The functional variant (Asp299gly) of toll-like receptor 4 (TLR4) influences TLR4-mediated cytokine production in rheumatoid arthritis.
OBJECTIVE
To investigate functional consequences of the Toll-like receptor 4 (TLR4) variant (Asp299Gly) in rheumatoid arthritis (RA).


METHODS
Peripheral blood mononuclear cells from 28 patients with RA carrying or not carrying the TLR4 variant were incubated with lipopolysaccharide (LPS) and heat shock protein B8 (HSPB8). Concentrations of interleukin 6 (IL-6), tumor necrosis factor-alpha(TNF-alpha), and IL-10 were determined along with TLR4 and CD14 expression.


RESULTS
TLR4 expression was similar in patients carrying or not carrying the variant. In contrast, both LPS and HSPB8 resulted in significantly lower secretion of IL-6, TNF-alpha, and IL-10 in those who carried the variant, whereas the frequency of CD14+ cells was higher in these individuals.


CONCLUSIONS
TLR4 variant clearly reduces its potency to mediate signaling. Correction for CD14+ cells is necessary in comparable experiments.
Roelofs
Mieke F
MF
Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Wenink
Mark H
MH
Toonen
Erik J M
EJ
Coenen
Marieke J H
MJ
Joosten
Leo A B
LA
van den Berg
Wim B
WB
van Riel
Piet L C M
PL
Radstake
Timothy R D J
TR
D000368:Aged; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000235:genetics*; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000494:pharmacology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones; D020125:Mutation, Missense; D017346:Protein Serine-Threonine Kinases / Q000494:pharmacology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism
D016207:Cytokines; C413214:HSPB8 protein, human; D006360:Heat-Shock Proteins; D008070:Lipopolysaccharides; D018832:Molecular Chaperones; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D017346:Protein Serine-Threonine Kinases