Identification of<i>S</i>-(2,3-Dihydroxypropyl)cystein in a Macrophage-Activating Lipopeptide from<i>Mycoplasma fermentans</i>

Mühlradt, Peter F.; Meyer, Holger; Jansen, Rolf

doi:10.1021/bi9602831

Cited by 55 publications

(64 citation statements)

References 46 publications

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“…The Pam 3 Cys motif of lipoproteins is abundant among different bacteria and has been described for Enterobacteriaceae (20), spirochetes (19,21), mycobacteria (23), and mycoplasms (24). In contrast, the Pam 2 Cys motif exhibiting two fatty acids has only been shown to be present in mycoplasms (25).…”

Section: Discussionmentioning

confidence: 99%

“…The Pam 3 Cys moiety was also reported to be present in cytokine-inducing lipoproteins of Mycobacterium and Mycoplasma spp. (23,24); thus, it can be regarded as a highly conserved molecular motif among different classes of bacteria. In Mycoplasma fermentans, the presence of a macrophage stimulating lipopeptide, termed 2-kDa macrophage-activating lipopeptide (MALP-2), was observed, being stimulatory active at picomolar concentrations (25).…”

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confidence: 99%

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Lipopolysaccharide Binding Protein Binds to Triacylated and Diacylated Lipopeptides and Mediates Innate Immune Responses

Schröder

Heine

Alexander

et al. 2004

The Journal of Immunology

146

118

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LPS binding protein (LBP) is an acute-phase protein synthesized predominantly in the liver of the mammalian host. It was first described to bind LPS of Gram-negative bacteria and transfer it via a CD14-enhanced mechanism to a receptor complex including TLR-4 and MD-2, initiating a signal transduction cascade leading to the release of proinflammatory cytokines. In recent studies, we found that LBP also mediates cytokine induction caused by compounds derived from Gram-positive bacteria, including lipoteichoic acid and peptidoglycan fragments. Lipoproteins and lipopeptides have repeatedly been shown to act as potent cytokine inducers, interacting with TLR-2, in synergy with TLR-1 or -6. In this study, we show that these compounds also interact with LBP and CD14. We used triacylated lipopeptides, corresponding to lipoproteins of Borrelia burgdorferi, mycobacteria, and Escherichia coli, as well as diacylated lipopeptides, corresponding to, e.g., 2-kDa macrophage activating lipopeptide of Mycoplasma spp. Activation of Chinese hamster ovary cells transfected with TLR-2 by both lipopeptides was enhanced by cotransfection of CD14. Responsiveness of human mononuclear cells to these compounds was greatly enhanced in the presence of human LBP. Binding of lipopeptides to LBP as well as competitive inhibition of this interaction by LPS was demonstrated in a microplate assay. Furthermore, we were able to show that LBP transfers lipopeptides to CD14 on human monocytes using FACS analysis. These results support that LBP is a pattern recognition receptor transferring a variety of bacterial ligands including the two major types of lipopeptides to CD14 present in different receptor complexes.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Lipopolysaccharide Binding Protein Binds to Triacylated and Diacylated Lipopeptides and Mediates Innate Immune Responses

Schröder

Heine

Alexander

et al. 2004

The Journal of Immunology

146

118

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“…4) was subsequently isolated and structurally characterized, 74 leading to the identification of S- (2,3-dihydroxypropyl)cysteine as the structural core of MALP-2. 84 Recent structure-activity relationships have sought to examine the stereochemistry, acylation pattern, and the contributions of the peptide unit. [85][86][87][88] In contradistinction to Gram-negative LPS which is recognized by TLR4, 21,32-37 the lipopeptides signal via TLR2.…”

Section: Tlr4 Agonists-lipopolysaccharide Monophosphoryl Lipid a Andmentioning

confidence: 99%

Potential adjuvantic properties of innate immune stimuli

et al. 2009

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Just as the prescient comment by Gaston Ramon was relegated to the last footnote of his 1926 paper, 1 so has research on the mechanisms of action of adjuvants, until recently, languished as parenthetical annotations and addenda in the archives of immunology and vaccine development. Ramon defined immunological adjuvants as "substances used in combination with a specific antigen that produced a more robust immune response than the antigen alone." Interestingly enough, he was referring to his empirical findings that the addition of bread crumbs, tapioca, saponin and 'starch oil' to antigenic preparations greatly enhanced antibody responses to diphtheria or tetanus. 2 A year later, the adjuvanticity of aluminum salts (primarily phosphate and hydroxide) was discovered by Glenny and coworkers. 3 In the 83 years that have elapsed, the repertoire of investigational adjuvants has grown to encompass a very wide range of materials, 4 but aluminum salt-based mineral salts (generically, and incorrectly, termed "alum") have remained the only adjuvants currently approved by the FDA. Aluminum salts have enjoyed a good safety record, but they are weak adjuvants for antibody induction and induce a T helper-2 (T H 2)-skewed, rather than a T helper-1 (T H 1) response. 5,6 Furthermore, not only are aluminum salts ineffective at inducing cytotoxic T lymphocyte (CTL) or mucosal IgA antibody responses, but also have a propensity to induce IgE responses, which have been associated with allergic reactions in some subjects. 5,6 Very recent reports implicate the Nalp3 inflammasome, a component of the innate immune response, as the effector limb of alum-associated adjuvanticity. [7][8][9] In 1962, Dresser observed that injection of purified soluble proteins not only failed to stimulate an immune response, but tolerized animals unless a bacterial extract was admixed with the protein immunogen. 10 This led him to redefine adjuvanticity as "a property of a substance which can act as a physiological switch, directing at least some immunologically competent cells to respond by making antibody rather than by becoming immunologically paralyzed by the antigen," 11 confirming Johnson's earlier observations that lipopolysaccharide (LPS) from Gram-negative bacteria exerted potent adjuvant properties, 12 and perhaps paved the way for the subsequent discovery of the wide range of microorganism-derived adjuvants. 13 TLRs are pattern recognition receptors present on diverse cell types that recognize specific molecular patterns present in molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). 14,15 There are 10 TLRs in the human genome;

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“…Since the initial description of a high molecular weight molecule derived from Mycoplasma fermentans, which in combination with IFN-␥ was able to induce the production of NO by murine macrophages [7], attempts were made to isolate and characterize the active principle, which was finally shown to be a lipopeptide [9,10]. Its structure was elucidated and it constitutes one of the most potent macrophage stimulators [11] together with a lipopeptide recently isolated from M. hyorhinis membranes [12].…”

Section: Introductionmentioning

confidence: 99%

Mycoplasma arginini enhances cytotoxicity of thioglycollate-elicited murine macrophages toward YAC-1 tumor cells through production of NO

Ribeiro‐Dias

Russo

Barbuto

et al. 1999

Journal of Leukocyte Biology

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Bacterial products stimulate macrophage tumoricidal activity through release of tumor necrosis factor (TNF) and nitric oxide (NO). We show here that thioglycollate-elicited macrophages acquire cytotoxic activity when cocultured with Mycoplasma arginini-infected YAC-1 tumor cells and release TNF and NO. Fixed mycoplasmainfected cells, supernatants from infected-cell cultures, or purified heat-killed mycoplasma obtained from cell-free cultures were all able to induce TNF and NO production. Thus, the mycoplasma per se and not a product of infected cells induce the release of these molecules. Addition of prostaglandin E 2 (PGE 2 ) to the cocultures, which reduced TNF release, or antibodies to TNF, did not affect macrophage cytotoxicity nor NO release. Inhibition of NO production by L-NAME or aminoguanidine reduced the cytotoxicity, and treatment with a NO donor was toxic to YAC-1 cells. These results indicate that M. arginini activates thioglycollateelicited murine macrophages for NO and TNF release increasing their cytotoxic activity toward YAC-1 cells and that this activity is dependent on NO but not TNF release. J. Leukoc. Biol. 65: 808-814; 1999.

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Identification ofS-(2,3-Dihydroxypropyl)cystein in a Macrophage-Activating Lipopeptide fromMycoplasma fermentans

Cited by 55 publications

References 46 publications

Lipopolysaccharide Binding Protein Binds to Triacylated and Diacylated Lipopeptides and Mediates Innate Immune Responses

Lipopolysaccharide Binding Protein Binds to Triacylated and Diacylated Lipopeptides and Mediates Innate Immune Responses

Potential adjuvantic properties of innate immune stimuli

Mycoplasma arginini enhances cytotoxicity of thioglycollate-elicited murine macrophages toward YAC-1 tumor cells through production of NO

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