The Toll-Like Receptor 4 Asp299Gly and Thr399Ile Polymorphisms Influence the Late Inflammatory Response in Human Endotoxemia

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Toll-like receptor 4 (TLR4) is the principal receptor for bacterial endotoxin recognition, and functional variants in the gene confer endotoxin hyporesponsiveness in humans (1). Recognition of endotoxin leads to the activation of intracellular signaling pathways, up-regulating a wide array of inflammatory modulators, which contribute to early host-cell response(2)(3). Recently, a common polymorphism in TLR4 (4) that is associated with hyporesponsiveness to inhaled endotoxin in humans was identified(5)(6)(7). This missense mutation (Asp299Gly) in the fourth exon of the TLR4 gene alters the extracellular domain of this receptor. An additional missense polymorphism (Thr399Ile) in the extracellular domain of the TLR4 receptor co-segregates with the Asp299Gly substitution in more than 95% of the Caucasian population(8). Recent studies showed that genetic variants of TLR4 may contribute to differences in risk in vivo (9) and may modulate in vitro response to bacterial lipopolysaccharide (LPS)(8) related to inflammatory markers. On the basis of these studies, we hypothesized that genetic variants of TLR4 might also contribute to the large interindividual differences in inflammatory marker concentrations after LPS challenge. The aim of our study was to investigate the association between TLR4 polymorphisms (Asp299Gly and Thr399Ile) and values for inflammatory markers in human experimental endotoxemia. The study protocols were approved by the Ethics Committee of the Medical University Vienna, and all participants gave written informed consent before entering the study. Complete data and DNA samples were available for 74 healthy male volunteers. These volunteers participated in several clinical trials receiving placebo in addition to endotoxin, including recently published studies (10)(11) and several unpublished trials. All volunteers were 19–35 years of age with a body mass index between the 15th and 85th percentiles. The LPS model has been described in detail previously (11). All volunteers received …