Antagonistic lipopolysaccharides block E-coli lipopolysaccharide function at human TLR4 via interaction with the human MD-2 lipopolysaccharide binding site

被引:58
作者
Coats, Stephen R. [1 ]
Do, Christopher T.
Karimi-Naser, Lisa M.
Braham, Pamela H.
Darveau, Richard P.
机构
[1] Univ Washington, Sch Dent, Dept Periodont, Seattle, WA 98195 USA
[2] Univ Washington, Sch Dent, Dept Oral Biol, Seattle, WA 98195 USA
关键词
D O I
10.1111/j.1462-5822.2006.00859.x
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Lipopolysaccharides containing underacylated lipid A structures exhibit reduced abilities to activate the human (h) Toll-like receptor 4 (TLR4) signalling pathway and function as potent antagonists against lipopolysaccharides bearing canonical lipid A structures. Expression of underacylated lipopolysaccharides has emerged as a novel mechanism utilized by microbial pathogens to modulate host innate immune responses. Notably, antagonistic lipopolysaccharides are prime therapeutic candidates for combating Gram negative bacterial sepsis. Penta-acylated msbB and tetra-acylated Porphyromonas gingivalis lipopolysaccharides functionally antagonize hexa-acylated Escherichia coli lipopolysaccharide-dependent activation of hTLR4 through the coreceptor, hMD-2. Here, the molecular mechanism by which these antagonistic lipopolysaccharides act at hMD-2 is examined. We present evidence that both msbB and P. gingivalis lipopolysaccharides are capable of direct binding to hMD-2. These antagonistic lipopolysaccharides can utilize at least two distinct mechanisms to block E. coli lipopolysaccharide-dependent activation of hTLR4. The main mechanism consists of direct competition between the antagonistic lipopolysaccharides and E. coli lipopolysaccharide for the same binding site on hMD-2, while the secondary mechanism involves the ability of antagonistic lipopolysaccharide-hMD-2 complexes to inhibit E. coli lipopolysaccharide-hMD-2 complexes function at hTLR4. It is also shown that both hTLR4 and hMD-2 contribute to the species-specific recognition of msbB and P. gingivalis lipopolysaccharides as antagonists at the hTLR4 complex.
引用
收藏
页码:1191 / 1202
页数:12
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共 59 条
[21]  
GOLENBOCK DT, 1991, J BIOL CHEM, V266, P19490
[22]   Structural model of MD-2 and functional role of its basic amino acid clusters involved in cellular lipopolysaccharide recognition [J].
Gruber, A ;
Mancek, M ;
Wagner, H ;
Kirschning, CJ ;
Jerala, R .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (27) :28475-28482
[23]   Human Toll-like receptor 4 recognizes host-specific LPS modifications [J].
Hajjar, AM ;
Ernst, RK ;
Tsai, JH ;
Wilson, CB ;
Miller, SI .
NATURE IMMUNOLOGY, 2002, 3 (04) :354-359
[24]   Cutting edge: Functional interactions between toll-like receptor (TLR) 2 and TLR1 or TLR6 in response to phenol-soluble modulin [J].
Hajjar, AM ;
O'Mahony, DS ;
Ozinsky, A ;
Underhill, DM ;
Aderem, A ;
Klebanoff, SJ ;
Wilson, CB .
JOURNAL OF IMMUNOLOGY, 2001, 166 (01) :15-19
[25]  
Hoshino K, 1999, J IMMUNOL, V162, P3749
[26]   The molecular pathogenesis of endotoxic shock and organ failure [J].
Karima, R ;
Matsumoto, S ;
Higashi, H ;
Matsushima, K .
MOLECULAR MEDICINE TODAY, 1999, 5 (03) :123-132
[27]   Modification of the structure and activity of lipid A in Yersinia pestis lipopolysaccharide by growth temperature [J].
Kawahara, K ;
Tsukano, H ;
Watanabe, H ;
Lindner, B ;
Matsuura, M .
INFECTION AND IMMUNITY, 2002, 70 (08) :4092-4098
[28]   An msbB homologue carried in plasmid pO157 encodes an acyltransferase involved in lipid a biosynthesis in Escherichia coli O157:H7 [J].
Kim, SH ;
Jia, WJ ;
Bishop, RE ;
Gyles, C .
INFECTION AND IMMUNITY, 2004, 72 (02) :1174-1180
[29]   Regulatory roles for MD-2 and TLR4 in ligand-induced receptor clustering [J].
Kobayashi, Makiko ;
Saitoh, Shin-ichiroh ;
Tanimura, Natsuko ;
Takahashi, Koichiro ;
Kawasaki, Kiyoshi ;
Nishijima, Masahiro ;
Fujimoto, Yukari ;
Fukase, Koichi ;
Akashi-Takamura, Sachiko ;
Miyake, Kensuke .
JOURNAL OF IMMUNOLOGY, 2006, 176 (10) :6211-6218
[30]   A cyanobacterial LPS antagonist prevents endotoxin shock and blocks sustained TLR4 stimulation required for cytokine expression [J].
Macagno, Annalisa ;
Molteni, Monica ;
Rinaldi, Andrea ;
Bertoni, Francesco ;
Lanzavecchia, Antonio ;
Rossetti, Carlo ;
Sallusto, Federica .
JOURNAL OF EXPERIMENTAL MEDICINE, 2006, 203 (06) :1481-1492