages. 18 The cellular receptor and signaling molecules for flavolipin have not been characterized well, and the essential moiety of flavolipin for the induction of an immune response has not been determined yet. The signaling…”

Section: Introductionmentioning

confidence: 99%

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Molecular basis for lipopolysaccharide mimetic action of Taxol<SUP>™</SUP> and flavolipin

Kawasaki¹,

Gomi²,

Kawai³

et al. 2003

J. Endotoxin Res.

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We previously reported that Taxol, which mimics the action of LPS on murine macrophages, induces signals via mouse TLR4/MD-2, but not via human TLR4/MD-2. Here we investigated the molecular basis for this species-specific action of Taxol. Expression of mouse MD-2 conferred both LPS and Taxol responsiveness on HEK293 cells expressing mouse TLR4, whereas expression of human MD-2 conferred LPS responsiveness alone, suggesting that MD-2 is responsible for the species-specificity of Taxol responsiveness. Furthermore, mouse MD-2 mutants, in which Gln-22 was changed to other amino acids, showed dramatically reduced ability to confer Taxol responsiveness, although their ability to confer LPS responsiveness was not affected. These results indicated that Gln-22 of mouse MD-2 is essential for Taxol signaling, but not for LPS signaling. In this study, we also found that the TLR4/MD-2 complex, together with CD14, mediated signal transduction induced by flavolipin, an amino acid-containing lipid unique to Flavobacterium meningosepticum.

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Section: Introductionmentioning

confidence: 58%

“…18 It has remained undetermined if TLR4 directly mediates flavolipin-induced signaling, and if MD-2, which associates with the extracellular portion of TLR4, is involved in the signaling.…”

Section: The Tlr4/md-2 Complex Mediates Signal Transduction Induced Bmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular basis for lipopolysaccharide mimetic action of Taxol<SUP>™</SUP> and flavolipin

Kawasaki¹,

Gomi²,

Kawai³

et al. 2003

J. Endotoxin Res.

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“…OLs have been implicated in high-temperature tolerance in Burkholderia cepacia (Taylor et al, 1998). In Bordetella pertussis and Flavobacterium meningosepticum OLs are involved in hemagglutination and stimulation of macrophages (Kawai and Yano, 1983; Kawai and Akagawa, 1989; Kawai et al, 1999). In Rhodobacter capsulatus OL is critical for optimal yields of cytochrome c (Aygun-Sunar et al, 2006).…”

Section: Importance Of Membrane Lipids For a Tumefaciens Physiology mentioning

confidence: 99%

Membrane lipids in Agrobacterium tumefaciens: biosynthetic pathways and importance for pathogenesis

et al. 2014

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Many cellular processes critically depend on the membrane composition. In this review, we focus on the biosynthesis and physiological roles of membrane lipids in the plant pathogen Agrobacterium tumefaciens. The major components of A. tumefaciens membranes are the phospholipids (PLs), phosphatidylethanolamine (PE), phosphatidylglycerol, phosphatidylcholine (PC) and cardiolipin, and ornithine lipids (OLs). Under phosphate-limited conditions, the membrane composition shifts to phosphate-free lipids like glycolipids, OLs and a betaine lipid. Remarkably, PC and OLs have opposing effects on virulence of A. tumefaciens. OL-lacking A. tumefaciens mutants form tumors on the host plant earlier than the wild type suggesting a reduced host defense response in the absence of OLs. In contrast, A. tumefaciens is compromised in tumor formation in the absence of PC. In general, PC is a rare component of bacterial membranes but amount to ~22% of all PLs in A. tumefaciens. PC biosynthesis occurs via two pathways. The phospholipid N-methyltransferase PmtA methylates PE via the intermediates monomethyl-PE and dimethyl-PE to PC. In the second pathway, the membrane-integral enzyme PC synthase (Pcs) condenses choline with CDP-diacylglycerol to PC. Apart from the virulence defect, PC-deficient A. tumefaciens pmtA and pcs double mutants show reduced motility, enhanced biofilm formation and increased sensitivity towards detergent and thermal stress. In summary, there is cumulative evidence that the membrane lipid composition of A. tumefaciens is critical for agrobacterial physiology and tumor formation.

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“…We speculated that coupling a flexible N-acylated aglycon to the structurally more conserved non-reducing sugar of MPL component 2 would permit energetically favored close packing of the six fatty acyl chains present in compound 2 as well as facilitate the intercalation of the acyl residues into the hydrophobic pocket of the TLR4 accessory molecule MD-2. The known immunostimulating ability of naturally occurring N-(3-acyloxylacyl)amino acids such as flavolipin [58,59], which was recently shown to require MD-2 and TLR4 [60], made the evaluation of seryl -O-glycosides of particular interest. It was also anticipated that the seryl carboxyl group could serve as a stable bioisostere of the labile anomeric phosphate of lipid A.…”

Section: Monosaccharide Mimetics Of S Minnesota Lipid Amentioning

confidence: 99%

Synthetic TLR4-active Glycolipids as Vaccine Adjuvants and Stand-alone Immunotherapeutics

Johnson¹

2008

CTMC

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The design of vaccine adjuvants and stand-alone immunotherapeutics has historically been a mix of alchemy and accident partly because of the complex nature of the molecular mechanisms involved in immune system function. The recent discovery of pattern recognition receptors and toll-like receptors (TLRs) in particular on cells of the immune system has shown the important role that stimulation of these cell receptors by microbial products plays in both innate and adaptive immune responses. Considerable effort has been directed at developing pharmaceutically acceptable mimetics of many TLR-active natural products, including the main cell-surface component of Gram-negative bacteria: lipopolysaccharide (LPS). LPS and its active principle, lipid A, are potent stimulators of host defense systems via their interaction with TLR4. However, the profound pyrogenicity and lethal toxicity of LPS and lipid A have precluded their medicinal use. Structure/activity investigations on natural S. minnesota R595 lipid A and its derivatives have led to the development of a novel class of synthetic lipid A mimetics known as aminoalkyl glucosaminide phosphates (AGPs). This review discusses the evolution of the AGPs and related TLR4-active glycolipids with emphasis on structure/activity relationships in the AGP series and pre-clinical/clinical development of selected AGPs, including the potent vaccine adjuvant RC-529.

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B-lymphocyte mitogenicity and adjuvanticity of an ornithine-containing lipid or a serine-containing lipid

Cited by 9 publications

References 9 publications

Molecular basis for lipopolysaccharide mimetic action of Taxol<SUP>™</SUP> and flavolipin

Molecular basis for lipopolysaccharide mimetic action of Taxol<SUP>™</SUP> and flavolipin

Membrane lipids in Agrobacterium tumefaciens: biosynthetic pathways and importance for pathogenesis

Synthetic TLR4-active Glycolipids as Vaccine Adjuvants and Stand-alone Immunotherapeutics

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