Individual LPS responsiveness depends on the variation of toll-like receptor (TLR) expression level

Abstract

An individual's immune response is critical for host protection from many different pathogens, and the responsiveness can be assessed by the amount of cytokine production upon stimulating bacterial components such as lipopolysaccharide (LPS). The difference between individuals in their peripheral blood mononuclear cells (PBMC responsiveness to LPS, a Gram-negative endotoxin, was investigated from 27 healthy individuals. We observed a large variation in IFN gamma production among different individuals. The PBMC of the consistently three highest and three lowest IFN gamma producers were investigated. Since previous studies described that a single point mutation in the coding region of TLR2 and TLR4 is linked to the individual responsiveness to pathogenic bacterial infections, we first examined the known point mutations in the coding region of TLR2(Pro681His), TLR4(Pro714His) located in the cytoplasmic regions of the Toll-like domain as well as TLR4(Asp299Gly) located in the extracellular region. None of these mutations were associated with an individual's responsiveness to LPS, despite the presence of TLR4(Asp299Gly) mutation. Further investigation revealed that the variation of PBMC responsiveness to LPS among healthy individuals was due to constitutive expression levels of TLR4 and TLR2. This result is consistent with an aging-related low expression of Toll-like receptors in the mouse model of LPS responsiveness. The present study therefore suggests that the constitutive expression levels of TLR2 and TLR4 may contribute to the individual response to LPS.