The Toll-Like Receptor 4 Asp299g1y and Thr399ile Polymorphisms Influence the Late Inflammatory Response in Human Endotoxemia (Technical Briefs‪)‬

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 (5-7). This missense mutation (Asp299G1y) 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 Asp299G1y substitution in more than 95% of the Caucasian population (8).