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 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).
Balistreri
Carmela Rita
CR
Gruppo di Studio sull'Immuno-senescenza, Dipartimento di Biopatologia e Metodologie Biomediche, Università di Palermo, Corso Tukory 211, 90134 Palermo, Italy. crbalistreri@unipa.it
Candore
Giuseppina
G
Listì
Florinda
F
Fazio
Teresa
T
Gangi
Simona
S
Incalcaterra
Egle
E
Caruso
Marco
M
Vecchi
Maurizio Li
ML
Lio
Domenico
D
Caruso
Calogero
C
D000328:Adult; D000375:Aging / Q000235:genetics* / Q000378:metabolism*; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D001773:Blood Cells / Q000378:metabolism; D002478:Cells, Cultured; D015232:Dinoprostone / Q000096:biosynthesis; D004926:Escherichia coli; D004927:Escherichia coli Infections / Q000235:genetics / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D007975:Leukotriene B4 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics* / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism*
D008070:Lipopolysaccharides; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D007975:Leukotriene B4; D015232:Dinoprostone