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Monomeric endotoxin:protein complexes are essential for TLR4-dependent cell activation
T L Gioannini1, A Teghanemt, DeS Zhang
1Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52241, USA. theresa-gioannini@uiowa.edu
Journal of Endotoxin Research
|June 14, 2005
Summary
Gram-negative bacterial endotoxin activates Toll-like receptor 4 (TLR4) via sequential protein interactions. Monomeric endotoxin:MD-2 complexes are the key agonists, with acylation level influencing potency.
Area of Science:
- Immunology
- Microbiology
- Biochemistry
Background:
- Potent cell activation by Gram-negative bacterial endotoxin relies on interactions with LBP, CD14, MD-2, and TLR4.
- LBP and CD14 extract endotoxin, forming monomeric endotoxin:CD14 complexes for MD-2 transfer.
Purpose of the Study:
- To elucidate the mechanism of endotoxin presentation and activation of TLR4.
- To investigate the role of endotoxin acylation in modulating TLR4 agonist potency.
Main Methods:
- Studied endotoxin-protein interactions involving LBP, CD14, MD-2, and TLR4.
- Utilized albumin-dependent and independent assays to analyze complex formation and cell activation.
- Compared the activity of differently acylated meningococcal endotoxin (LOS) forms.
Main Results:
- Monomeric endotoxin:MD-2 complexes are the primary TLR4 agonists, activating TLR4 at picomolar concentrations.
- Albumin facilitates endotoxin transfer to MD-2, forming the active complex.
- Under-acylated LOS:MD-2 complexes exhibit reduced TLR4 agonist potency compared to hexa-acylated forms.
Conclusions:
- The formation of monomeric endotoxin:MD-2 complexes is crucial for TLR4 activation.
- The degree of endotoxin acylation directly impacts the potency of TLR4 agonism.