Effect of the Toll‐like receptor 4 (TLR‐4) variants on intima‐media thickness and monocyte‐derived macrophage response to LPS

Abstract

Abstract. Norata GD, Garlaschelli K, Ongari M, Raselli S, Grigore L, Benvenuto F, Maggi FM, Catapano AL (University of Milan; and Center for the Study of Atherosclerosis, Ospedale Bassini, Cinisello Balsamo; Italy). Effect of the Toll-like receptor 4 (TLR-4) variants on intima-media thickness and monocyte-derived macrophage response to LPS. J Intern Med 2005; 258: 21-27.Objectives. Toll-like receptor 4 (TLR-4) is believed to contribute to the initiation and progression of atherosclerosis. The association of the D299G polymorphism of the TLR-4 gene with the progression of coronary and carotid atherosclerosis, risk of cardiovascular events and myocardial infarction is controversial. We have investigated whether the presence of the D299G polymorphism and the co-segregated T399I polymorphism affects the intima-media thickness (IMT) in the general population. Subjects. The PLIC study population (n ¼ 1256) was genotyped for the D299G and the T399I polymorphisms. Results. The presence of both the D299G and T399I alleles was observed in the 13.0% of the population, carriers of the T399I alone were 1.8% and of the D299G alone were 0.9%. No difference in IMT was detected within the carriers of the D299G and T399I alleles and the wild-type subjects in the PLIC population. Furthermore, we investigated whether monocyte from D299G to T399I subjects present a defective response to CD40, interleukin (IL)-6, monocyte chemotactic protein (MCP)-1, cyclooxygenase (COX)-2 and PTX3 expression induced by lipopolysaccharide (LPS). When the monocytederived macrophages of these subjects were challenged with LPS (1 lg mL )1 ), no impact of the polymorphisms on the induction of CD40, MCP-1 and PTX3 was observed. Only IL-6 and COX-2 induction by LPS resulted reduced in the D299G/ T399I carriers. Conclusion. The presence of the D299G and T399I polymorphisms of the TLR-4 gene does not play a major role on the progression of carotid atherosclerosis. Macrophages from the subjects carrying the polymorphisms show an impaired response to LPS limited only to a IL-6 and COX-2.

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

“…Some literature data agree with the results of our study, while others show contrasting results (Arbour et al, 2000;Child et al, 2003;Erridge et al, 2003;Heesen et al, 2003;Imahara et al, 2005;Michel et al, 2003;Norata et al, 2005;Read et al, 2001;Schippers et al, 2005;Werner et al, 2003;von Aulock et al, 2003;Yang et al, 2004). The different associations between the genotypes of +896A/ G SNP and the levels of inflammatory mediators evidenced in different studies may be ascribed to some factors.…”

“…One or more functional SNPs in one or more genes might be responsible. Accordingly, recent studies have suggested the role of +896A/G TLR4 SNP in cytokine and eicosanoid production (Arbour et al, 2000;Ferwerda et al, 2007Ferwerda et al, , 2008Hoshino et al, 1999;Michel et al, 2003;Norata et al, 2005;Poltorak et al, 1998;von Aulock et al, 2003;Werner et al, 2003). 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).…”

Plasma resistin levels correlate with determinants of the metabolic syndrome

“…The subjects signed an informed consent, and this study was approved by the Ethics Committee of the Centre and conducted under the principles of the Declaration of Helsinki. The clinical outcome measures, such as triglycerides, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), total cholesterol, systolic and diastolic blood pressure (SBP and DBP), body-mass index (BMI), waist/hip ratio, and cardiovascular risk calculated according to the Framingham algorithm (RCV), were obtained as previously described (27,28). Glucose was measured using the Trinder enzymatic assay and the Cobas Mira Plus analyser (Horiba, Montpellier, ABX, France), while ApoAI and ApoB were measured following turbidimetric analysis and processing in the Cobas Mira Plus analyser.…”

“…Data on insulin plasma levels and homeostasis model assessment (HOMA) are available from 300 randomly selected subjects. IMT was evaluated in all subjects at the beginning of the study (IMT 0 ) and after 2 years of follow-up (27) and data are presented as IMT progression (DIMT). To avoid any confounding effect due to pharmacological treatment, among the subjects enrolled in the PLIC study, we excluded 291 subjects taking medication for dyslipidemia and/or diabetes and we randomly selected 1090 subjects stratified according to cardiovascular risk for the analysis of resistin plasma levels.…”

Leptin:Adiponectin Ratio Is an Independent Predictor of Intima Media Thickness of the Common Carotid Artery

“…Five standardized points 5, 10, 20, 25, and 30 mm from the carotid bulb were measured in both arteries and averaged to calculate the mean IMT for each subject. 8 Circulating concentrations of total leptin were measured using a commercial radioimmunoassay kit for human leptin (Linco Research Inc, St. Louis, Mo) and plasma adiponectin levels (all the isoforms) were measured using a commercial enzyme-linked immunosorbent assay kit (Assaypro, Wienfield, Mo). The presence of metabolic syndrome was defined according to the National Cholesterol Program, Adult Treatment Panel III (NCP-ATPIII) guidelines.…”