The role of TLR4 in endotoxin responsiveness in humans.
Despite the tremendous inter-individual variability in the response to inhaled toxins, we simply do not understand why certain people develop disease when challenged with environmental agents and others remain healthy. To address this concern, we investigated whether the Toll-4 (TLR4) gene, that has been shown to affect lipopolysaccharide (LPS) responsiveness in mice, underlies the variability in airway responsiveness to inhaled LPS in humans. Here we show that common, co-segregating missense mutations (Asp299Gly and Thr399Ile) in the extracellular domain of the TLR4 receptor are associated with a significantly blunted response to inhaled LPS in 83 humans. Transfection of THP-1 cells demonstrates that the Asp299Gly mutation (but not the Thr399Ile mutation) interrupts TLR4-mediated LPS signaling. Moreover, the wild-type allele of TLR4 rescues the LPS hyporesponsive phenotype in either primary airway epithelial cells or alveolar macrophages obtained from individuals with the TLR4 mutations. Our findings provide the first genetic evidence that common mutations in TLR4 are associated with differences in LPS responsiveness in humans, and demonstrate that gene sequence changes can alter the ability of the host to respond to environmental stress.
Schwartz
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Pulmonary and Critical Care Division, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA. david.schwartz@duke.edu
D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000235:genetics*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D029721:Drosophila Proteins; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D020125:Mutation, Missense; D011956:Receptors, Cell Surface / Q000235:genetics*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014132:Trachea / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D029721:Drosophila Proteins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors