Polymorphisms in Toll-like receptor 4 and the systemic inflammatory response syndrome

Abstract

The systemic inflammatory response syndrome (SIRS) is a major cause of morbidity and mortality, and is thought to be due to an over-amplification of an inflammatory response. The Toll-like receptor 4 ( TLR4 ) Asp-299-->Gly polymorphism has been shown to reduce lipopolysaccharide responsiveness. We examined whether this TLR4 polymorphism is associated with severity of SIRS. A trend was found between the minor allele and mortality in SIRS (odds ratio of 4.3; P =0.076), suggesting a role for TLR4 signalling in the severity of SIRS.

The TLR4 +896 polymorphism is not associated with lipopolysaccharide hypo-responsiveness in leukocytes

“…[13][14][15] Studies that have not demonstrated an association were focused primarily on endotoxin responses in circulating leukocytes, 20,22,24,25 which mimics endotoxemia and clinical sepsis. 19,21 Numerous factors, including LBP, CD14 and serum HDL, among other molecules modulate LPS recognition and binding to TLR4, and interindividual differences in their effects may have important influences on leukocyte responses to endotoxin measured in our studies and seen clinically.…”

“…Furthermore, other clinical and basic science investigations have failed to demonstrate a role for TLR4 in altering the inflammatory response. [19][20][21][22][23][24][25] There are several possibilities that may explain the lack of association between TLR4 genotype and measures of endotoxin signaling we have observed. [26][27][28] First, as there were no individuals homozygous for the TLR4 þ 896G allele, the remaining wild-type TLR4 allele in heterozygous carriers may be sufficient to elicit a normal response to endotoxin.…”

“…Carriers have been reported to have an impaired response to bacterial endotoxin exposure compared to wild-type controls, [13][14][15][16] and they may be at increased risk for Gram negative infections and septic shock, and mortality from systemic inflammatory response syndrome (SIRS). [17][18][19] However, other in vivo and clinical studies have shown inconsistencies in the link between coding SNPs in the TLR4 gene and the inflammatory response. [20][21][22] We sought to determine the effect of the A þ 896G polymorphism within the TLR4 gene on the response to LPS in a population of healthy donors.…”

LPS-mediated production of pro/anti-inflammatory cytokines and eicosanoids in whole blood samples: Biological effects of +896A/G TLR4 polymorphism in a Sicilian population of healthy subjects

“…On the other hand, an association of this TLR4 SNP with an increased risk of Gram negative infections and septic shock has been demonstrated (Agnese et al, 2002;Lorenz et al, 2002;Schrö der and Schumann, 2005). However, contrasting data have been obtained in other studies (Child et al, 2003;Erridge et al, 2003;Read et al, 2001;Heesen et al, 2003;Imahara et al, 2005;Schippers et al, 2005;von Aulock et al, 2003;Yang et al, 2004). Changes in eicosanoid levels are also correlated with SNPs in the promoter region of PTGS2 and 5-Lo genes, respectively codifying the cyclooxygenase-(Cox)-2 and 5-lipoxygenase (5-Lo), enzymes involved in arachidonic acid metabolism.…”

Exploitation of the Toll-like receptor system in cancer: a doubled-edged sword?

“…The initially identified and best studied D299G polymorphism (an amino acid substitution, from aspartic acid to glycine at position 299 in the TLR-4 gene) is associated with an increased frequency of Gram-negative infection and increased severity of Gram-negative sepsis (Child et al, 2003). also been linked to a rare, heterozygous missense TLR4 mutation (Smirnova et al, 2003).…”