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TLR4 gene dosage contributes to endotoxin‐induced acute respiratory inflammation
Author(s) -
Togbe Dieudonnée,
SchnyderCandrian Silvia,
Schnyder Bruno,
Couillin Isabelle,
Maillet Isabelle,
Bihl Franck,
Malo Danielle,
Ryffel Bernhard,
Quesniaux Valerie F. J.
Publication year - 2006
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0206099
Subject(s) - biology , inflammation , respiratory system , tlr4 , immunology , gene , pharmacology , genetics , anatomy
Toll‐like receptor (TLR)4 is critical for endotoxin recognition and cellular responses. Using Tlr4 transgenic mice, we investigated the influence of Tlr4 gene dosage on acute respiratory response to endotoxin. Transgenic mice expressing three, six, or 30 copies of Tlr4 , control, and Tlr4 ‐deficient mice received intranasal administration of lipopolysaccharide (LPS; 10 ug), and the airway response was analyzed by plethysmography, lung histology, cell recruitment, cytokine and chemokine secretion and protein leakage into the bronchoalveolar space. We demonstrate that overexpression of Tlr4 augmented a LPS‐induced bronchoconstrictive effect, as well as tumor necrosis factor and CXC chemokine ligand 1 (keratinocyte‐derived chemokine) production. Neutrophil recruitment, microvascular and alveolar epithelial injury with protein leak in the airways, and damage of the lung microarchitecture were Tlr4 gene dose‐dependently increased. Therefore, the TLR4 expression level determines the extent of acute pulmonary response to inhaled endotoxin, and TLR4 may thus be a valuable target for immunointervention in acute lung inflammation as a result of endotoxins.