International Immunology Advance Access originally published online on June 7, 2004
International Immunology 2004 16(7):961-969; doi:10.1093/intimm/dxh097
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
International Immunology, Vol. 16, No. 7, pp. 961-969,
July 2004
© 2004 Japanese Society for Immunology
Lipid A antagonist, lipid IVa, is distinct from lipid A in interaction with Toll-like receptor 4 (TLR4)-MD-2 and ligand-induced TLR4 oligomerization
1 Division of Infectious Genetics, Institute of Medical Science, University of Tokyo, Tokyo, Japan 2 Department of Medical Technology and Science, Graduate School of Medicine and 3 Department of Chemistry, Graduate School of Science, Osaka University, Osaka, Japan 4 CREST, Japan Science and Technology Corporation, Tokyo, Japan
Correspondence to: K. Miyake; Email: kmiyake{at}ims.u-tokyo.ac.jp
Transmitting editor: K. Inaba
Toll-like receptor 4 (TLR4) and MD-2 recognizes lipid A, the active moiety of microbial lipopolysaccharide (LPS). Little is known about mechanisms for LPS recognition by TLR4–MD-2. Here we show ligand-induced TLR4 oligomerization, homotypic interaction of TLR4, which directly leads to TLR4 signaling. Since TLR4 oligomerization normally occurred in the absence of the cytoplasmic portion of TLR4, TLR4 oligomerization works upstream of TLR4 signaling. Lipid IVa, a lipid A precursor, is agonistic on mouse TLR4–MD-2 but turns antagonistic on chimeric mouse TLR4–human MD-2, demonstrating that the antagonistic activity of lipid IVa is determined by human MD-2. Binding studies with radioactive lipid A and lipid IVa revealed that lipid IVa is similar to lipid A in dose-dependent and saturable binding to mouse TLR4–human MD-2. Lipid IVa, however, did not induce TLR4 oligomerization, and inhibited lipid A-dependent oligomerization of mouse TLR4–human MD-2. Thus, lipid IVa binds mouse TLR4–human MD-2 but does not trigger TLR4 oligomerization. Binding study further revealed that the antagonistic activity of lipid IVa correlates with augmented maximal binding to mouse TLR4–human MD-2, which was 
2-fold higher than lipid A. Taken together, lipid A antagonist lipid IVa is distinct from lipid A in binding to TLR4–MD-2 and in subsequent triggering of TLR4 oligomerization. Given that the antagonistic activity of lipid IVa is determined by MD-2, MD-2 has an important role in a link between ligand interaction and TLR4 oligomerization.
Keywords: TLR4, MD-2, LPS, antagonist, oligomerization
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  K. M. Rodgers, M. R. Hutchinson, A. Northcutt, S. F. Maier, L. R. Watkins, and D. S. Barth The cortical innate immune response increases local neuronal excitability leading to seizures Brain, June 30, 2009; (2009) awp177v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. A. J. O'Neill, C. E. Bryant, and S. L. Doyle Therapeutic Targeting of Toll-Like Receptors for Infectious and Inflammatory Diseases and Cancer Pharmacol. Rev., June 1, 2009; 61(2): 177 - 197. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Resman, J. Vasl, A. Oblak, P. Pristovsek, T. L. Gioannini, J. P. Weiss, and R. Jerala Essential Roles of Hydrophobic Residues in Both MD-2 and Toll-like Receptor 4 in Activation by Endotoxin J. Biol. Chem., May 29, 2009; 284(22): 15052 - 15060. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kiyokawa, S. Akashi-Takamura, T. Shibata, F. Matsumoto, C. Nishitani, Y. Kuroki, Y. Seto, and K. Miyake A single base mutation in the PRAT4A gene reveals differential interaction of PRAT4A with Toll-like receptors Int. Immunol., November 1, 2008; 20(11): 1407 - 1415. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Jain, A. Halle, K. A. Halmen, E. Lien, M. Charrel-Dennis, S. Ram, D. T. Golenbock, and A. Visintin Phagocytosis and intracellular killing of MD-2 opsonized Gram-negative bacteria depend on TLR4 signaling Blood, May 1, 2008; 111(9): 4637 - 4645. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Teghanemt, F. Re, P. Prohinar, R. Widstrom, T. L. Gioannini, and J. P. Weiss Novel Roles in Human MD-2 of Phenylalanines 121 and 126 and Tyrosine 131 in Activation of Toll-like Receptor 4 by Endotoxin J. Biol. Chem., January 18, 2008; 283(3): 1257 - 1266. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Rallabhandi, A. Awomoyi, K. E. Thomas, A. Phalipon, Y. Fujimoto, K. Fukase, S. Kusumoto, N. Qureshi, M. B. Sztein, and S. N. Vogel Differential Activation of Human TLR4 by Escherichia coli and Shigella flexneri 2a Lipopolysaccharide: Combined Effects of Lipid A Acylation State and TLR4 Polymorphisms on Signaling J. Immunol., January 15, 2008; 180(2): 1139 - 1147. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Gradisar, M. M. Keber, P. Pristovsek, and R. Jerala MD-2 as the target of curcumin in the inhibition of response to LPS J. Leukoc. Biol., October 1, 2007; 82(4): 968 - 974. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. L. Gioannini, A. Teghanemt, D. Zhang, P. Prohinar, E. N. Levis, R. S. Munford, and J. P. Weiss Endotoxin-binding Proteins Modulate the Susceptibility of Bacterial Endotoxin to Deacylation by Acyloxyacyl Hydrolase J. Biol. Chem., March 16, 2007; 282(11): 7877 - 7884. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Prohinar, F. Re, R. Widstrom, D. Zhang, A. Teghanemt, J. P. Weiss, and T. L. Gioannini Specific High Affinity Interactions of Monomeric Endotoxin{middle dot}Protein Complexes with Toll-like Receptor 4 Ectodomain J. Biol. Chem., January 12, 2007; 282(2): 1010 - 1017. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Hajjar, M. D. Harvey, S. A. Shaffer, D. R. Goodlett, A. Sjostedt, H. Edebro, M. Forsman, M. Bystrom, M. Pelletier, C. B. Wilson, et al. Lack of In Vitro and In Vivo Recognition of Francisella tularensis Subspecies Lipopolysaccharide by Toll-Like Receptors Infect. Immun., December 1, 2006; 74(12): 6730 - 6738. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Visintin, K. A. Halmen, N. Khan, B. G. Monks, D. T. Golenbock, and E. Lien MD-2 expression is not required for cell surface targeting of Toll-like receptor 4 (TLR4) J. Leukoc. Biol., December 1, 2006; 80(6): 1584 - 1592. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Mitsuzawa, C. Nishitani, N. Hyakushima, T. Shimizu, H. Sano, N. Matsushima, K. Fukase, and Y. Kuroki Recombinant Soluble Forms of Extracellular TLR4 Domain and MD-2 Inhibit Lipopolysaccharide Binding on Cell Surface and Dampen Lipopolysaccharide-Induced Pulmonary Inflammation in Mice J. Immunol., December 1, 2006; 177(11): 8133 - 8139. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Mancek-Keber and R. Jerala Structural similarity between the hydrophobic fluorescent probe and lipid A as a ligand of MD-2 FASEB J, September 1, 2006; 20(11): 1836 - 1842. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Miyake Invited review: Roles for accessory molecules in microbial recognition by Toll-like receptors Innate Immunity, August 1, 2006; 12(4): 195 - 204. [Abstract] [PDF]
|
|
|
|
|
|
M. Kobayashi, S.-i. Saitoh, N. Tanimura, K. Takahashi, K. Kawasaki, M. Nishijima, Y. Fujimoto, K. Fukase, S. Akashi-Takamura, and K. Miyake Regulatory Roles for MD-2 and TLR4 in Ligand-Induced Receptor Clustering J. Immunol., May 15, 2006; 176(10): 6211 - 6218. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. I Duenas, M. Aceves, A. Orduna, R. Diaz, M. Sanchez Crespo, and C. Garcia-Rodriguez Francisella tularensis LPS induces the production of cytokines in human monocytes and signals via Toll-like receptor 4 with much lower potency than E. coli LPS Int. Immunol., May 1, 2006; 18(5): 785 - 795. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Akashi-Takamura, T. Furuta, K. Takahashi, N. Tanimura, Y. Kusumoto, T. Kobayashi, S.-i. Saitoh, Y. Adachi, T. Doi, and K. Miyake Agonistic Antibody to TLR4/MD-2 Protects Mice from Acute Lethal Hepatitis Induced by TNF-{alpha} J. Immunol., April 1, 2006; 176(7): 4244 - 4251. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-H. Lee, K.-K. Kim, I.-C. Rhyu, S. Koh, D.-S. Lee, and B.-K. Choi Phenol/water extract of Treponema socranskii subsp. socranskii as an antagonist of Toll-like receptor 4 signalling Microbiology, February 1, 2006; 152(2): 535 - 546. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Fujimoto, Y. Adachi, M. Akamatsu, Y. Fukase, M. Kataoka, Y. Suda, K. Fukase, and S. Kusumoto Synthesis of lipid A and its analogues for investigation of the structural basis for their bioactivity Innate Immunity, December 1, 2005; 11(6): 341 - 347. [Abstract] [PDF]
|
|
|
|
|
|
A. Visintin, K. A. Halmen, E. Latz, B. G. Monks, and D. T. Golenbock Pharmacological Inhibition of Endotoxin Responses Is Achieved by Targeting the TLR4 Coreceptor, MD-2 J. Immunol., November 15, 2005; 175(10): 6465 - 6472. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Coats, T.-T. T. Pham, B. W. Bainbridge, R. A. Reife, and R. P. Darveau MD-2 Mediates the Ability of Tetra-Acylated and Penta-Acylated Lipopolysaccharides to Antagonize Escherichia coli Lipopolysaccharide at the TLR4 Signaling Complex J. Immunol., October 1, 2005; 175(7): 4490 - 4498. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Teghanemt, D. Zhang, E. N. Levis, J. P. Weiss, and T. L. Gioannini Molecular Basis of Reduced Potency of Underacylated Endotoxins J. Immunol., October 1, 2005; 175(7): 4669 - 4676. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D.R. Dixon and R.P. Darveau Lipopolysaccharide Heterogeneity: Innate Host Responses to Bacterial Modification of Lipid A Structure Journal of Dental Research, July 1, 2005; 84(7): 584 - 595. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Nagaoka, K. Takahara, K. Tanaka, H. Yoshida, R. M. Steinman, S.-i. Saitoh, S. Akashi-Takamura, K. Miyake, Y. S. Kang, C. G. Park, et al. Association of SIGNR1 with TLR4-MD-2 enhances signal transduction by recognition of LPS in gram-negative bacteria Int. Immunol., July 1, 2005; 17(7): 827 - 836. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Zughaier, S. M. Zimmer, A. Datta, R. W. Carlson, and D. S. Stephens Differential Induction of the Toll-Like Receptor 4-MyD88-Dependent and -Independent Signaling Pathways by Endotoxins Infect. Immun., May 1, 2005; 73(5): 2940 - 2950. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Takeda and S. Akira Toll-like receptors in innate immunity Int. Immunol., January 1, 2005; 17(1): 1 - 14. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Wang, M. J. Karbarz, S. C. McGrath, R. J. Cotter, and C. R. H. Raetz MsbA Transporter-dependent Lipid A 1-Dephosphorylation on the Periplasmic Surface of the Inner Membrane: TOPOGRAPHY OF FRANCISELLA NOVICIDA LpxE EXPRESSED IN ESCHERICHIA COLI J. Biol. Chem., November 19, 2004; 279(47): 49470 - 49478. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-i. Saitoh, S. Akashi, T. Yamada, N. Tanimura, F. Matsumoto, K. Fukase, S. Kusumoto, A. Kosugi, and K. Miyake Ligand-dependent Toll-like receptor 4 (TLR4)-oligomerization is directly linked with TLR4-signaling Innate Immunity, August 1, 2004; 10(4): 257 - 260. [Abstract] [PDF]
|
|