Role of TLR4 polymorphisms in inflammatory responses: implications for unsuccessful aging

The total burden of infection at various sites may affect the progression of atherosclerosis and Alzheimer's disease (AD), the risk being modulated by host genotype. The role of lipopolysaccharide (LPS) receptor TLR4 is paradigmatic. It initiates the innate immune response against gram-negative...

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Bibliographic Details
Published in:Annals of the New York Academy of Sciences 2007-11, Vol.1119 (1), p.203-207
Main Authors: Balistreri, Carmela Rita, Candore, Giuseppina, Listì, Florinda, Fazio, Teresa, Gangi, Simona, Incalcaterra, Egle, Caruso, Marco, Vecchi, Maurizio Li, Lio, Domenico, Caruso, Calogero
Format: Article
Language:English
Subjects:
Adult
Aging - genetics
Aging - metabolism
Alzheimer Disease - genetics
Alzheimer Disease - metabolism
Blood Cells - metabolism
Cells, Cultured
Dinoprostone - biosynthesis
Escherichia coli
Escherichia coli Infections - genetics
Escherichia coli Infections - metabolism
Female
Genotype
Humans
Immunity, Innate - genetics
Inflammation - genetics
Inflammation - metabolism
Leukotriene B4 - biosynthesis
Lipopolysaccharides - pharmacology
Male
Middle Aged
Myocardial Infarction - genetics
Myocardial Infarction - metabolism
Polymorphism, Single Nucleotide
Time Factors
Toll-Like Receptor 4 - genetics
Toll-Like Receptor 4 - metabolism
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Summary:The total burden of infection at various sites may affect the progression of atherosclerosis and Alzheimer's disease (AD), the risk being modulated by host genotype. The role of lipopolysaccharide (LPS) receptor TLR4 is paradigmatic. It initiates the innate immune response against gram-negative bacteria, and TLR4 single nucleotide polymorphisms (SNPs), such as +896A/G, known to attenuate receptor signaling, have been described. This SNP shows a significantly lower frequency in patients affected by myocardial infarction or AD. Thus, people genetically predisposed to developing lower inflammatory activity seem to have less chance of developing cardiovascular disease (CVD) or AD. In the present report, to validate this hypothesis, the levels of the eicosanoids, leukotriene B4 (LTB4) and prostaglandin E2 (PGE2), known to be involved as mediators in age-related diseases, were determined by an enzyme-linked immunosorbent assay in supernatants from a whole blood assay, after stimulation with subliminal doses of LPS from Escherichia coli. The samples, genotyped for the +896A/G SNP, were challenged with LPS for 4, 24, and 48 h. Both LTB4 and PGE2 values were significantly lower in carriers bearing the TLR4 mutation. Therefore, the pathogen burden, by interacting with the host genotype, determines the type and intensity of the inflammatory responses accountable for proinflammatory status, CVD, AD, and unsuccessful aging (i.e., age-related inflammatory diseases).
ISSN:0077-8923
1749-6632
DOI:10.1196/annals.1404.003