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

Balistreri, Carmela Rita; Caruso, Calogero; Listı́, Florinda; Colonna‐Romano, Giuseppina; Lio, Domenico; Candore, Giuseppina

doi:10.1016/j.mad.2010.12.005

Cited by 27 publications

(27 citation statements)

References 53 publications

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“…These results are in agreement with our previous data [54, 55]. Indeed, in clarifying and confirming the biological effects of rs4986790 TLR4 polymorphism and its role in the pathophysiology of age-related diseases, including CVDs, Alzheimer disease, prostate cancer, diabetes, and longevity, we assessed the levels of IL-6, TNF- α , IL-10, and eicosanoids in LPS-stimulated whole blood samples in vitro of 50 young healthy Sicilians, screened for the presence of rs4986790 TLR4 and −765G>C PTGS2, −1708G>A 5-Lo polymorphisms [54]. Significantly higher levels of both proinflammatory cytokines and eicosanoids were observed in individuals bearing the rs4986790 TLR4 polymorphism.…”

Section: Discussionsupporting

confidence: 94%

“…However, their magnitude significantly was more increased in individual's carriers of their combined genotype. In addition, significantly lower levels of inflammatory mediators were observed in carriers bearing the TLR4 mutation (the +896G allele), whereas the anti-inflammatory IL-10 values were higher [54]. The same results were detected in this study in the controls carriers of the +896G TLR4 allele.…”

Section: Discussionsupporting

confidence: 84%

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Can the TLR-4-Mediated Signaling Pathway Be “A Key Inflammatory Promoter for Sporadic TAA”?

Ruvolo

Pisano

Candore

et al. 2014

Mediators of Inflammation

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Thoracic aorta shows with advancing age various changes and a progressive deterioration in structure and function. As a result, vascular remodeling (VR) and medial degeneration (MD) occur as pathological entities responsible principally for the sporadic TAA onset. Little is known about their genetic, molecular, and cellular mechanisms. Recent evidence is proposing the strong role of a chronic immune/inflammatory process in their evocation and progression. Thus, we evaluated the potential role of Toll like receptor- (TLR-) 4-mediated signaling pathway and its polymorphisms in sporadic TAA. Genetic, immunohistochemical, and biochemical analyses were assessed. Interestingly, the rs4986790 TLR4 polymorphism confers a higher susceptibility for sporadic TAA (OR = 14.4, P = 0.0008) and it represents, together with rs1799752 ACE, rs3918242 MMP-9, and rs2285053 MMP-2 SNPs, an independent sporadic TAA risk factor. In consistency with these data, a significant association was observed between their combined risk genotype and sporadic TAA. Cases bearing this risk genotype showed higher systemic inflammatory mediator levels, significant inflammatory/immune infiltrate, a typical MD phenotype, lower telomere length, and positive correlations with histopatological abnormalities, hypertension, smoking, and ageing. Thus, TLR4 pathway should seem to have a key role in sporadic TAA. It might represent a potential useful tool for preventing and monitoring sporadic TAA and developing personalized treatments.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 84%

Can the TLR-4-Mediated Signaling Pathway Be “A Key Inflammatory Promoter for Sporadic TAA”?

Ruvolo

Pisano

Candore

et al. 2014

Mediators of Inflammation

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“…Both secreted and intracellular IL-8 were reduced in TLR4 Asp299Gly cell lines in response to LPS compared to that of the wild type and Thr399Ile cell groups. Our results were consistent with previous in vitro [22], [26], [27], [34] and ex vivo studies [29], [30], [35]–[37]. We also showed reduced protein levels of total and phosphorylated NF-κB as a result of the Asp299Gly but not Thr399Ile SNP at early time points (30–60 min) but not later time points (120 min).…”

Section: Discussionsupporting

confidence: 93%

The Toll-Like Receptor 4 Polymorphism Asp299Gly but Not Thr399Ile Influences TLR4 Signaling and Function

et al. 2014

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The common, co-segregating Toll-like receptor 4 (TLR4) non-synonymous single nucleotide polymorphisms (SNPs), Asp299Gly and Thr399Ile, are associated with hyporesponsiveness to inhaled lipopolysaccharide (LPS) and increased susceptibility to Gram negative pathogens in humans. The purpose of this study was to identify the relative contributions of the Asp299Gly and the Thr399Ile variants in inhibiting the function of TLR4. 293/hMD2-CD14 cell line was transfected with lentiviral constructs containing human wild type (WT) TLR4-EGFP or TLR4-EGFP with Asp299Gly, Thr399Ile or Asp299Gly/Thr399Ile complementary DNA (cDNA). Multiple stable cell lines were established for each construct: three for WT TLR4, Asp299Gly, and Thr399Ile, and only two for Asp299Gly/Thr399Ile mutants and EGFP control. We did not observe a significant effect of polymorphisms on cell surface and intracellular TLR4 expression nor were there any significant differences in TLR4 and EGFP protein levels assessed by Western blotting and confocal microscopy among the multiple cell lines of each of the constructs. All cell lines had a dose-dependent responsiveness to LPS stimulation. However, compared to the WT TLR4, cells expressing TLR4 with Asp299Gly but not Thr399Ile polymorphism produced significantly less (P<0.05) IL-8 following LPS stimulation. Similarly, cells expressing TLR4 Asp299Gly but not Thr399Ile allele had significantly lower percentage of phosphorylated and total NF-κB P65 following LPS stimulation. While we could not do statistics on the Asp299Gly/Thr399Ile group, we observed a reduced responsiveness to LPS compared to WT TLR4. Taken together, we observed that the TLR4 Asp299Gly variant, but not the Thr399Ile variant, is responsible for impaired responsiveness of TLR4 to LPS and corresponding activation of NF-κB.

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“…For example, cyclooxygenase-2 (COX-2) mediated high production of prostaglandin E 2 (PGE 2 ) and, to a lesser extent, other prostanoids after LPS stimulation [11]. In contrast, LPS down-regulated COX-1 and COX-1 deficiency increased PGE 2 production following LPS stimulation in astrocytes [12].…”

Section: Toll-like Receptors and Bioactive Lipids In Sepsismentioning

confidence: 99%

State of the art papers HLA-DR expression, cytokines and bioactive lipids in sepsis

Das¹

2014

aoms

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Sepsis accounts for more than 200,000 deaths annually in the USA alone. Both inflammatory and anti-inflammatory responses occur simultaneously in sepsis, the early phase dominated by the hyperinflammatory response and the late phase by immunosuppression. This late immunosuppression phase leads to loss of the delayed type hypersensitivity response, failure to clear the primary infection and development of secondary infections. Based on the available data, I hypothesize that failure to produce adequate amounts of inflammation resolving lipid mediators may be at the centre of both the hyperinflammatory response and late immunosuppression seen in sepsis. These proresolving lipids – lipoxins, resolvins and protectins – suppress exacerbated activation of leukocytes and macrophages, inhibit excess production of pro-inflammatory cytokines, initiate resolution of inappropriate inflammation, augment clearance of bacteria and other pathogens, and restore homeostasis. If true, this implies that administration of naturally occurring lipoxins, resolvins, protectins, maresins and nitrolipids by themselves or their more stable synthetic analogues such as 15-epi-16-(para-fluorophenoxy)-lipoxin A4-methyl ester, a synthetic analogue of 15-epi-lipoxin A4, and 15(R/S)-methyl-LXA4 may form a new approach in the prevention (in the high-risk subjects), management of sepsis and in resolving the imbalanced inflammatory process such that sepsis is ameliorated early. In addition, recent studies have suggested that nociceptin and cold inducible RNA binding protein (CIRBP) also have a role in the pathobiology of sepsis. It is suggested that both nociceptin and CIRBP inhibit the production of lipoxins, resolvins, protectins, maresins, and nitrolipids and thus play a role in sepsis and septic shock.

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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

Cited by 27 publications

References 53 publications

Can the TLR-4-Mediated Signaling Pathway Be “A Key Inflammatory Promoter for Sporadic TAA”?

Can the TLR-4-Mediated Signaling Pathway Be “A Key Inflammatory Promoter for Sporadic TAA”?

The Toll-Like Receptor 4 Polymorphism Asp299Gly but Not Thr399Ile Influences TLR4 Signaling and Function

State of the art papers HLA-DR expression, cytokines and bioactive lipids in sepsis

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