Cutting Edge: Preferentially the <i>R</i>-Stereoisomer of the Mycoplasmal Lipopeptide Macrophage-Activating Lipopeptide-2 Activates Immune Cells Through a Toll-Like Receptor 2- and MyD88-Dependent Signaling Pathway

Takeuchi, Osamu; Kaufmann, Andreas M.; Grote, Karsten; Kawai, Taro; Hoshino, Katsuaki; Morr, Michael; Mühlradt, Peter F.; Akira, Shizuo

doi:10.4049/jimmunol.164.2.554

Cited by 541 publications

(428 citation statements)

References 30 publications

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“…By contrast, LPS responses of TLR2 knockout animals appear normal (6). Rather, TLR2 responds to synthetic lipoproteins in a stereospecific fashion (46), and lipoprotein effects on cell lines can be blocked by mAbs to TLR2 (47). TLR2 responses to several other bacterial preparations of less defined composition have also been described (35, 48 -50).…”

Section: Discussionmentioning

confidence: 99%

Evidence for an Accessory Protein Function for Toll-Like Receptor 1 in Anti-Bacterial Responses

Wyllie

Kiss-Tóth

Visintin

et al. 2000

The Journal of Immunology

245

151

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Members of the Toll-like receptor (TLR) family are components of the mammalian anti-microbial response, signaling with a domain closely related to that of IL-1 receptors. In this report the expression and function of TLR1, a TLR of unknown function, are examined. TLR1 is expressed by monocytes, as demonstrated using a novel mAb. Monocytes also express TLR2. TLR1 transfection of HeLa cells, which express neither TLR1 nor TLR2, was not sufficient to confer responsiveness to several microbial extracts. However, cotransfection of TLR1 and TLR2 resulted in enhanced signaling by HeLa cells to soluble factors released from Neisseria meningitidis relative to the response with either TLR alone. This phenomenon was also seen with high concentrations of some preparations of LPS. The N. meningitidis factors recognized by TLR1/TLR2 were not released by N. meningitidis mutant in the LpxA gene. Although LpxA is required for LPS biosynthesis, because cooperation between TLR1 and TLR2 was not seen with all LPS preparations, the microbial component(s) TLR1/2 recognizes is likely to be a complex of LPS and other molecules or a compound metabolically and chemically related to LPS. The functional IL-1R consists of a heterodimer; this report suggests a similar mechanism for TLR1 and TLR2, for certain agonists. These data further suggest that mammalian responsiveness to some bacterial products may be mediated by combinations of TLRs, suggesting a mechanism for diversifying the repertoire of Toll-mediated responses.

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Section: Discussionmentioning

confidence: 99%

Evidence for an Accessory Protein Function for Toll-Like Receptor 1 in Anti-Bacterial Responses

Wyllie

Kiss-Tóth

Visintin

et al. 2000

The Journal of Immunology

245

151

View full text Add to dashboard Cite

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“…g/ml gentamycin (Sigma). After lysis of erythrocytes using ACK buffer (155 mM NH 4 Cl, 10 mM KHCO 3 , 1 mM EDTA, pH 7.3), 1×10 8 cells were plated on 100-mm tissue culture dishes and incubated at 37°C in the presence of 5% CO 2 for 2 h. Non-adherent cells were harvested and replated in 6-or 24-well-plates at 1×10 6 cells/ml in medium supplemented with 5×10 4 U/ml recombinant murine granulocyte-macrophage colony-stimulating factor (rmGM-CSF, BD PharMingen) and further incubated. On day 3 and thereafter every second day, a third of the supernatant was replaced with fresh medium.…”

Section: Preparation Of Bone Marrow-derived DCmentioning

confidence: 99%

“…Like the natural MALP-2, a synthetic derivative (S-[2,3-bispalmitoyloxypropyl] cysteinyl-GNNDESNISFKEK]) is a powerful inducer of chemokines and cytokines [2,3]. This seems to be mediated, at least in part, by the binding of MALP-2 to the Toll-like receptor 2 and 6, which in turn results in a MyD88-dependent activation of NF-‹ B [4,5]. In contrast to other bacterial lipoproteins, MALP-2 is a small molecule (molecular mass approximately 2 kDa) with two ester-bond long-chain fatty acids and a free NH 2 -terminus.…”

Section: Introductionmentioning

confidence: 99%

The Toll‐like receptor ligand MALP‐2 stimulates dendritic cell maturation and modulates proteasome composition and activity

et al. 2004

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A 2-kDa synthetic derivative of the macrophage-activating lipopeptide (MALP-2) from Mycoplasma fermentans is a potent inducer of monocytes/macrophages and improves the immunogenicity of antigens co-administered by systemic and mucosal routes. Dendritic cells (DC) are the most potent antigen-presenting cells, which are able to prime naive T cells in vivo. To elucidate the underlying mechanisms of MALP-2 adjuvanticity, we analyzed its activity on bone marrow-derived murine DC. In vitro stimulation of immature murine DC with MALP-2 resulted in the induction of maturation with up-regulated expression of MHC class II, costimulatory (CD80, CD86) and adhesion (CD40, CD54) molecules. MALP-2 also enhances the secretion of cytokines (IL-1 § , IL-6 and IL-12), and increases DC stimulatory activity on naive and antigen-specific T cells. Further studies demonstrated that MALP-2 treatment of DC results in a dose-dependent shift from the protein pattern of proteasomes to immunoproteasomes (up-regulation of LMP2, LMP7 and MECL1), which correlates with an increased proteolytic activity. Thus, the adjuvanticity of MALP-2 can be mediated, at least in part, by the stimulation of DC maturation, which in turn leads to an improved antigen presentation. Therefore, MALP-2 is a promising molecule for the development of immune therapeutic or prophylactic interventions.

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“…5,6 TLR2, in concert with TLR1 or TLR6, recognizes various bacterial components, including peptidoglycan, lipopeptide and lipoprotein of Gram-positive bacteria and mycoplasma lipopeptide. [8][9][10][11][12] In particular, TLR1/ 2 and TLR2/6 discriminate triacyl lipopeptide and diacyl lipopeptide, respectively. TLR3 recognizes double-stranded RNA (dsRNA) that is produced from many viruses during replication.…”

Section: Introductionmentioning

confidence: 99%

TLR signaling

2006

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The Toll-like receptor (TLR) family plays an instructive role in innate immune responses against microbial pathogens, as well as the subsequent induction of adaptive immune responses. TLRs recognize specific molecular patterns found in a broad range of microbial pathogens such as bacteria and viruses, triggering inflammatory and antiviral responses and dendritic cell maturation, which result in the eradication of invading pathogens. Individual TLRs interact with different combinations of adapter proteins and activate various transcription factors such as nuclear factor (NF)-jB, activating protein-1 and interferon regulatory factors, driving a specific immune response. This review outlines the recent advances in our understanding of TLR-signaling pathways and their roles in immune responses. Further, we also discuss a new concept of TLR-independent mechanisms for recognition of microbial pathogens.

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Cutting Edge: Preferentially the R-Stereoisomer of the Mycoplasmal Lipopeptide Macrophage-Activating Lipopeptide-2 Activates Immune Cells Through a Toll-Like Receptor 2- and MyD88-Dependent Signaling Pathway

Cited by 541 publications

References 30 publications

Evidence for an Accessory Protein Function for Toll-Like Receptor 1 in Anti-Bacterial Responses

Evidence for an Accessory Protein Function for Toll-Like Receptor 1 in Anti-Bacterial Responses

The Toll‐like receptor ligand MALP‐2 stimulates dendritic cell maturation and modulates proteasome composition and activity

TLR signaling

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