The TLR4 +896 polymorphism is not associated with lipopolysaccharide hypo-responsiveness in leukocytes.
Toll-like receptor 4 (TLR-4) is required for detection of Gram negative bacterial infections by binding lipopolysaccharide (LPS) and for the initiation of inflammatory signaling. Recent studies have demonstrated that a nonsynonymous single-nucleotide polymorphism (Asp299Gly, A+896G) is associated with decreased endotoxin responsiveness and poor outcomes from sepsis. We show that human carriers of this polymorphism show no deficit in LPS induced peripheral blood mononuclear cell (PBMC) mitogen-activated protein kinase (MAPK) activity, no reduction in sensitivity to endotoxin, and variable differences in whole-blood inflammatory cytokine production. These results indicate that this mutation is not a primary determinant of human endotoxin sensitivity.
Imahara
S D
SD
Department of Surgery, University of Washington and Harborview Medical Center, Seattle, Washington 98104, USA. imaharas@u.washington.edu
Jelacic
S
S
Junker
C E
CE
O'Keefe
G E
GE
D019943:Amino Acid Substitution / Q000235:genetics* / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics* / Q000502:physiology; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D016207:Cytokines; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors