TLR4 mutations are associated with endotoxin hyporesponsiveness in humans View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2000-06

AUTHORS

Nancy C. Arbour, Eva Lorenz, Brian C. Schutte, Joseph Zabner, Joel N. Kline, Michael Jones, Kathy Frees, Janet L. Watt, David A. Schwartz

ABSTRACT

There is much variability between individuals in the response to inhaled toxins, but it is not known why certain people develop disease when challenged with environmental agents and others remain healthy. To address this, we investigated whether TLR4 (encoding the toll-like receptor-4), which has been shown to affect lipopolysaccharide (LPS) responsiveness in mice1,2, underlies the variability in airway responsiveness to inhaled LPS in humans3. Here we show that common, co-segregating missense mutations (Asp299Gly and Thr399Ile) affecting the extracellular domain of the TLR4 receptor are associated with a blunted response to inhaled LPS in humans. Transfection of THP-1 cells demonstrates that the Asp299Gly mutation (but not the Thr399Ile mutation) interrupts TLR4-mediated LPS signalling. 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. More... »

PAGES

187-191

Journal

TITLE

Nature Genetics

ISSUE

2

VOLUME

25

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/76048

DOI

http://dx.doi.org/10.1038/76048

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1034294158

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/10835634


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