Inhaled endotoxin, a risk for airway disease in some people

Despite the tremendous inter-individual variability in the response to inha led toxins, we simply do not understand why certain people develop disease when challenged with environmental agents and others remain healthy. To add ress this concern, we investigated whether the toll-4 (TLR4) gene, that has been shown to affect lipopolysaccharide (LPS) responsiveness in mice, unde rlies the variability in airway responsiveness to inhaled LPS in humans. He re we show that common, co-segregating missense mutations (Asp299Gly and Th r399Ile) in the extracellular domain of the TLR4 receptor are associated wi th a significantly blunted response to inhaled LPS in 83 humans. Transfecti on of THP-1 cells demonstrates that the Asp299Gly mutation (but not the Thr 399Ile mutation) interrupts TLR4-mediated LPS signaling. Moreover, the wild type allele of TLR4 rescues the LPS hyporesponsive phenotype in either pri mary airway epithelial cells or alveolar macrophages obtained from individu als with the TLR4 mutations. Our findings provide the first genetic evidenc e that common mutations in TLR4 are associated with differences in LPS resp onsiveness in humans, and demonstrate that gene sequence changes can alter the ability of the host to respond to environmental stress. (C) 2001 Elsevi er Science B.V. All rights reserved.