TLR4 mutations are associated with endotoxin hyporesponsiveness in humans.
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 mice, underlies the variability in airway responsiveness to inhaled LPS in humans. 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.
Arbour
N C
NC
[1] Department of Medicine, Department of Veterans Affairs Medical Center, The University of Iowa, Iowa City, Iowa, USA.
Lorenz
E
E
Schutte
B C
BC
Zabner
J
J
Kline
J N
JN
Jones
M
M
Frees
K
K
Watt
J L
JL
Schwartz
D A
DA
D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D029721:Drosophila Proteins; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012130:Respiratory Hypersensitivity / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
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