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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Gioannini, Theresa L. Weiss, Jerrold P. Teghanemt, Athmane Dockstader, Wendie Ramaswamy, S. Zhang, Desheng Coussens, Nathan P. |
| Description | Author Affiliation: Gioannini TL ( Inflammation Program, Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. theresa.gioannini@uiowa.edu); |
| Abstract | Host proinflammatory responses to minute amounts of endotoxins derived from many Gram-negative bacteria require the interaction of lipopolysaccharide-binding protein (LBP), CD14, Toll-like receptor 4 (TLR4) and MD-2. Optimal sensitivity to endotoxin requires an ordered series of endotoxin-protein and protein-protein interactions. At substoichiometric concentrations, LBP facilitates delivery of endotoxin aggregates to soluble CD14 (sCD14) to form monomeric endotoxin-sCD14 complexes. Subsequent interactions of endotoxin-sCD14 with TLR4 and/or MD-2 have not been specifically defined. This study reports the purification of a stable, monomeric, bioactive endotoxin-MD-2 complex generated by treatment of endotoxin-sCD14 with recombinant MD-2. Efficient generation of this complex occurred at picomolar concentrations of endotoxin and nanogram per milliliter doses of MD-2 and required presentation of endotoxin to MD-2 as a monomeric endotoxin-CD14 complex. TLR4-dependent delivery of endotoxin to human embryonic kidney (HEK) cells and cell activation at picomolar concentrations of endotoxin occurred with the purified endotoxin-MD-2 complex, but not with purified endotoxin aggregates with or without LBP and/or sCD14. The presence of excess MD-2 inhibited delivery of endotoxin-MD-2 to HEK/TLR4 cells and cell activation. These findings demonstrate that TLR4-dependent activation of host cells by picomolar concentrations of endotoxin occurs by sequential interaction and transfer of endotoxin to LBP, CD14, and MD-2 and simultaneous engagement of endotoxin and TLR4 by MD-2. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 12 |
| Volume Number | 101 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2004-03-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Antigens, Surface Isolation & Purification Endotoxins Animals Antigens, CD14 Metabolism Immune System Immunology Insects Lymphocyte Antigen 96 Membrane Glycoproteins Receptors, Cell Surface Toll-Like Receptor 4 Toll-Like Receptors Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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