Functional consequences of the Asp299Gly Toll-like receptor-4 polymorphism.
Toll-like receptor-4 (TLR4) is a pattern-recognition receptor not only for exogenous ligands such as lipopolysaccharide (LPS) of Gram-negative bacteria, but also for endogenous ligands such as fibronectin, heat shock proteins and hyaluronan oligosaccharides. The Asp299Gly allele of the TLR4 gene has been associated with increased risk for severe infections, but reduced progression of atherosclerosis. We have investigated the consequences of the presence of Asp299Gly polymorphism after stimulation of mononuclear cells with lipopolysaccharide (LPS), the non-LPS TLR4 microbial stimuli Aspergillus fumigatus and Cryptococcus neoformans, and the endogenous TLR4 ligand heat shock protein 60. No differences in either production of the proinflammatory cytokine TNF or the antiinflammatory cytokine interleukin-10 were observed between volunteers with the wild-type allele, volunteers heterozygous for the Asp299Gly allele and one volunteer homozygous for the TLR4 variant. In conclusion, the presence of the Asp299Gly TLR4 polymorphism does not result in defective pro and antiinflammatory cytokine production after stimulation with either exogenous (LPS and non-LPS) or endogenous TLR4 ligands, and alternative explanations are likely to be responsible for the epidemiological data showing associations with inflammatory conditions. In addition, this is the first study to demonstrate that even homozygosity for the Asp299Gly mutation does not confer hyporesponsiveness to stimulation with TLR4 stimuli.
van der Graaf
Chantal
C
Department of Medicine, University Medical Center St. Radboud Nijmegen, The Netherlands.
Kullberg
Bart Jan
BJ
Joosten
Leo
L
Verver-Jansen
Trees
T
Jacobs
Liesbeth
L
Van der Meer
Jos W M
JW
Netea
Mihai G
MG
D000328:Adult; D001224:Aspartic Acid / Q000235:genetics / Q000378:metabolism*; D018834:Chaperonin 60 / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000819:agonists / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000819:agonists / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D018834:Chaperonin 60; D016207:Cytokines; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D001224:Aspartic Acid