TLR4 mutations are associated with endotoxin hyporesponsiveness in humans

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

doi:10.1038/76048

Back

TLR4 mutations are associated with endotoxin hyporesponsiveness in humans

Journal article

Peer reviewed

TLR4 mutations are associated with endotoxin hyporesponsiveness in humans

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

Nature genetics, Vol.25(2), pp.187-191

06/2000

DOI: 10.1038/76048

PMID: 10835634

View Online

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 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.

Respiratory Mucosa - drug effects

Toll-Like Receptor 4

Forced Expiratory Volume - drug effects

Membrane Glycoproteins - metabolism

Humans

Lipopolysaccharides - administration & dosage

Membrane Glycoproteins - chemistry

Middle Aged

Molecular Sequence Data

Male

Mutation, Missense - genetics

Toll-Like Receptors

DNA Mutational Analysis

Base Sequence

Respiratory Hypersensitivity - physiopathology

Adult

Female

Receptors, Cell Surface - chemistry

Amino Acid Sequence

Drosophila Proteins

Respiratory Hypersensitivity - chemically induced

Cells, Cultured

Administration, Inhalation

Macrophages, Alveolar - physiology

Receptors, Cell Surface - metabolism

Membrane Glycoproteins - genetics

Respiratory Hypersensitivity - genetics

Signal Transduction - drug effects

Macrophages, Alveolar - drug effects

Adolescent

Alleles

Lipopolysaccharides - pharmacology

Respiratory Mucosa - physiology

Receptors, Cell Surface - genetics

Details

Title: Subtitle: TLR4 mutations are associated with endotoxin hyporesponsiveness in humans
Creators: Nancy C Arbour - Department of Medicine, Department of Veterans Affairs Medical Center, The University of Iowa, Iowa City, Iowa, USA
Eva Lorenz
Brian C Schutte
Joseph Zabner
Joel N Kline
Michael Jones
Kathy Frees
Janet L Watt
David A Schwartz
Resource Type: Journal article
Publication Details: Nature genetics, Vol.25(2), pp.187-191
DOI: 10.1038/76048
PMID: 10835634
NLM abbreviation: Nat Genet
ISSN: 1061-4036
eISSN: 1546-1718
Publisher: United States
Grant note: ES09607 / NIEHS NIH HHS ES06537 / NIEHS NIH HHS ES07498 / NIEHS NIH HHS
Language: English
Date published: 06/2000
Academic Unit: Statistics and Actuarial Science; Pulmonary, Critical Care, and Occupational Medicine; Occupational and Environmental Health; Biostatistics; Public Policy Center (Archive); Otolaryngology; Internal Medicine
Record Identifier: 9983985847802771

Metrics

19 Record Views

1667 Times Cited - Web of Science

See more details