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.
Armstrong
L
L
Lung Research Group, University of Bristol Division of Medicine, Southmead Hospital, Bristol, UK. lynne.armstrong@bris.ac.uk
Medford
A R L
AR
Hunter
K J
KJ
Uppington
K M
KM
Millar
A B
AB
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis* / Q000235:genetics; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface / Q000032:analysis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018805:Sepsis / Q000378:metabolism*; D018709:Statistics, Nonparametric; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors