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*Substance via MeSH
The Journal of Immunology, 2000, 164: 554-557.
Copyright © 2000 by The American Association of Immunologists

CUTTING EDGE

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 Pathway1

Osamu Takeuchi*,{dagger}, Andreas Kaufmann{ddagger}, Karsten Grote§, Taro Kawai*,{dagger}, Katsuaki Hoshino*,{dagger}, Michael Morr§, Peter F. Mühlradt2,§ and Shizuo Akira2,3,*,{dagger}

* Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan; {dagger} Core Research for Evolutional Science and Technology of Japan Science and Technology Corporation, Osaka, Japan; {ddagger} Institute of Immunology, Philipps University, Marburg, Germany; and § Immunobiology Research Group, Gesellschaft für Biotechnologische Forschung, Braunschweig, Germany

Mycoplasmas and their membranes are potent activators of macrophages, the active principle being lipoproteins and lipopeptides. Two stereoisomers of the mycoplasmal lipopeptide macrophage-activating lipopeptide-2 (MALP-2) differing in the configuration of the lipid moiety were synthesized and compared in their macrophage-activating potential, the R-MALP being >100 times more active than the S-MALP in stimulating the release of cytokines, chemokines, and NO. To assess the role of the Toll-like receptor (TLR) family in mycoplasmal lipopeptide signaling, the MALP-2-mediated responses were analyzed using macrophages from wild-type, TLR2-, TLR4-, and MyD88-deficient mice. TLR2- and MyD88-deficient cells showed severely impaired cytokine productions in response to R- and S-MALP. The MALP-induced activation of intracellular signaling molecules was fully dependent on both TLR2 and MyD88. There was a strong preference for the R-MALP in the recognition by its functional receptor, TLR2.




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 J. Immunol.Home page
M. A. Campos, M. Closel, E. P. Valente, J. E. Cardoso, S. Akira, J. I. Alvarez-Leite, C. Ropert, and R. T. Gazzinelli
Impaired Production of Proinflammatory Cytokines and Host Resistance to Acute Infection with Trypanosoma cruzi in Mice Lacking Functional Myeloid Differentiation Factor 88
J. Immunol., February 1, 2004; 172(3): 1711 - 1718.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
S. Akira
Toll-like Receptor Signaling
J. Biol. Chem., October 3, 2003; 278(40): 38105 - 38108.
[Full Text] [PDF]

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 J. Biol. Chem.Home page
K. Saito, T. Yajima, H. Nishimura, K. Aiba, R. Ishimitsu, T. Matsuguchi, T. Fushimi, Y. Ohshima, Y. Tsukamoto, and Y. Yoshikai
Soluble Branched {beta}-(1,4)Glucans from Acetobacter Species Show Strong Activities to Induce Interleukin-12 in Vitro and Inhibit T-helper 2 Cellular Response with Immunoglobulin E Production in Vivo
J. Biol. Chem., October 3, 2003; 278(40): 38571 - 38578.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
M. Fujita, T. Into, M. Yasuda, T. Okusawa, S. Hamahira, Y. Kuroki, A. Eto, T. Nisizawa, M. Morita, and K.-i. Shibata
Involvement of Leucine Residues at Positions 107, 112, and 115 in a Leucine-Rich Repeat Motif of Human Toll-Like Receptor 2 in the Recognition of Diacylated Lipoproteins and Lipopeptides and Staphylococcus aureus Peptidoglycans
J. Immunol., October 1, 2003; 171(7): 3675 - 3683.
[Abstract] [Full Text] [PDF]

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 BloodHome page
F. Hayashi, T. K. Means, and A. D. Luster
Toll-like receptors stimulate human neutrophil function
Blood, October 1, 2003; 102(7): 2660 - 2669.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
J. Y. Lee, J. Ye, Z. Gao, H. S. Youn, W. H. Lee, L. Zhao, N. Sizemore, and D. H. Hwang
Reciprocal Modulation of Toll-like Receptor-4 Signaling Pathways Involving MyD88 and Phosphatidylinositol 3-Kinase/AKT by Saturated and Polyunsaturated Fatty Acids
J. Biol. Chem., September 26, 2003; 278(39): 37041 - 37051.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
M. Matsumoto, K. Funami, M. Tanabe, H. Oshiumi, M. Shingai, Y. Seto, A. Yamamoto, and T. Seya
Subcellular Localization of Toll-Like Receptor 3 in Human Dendritic Cells
J. Immunol., September 15, 2003; 171(6): 3154 - 3162.
[Abstract] [Full Text] [PDF]

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 Infect. Immun.Home page
K. A. Marr, S. Arunmozhi Balajee, T. R. Hawn, A. Ozinsky, U. Pham, S. Akira, A. Aderem, and W. Conrad Liles
Differential Role of MyD88 in Macrophage-Mediated Responses to Opportunistic Fungal Pathogens
Infect. Immun., September 1, 2003; 71(9): 5280 - 5286.
[Abstract] [Full Text] [PDF]

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 Infect. Immun.Home page
U. Deiters, M. Gumenscheimer, C. Galanos, and P. F. Muhlradt
Toll-Like Receptor 2- and 6-Mediated Stimulation by Macrophage-Activating Lipopeptide 2 Induces Lipopolysaccharide (LPS) Cross Tolerance in Mice, Which Results in Protection from Tumor Necrosis Factor Alpha but in Only Partial Protection from Lethal LPS Doses
Infect. Immun., August 1, 2003; 71(8): 4456 - 4462.
[Abstract] [Full Text] [PDF]

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 Clin. Microbiol. Rev.Home page
E. S. Van Amersfoort, T. J. C. Van Berkel, and J. Kuiper
Receptors, Mediators, and Mechanisms Involved in Bacterial Sepsis and Septic Shock
Clin. Microbiol. Rev., July 1, 2003; 16(3): 379 - 414.
[Abstract] [Full Text] [PDF]

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 Am. J. Respir. Cell Mol. Bio.Home page
G. Fenhalls, G. R. Squires, L. Stevens-Muller, J. Bezuidenhout, G. Amphlett, K. Duncan, and P. T. Lukey
Associations between Toll-Like Receptors and Interleukin-4 in the Lungs of Patients with Tuberculosis
Am. J. Respir. Cell Mol. Biol., July 1, 2003; 29(1): 28 - 38.
[Abstract] [Full Text] [PDF]

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 Infect. Immun.Home page
M. Muroi, T. Ohnishi, S. Azumi-Mayuzumi, and K.-i. Tanamoto
Lipopolysaccharide-Mimetic Activities of a Toll-Like Receptor 2-Stimulatory Substance(s) in Enterobacterial Lipopolysaccharide Preparations
Infect. Immun., June 1, 2003; 71(6): 3221 - 3226.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
Z. Jiang, M. Zamanian-Daryoush, H. Nie, A. M. Silva, B. R. G. Williams, and X. Li
Poly(dI{middle dot}dC)-induced Toll-like Receptor 3 (TLR3)-mediated Activation of NFkappa B and MAP Kinase Is through an Interleukin-1 Receptor-associated Kinase (IRAK)-independent Pathway Employing the Signaling Components TLR3-TRAF6-TAK1-TAB2-PKR
J. Biol. Chem., May 2, 2003; 278(19): 16713 - 16719.
[Abstract] [Full Text] [PDF]

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 Am. J. Respir. Cell Mol. Bio.Home page
J. L. Curtis and A. Punturieri
Enhancing Antitumor Immunity Perioperatively: A Matter of Timing, Cooperation, and Specificity
Am. J. Respir. Cell Mol. Biol., May 1, 2003; 28(5): 541 - 545.
[Full Text] [PDF]

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 Am. J. Respir. Cell Mol. Bio.Home page
K. Shingu, C. Kruschinski, A. Luhrmann, K. Grote, T. Tschernig, S. von Horsten, and R. Pabst
Intratracheal Macrophage-Activating Lipopeptide-2 Reduces Metastasis in the Rat Lung
Am. J. Respir. Cell Mol. Biol., March 1, 2003; 28(3): 316 - 321.
[Abstract] [Full Text] [PDF]

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 JEMHome page
J.-Y. Choe, B. Crain, S. R. Wu, and M. Corr
Interleukin 1 Receptor Dependence of Serum Transferred Arthritis Can be Circumvented by Toll-like Receptor 4 Signaling
J. Exp. Med., February 17, 2003; 197(4): 537 - 542.
[Abstract] [Full Text] [PDF]

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 JEMHome page
M. T. Harte, I. R. Haga, G. Maloney, P. Gray, P. C. Reading, N. W. Bartlett, G. L. Smith, A. Bowie, and L. A.J. O'Neill
The Poxvirus Protein A52R Targets Toll-like Receptor Signaling Complexes to Suppress Host Defense
J. Exp. Med., February 3, 2003; 197(3): 343 - 351.
[Abstract] [Full Text] [PDF]

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 J. Pharmacol. Exp. Ther.Home page
T. Morichika, H. K. Takahashi, H. Iwagaki, T. Yoshino, R. Tamura, M. Yokoyama, S. Mori, T. Akagi, M. Nishibori, and N. Tanaka
Histamine Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor-{alpha} Production in an Intercellular Adhesion Molecule-1- and B7.1-Dependent Manner
J. Pharmacol. Exp. Ther., February 1, 2003; 304(2): 624 - 633.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
M. Yamamoto, S. Sato, K. Mori, K. Hoshino, O. Takeuchi, K. Takeda, and S. Akira
Cutting Edge: A Novel Toll/IL-1 Receptor Domain-Containing Adapter That Preferentially Activates the IFN-{beta} Promoter in the Toll-Like Receptor Signaling
J. Immunol., December 15, 2002; 169(12): 6668 - 6672.
[Abstract] [Full Text] [PDF]

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 Innate ImmunityHome page
K. Takeda, O. Takeuchi, and S. Akira
Recognition of lipopeptides by Toll-like receptors
Innate Immunity, December 1, 2002; 8(6): 459 - 463.
[Abstract] [PDF]

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 Infect. Immun.Home page
T. Liu, T. Matsuguchi, N. Tsuboi, T. Yajima, and Y. Yoshikai
Differences in Expression of Toll-Like Receptors and Their Reactivities in Dendritic Cells in BALB/c and C57BL/6 Mice
Infect. Immun., December 1, 2002; 70(12): 6638 - 6645.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
D. Schilling, K. Thomas, K. Nixdorff, S. N. Vogel, and M. J. Fenton
Toll-Like Receptor 4 and Toll-IL-1 Receptor Domain-Containing Adapter Protein (TIRAP)/Myeloid Differentiation Protein 88 Adapter-Like (Mal) Contribute to Maximal IL-6 Expression in Macrophages
J. Immunol., November 15, 2002; 169(10): 5874 - 5880.
[Abstract] [Full Text] [PDF]

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 Int ImmunolHome page
T. Ogawa, Y. Asai, M. Hashimoto, O. Takeuchi, T. Kurita, Y. Yoshikai, K. Miyake, and S. Akira
Cell activation by Porphyromonas gingivalis lipid A molecule through Toll-like receptor 4- and myeloid differentiation factor 88-dependent signaling pathway
Int. Immunol., November 1, 2002; 14(11): 1325 - 1332.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
A. E. Medvedev, A. Lentschat, L. M. Wahl, D. T. Golenbock, and S. N. Vogel
Dysregulation of LPS-Induced Toll-Like Receptor 4-MyD88 Complex Formation and IL-1 Receptor-Associated Kinase 1 Activation in Endotoxin-Tolerant Cells
J. Immunol., November 1, 2002; 169(9): 5209 - 5216.
[Abstract] [Full Text] [PDF]

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 JEMHome page
E. Kopp and R. Medzhitov
A Plague on Host Defense
J. Exp. Med., October 21, 2002; 196(8): 1009 - 1012.
[Full Text] [PDF]

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 Innate ImmunityHome page
H. Takada, S. Yokoyama, and Shuhua Yang
Mini-review: Enhancement of endotoxin activity by muramyldipeptide
Innate Immunity, October 1, 2002; 8(5): 337 - 342.
[Abstract] [PDF]

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 Int ImmunolHome page
K. Hoshino, T. Kaisho, T. Iwabe, O. Takeuchi, and S. Akira
Differential involvement of IFN-{beta} in Toll-like receptor-stimulated dendritic cell activation
Int. Immunol., October 1, 2002; 14(10): 1225 - 1231.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
P. Henneke, O. Takeuchi, R. Malley, E. Lien, R. R. Ingalls, M. W. Freeman, T. Mayadas, V. Nizet, S. Akira, D. L. Kasper, et al.
Cellular Activation, Phagocytosis, and Bactericidal Activity Against Group B Streptococcus Involve Parallel Myeloid Differentiation Factor 88-Dependent and Independent Signaling Pathways
J. Immunol., October 1, 2002; 169(7): 3970 - 3977.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
J. H. Wang, M. Doyle, B. J. Manning, Q. Di Wu, S. Blankson, and H. P. Redmond
Induction of Bacterial Lipoprotein Tolerance Is Associated with Suppression of Toll-like Receptor 2 Expression
J. Biol. Chem., September 20, 2002; 277(39): 36068 - 36075.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
T. H. Flo, L. Ryan, E. Latz, O. Takeuchi, B. G. Monks, E. Lien, O. Halaas, S. Akira, G. Skjak-Brak, D. T. Golenbock, et al.
Involvement of Toll-like Receptor (TLR) 2 and TLR4 in Cell Activation by Mannuronic Acid Polymers
J. Biol. Chem., September 13, 2002; 277(38): 35489 - 35495.
[Abstract] [Full Text] [PDF]

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 Infect. Immun.Home page
S. A. Leigh and K. S. Wise
Identification and Functional Mapping of the Mycoplasma fermentans P29 Adhesin
Infect. Immun., September 1, 2002; 70(9): 4925 - 4935.
[Abstract] [Full Text] [PDF]

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 Infect. Immun.Home page
T. Into, M. Fujita, T. Okusawa, A. Hasebe, M. Morita, and K.-I. Shibata
Synergic Effects of Mycoplasmal Lipopeptides and Extracellular ATP on Activation of Macrophages
Infect. Immun., July 1, 2002; 70(7): 3586 - 3591.
[Abstract] [Full Text] [PDF]

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 Infect. Immun.Home page
A. Luhrmann, U. Deiters, J. Skokowa, M. Hanke, J. E. Gessner, P. F. Muhlradt, R. Pabst, and T. Tschernig
In Vivo Effects of a Synthetic 2-Kilodalton Macrophage-Activating Lipopeptide of Mycoplasma fermentans after Pulmonary Application
Infect. Immun., July 1, 2002; 70(7): 3785 - 3792.
[Abstract] [Full Text] [PDF]


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