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CD14 enhances cellular responses to endotoxin without imparting ligand-specific recognition
R L Delude1, R Savedra, H Zhao
1Evans Department of Clinical Research and Medicine, Boston University Medical Center Hospital, MA 02118, USA.
Summary
Lipid A analogs show species-specific activity, acting as agonists or antagonists depending on the species. This suggests a target distinct from CD14 is responsible for lipopolysaccharide (LPS) recognition and signaling.
Area of Science:
- Immunology
- Molecular Biology
Background:
- Lipopolysaccharide (LPS) binding to CD14 activates phagocytes, initiating septic shock.
- Lipid A analogs, lipid IVA and RSLA, exhibit species-specific LPS antagonism.
- Human phagocytes treat both as antagonists, while murine phagocytes respond differently to lipid IVA.
Purpose of the Study:
- To investigate if CD14 mediates the species-specific pharmacology of LPS antagonists.
- To identify the cellular target responsible for differential responses to lipid A analogs.
Main Methods:
- Transfection of human, mouse, and hamster cell lines with human or murine CD14 cDNA.
- Examination of cell line responses to lipid IVA and RSLA.
- Comparison of responses across species and CD14 source.
Main Results:
- Transfected cells mirrored the species-specific sensitivities of native macrophages, irrespective of CD14 source.
- Hamster cells (macrophages and fibroblasts) with either human or mouse CD14 acted as LPS mimetics.
- Human cells with either CD14 source acted as LPS antagonists.
Conclusions:
- The species-specific target of LPS antagonists is distinct from CD14.
- CD14 is necessary for LPS sensitivity but does not discriminate between lipid A variants.
- A novel lipid A recognition protein, functioning as a signaling receptor post-CD14 interaction, is hypothesized.