Differential expression of Toll‐like receptor (TLR)‐2 and TLR‐4 on monocytes in human sepsis
Toll‐like receptors (TLRs) are a recently described family of immune receptors involved in the recognition of pathogen‐associated molecular patterns (PAMPs). The central role of TLR‐2 and TLR‐4 in microbial responses suggests they may be implicated in the pathogenesis of human sepsis. We hypothesized that the incidence and outcome of sepsis would be influenced by the expression of TLR‐2 and TLR‐4 on monocytes. We have examined the expression of TLR‐2 and TLR‐4 mRNA and protein and their response to pro‐ and anti‐inflammatory agents on monocytes from subjects in the intensive therapy unit (ITU) with and without Gram‐negative, Gram‐positive or polymicrobial sepsis. We compared these data to ITU and healthy control subjects. TLR‐2 mRNA was significantly up‐regulated on monocytes from subjects with both Gram‐positive and Gram‐negative sepsis. Similarly, we detected increased levels of TLR‐2 protein on the surface of monocytes from sepsis subjects relative to ITU controls. TLR‐4 mRNA was increased in Gram‐positive subjects; however, there was no corresponding increase in TLR‐4 protein. Although TLR‐4 mRNA expression in healthy control monocytes could be modulated in vitro by culture with lipopolysaccharide or interleukin‐10, this was not observed in monocytes obtained from sepsis and ITU control subjects, suggesting that septic and ITU control milieus may alter the immunoregulation of TLR‐4 mRNA expression on monocytes. TLR‐2 mRNA was not modulated in culture by any stimulus in any group. We suggest that expression and regulatory response of monocyte TLR‐2, and to a lesser extent TLR‐4 may be abnormal in human sepsis.