title: Effect of the Toll-like receptor 4 (TLR-4) variants on intima-media thickness and monocyte-derived macrophage response to LPS.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  The PLIC study population (n = 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, cyclo-oxygenase (COX)-2 and PTX3 expression induced by lipopolysaccharide (LPS). When the monocyte-derived macrophages of these subjects were challenged with LPS (1 mug 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacological Sciences, University of Milan, Milan, Italy.
authors.forename: G D
authors.initials: GD
authors.lastname: Norata
authors.forename: K
authors.initials: K
authors.lastname: Garlaschelli
authors.forename: M
authors.initials: M
authors.lastname: Ongari
authors.forename: S
authors.initials: S
authors.lastname: Raselli
authors.forename: L
authors.initials: L
authors.lastname: Grigore
authors.forename: F
authors.initials: F
authors.lastname: Benvenuto
authors.forename: F M
authors.initials: FM
authors.lastname: Maggi
authors.forename: A L
authors.initials: AL
authors.lastname: Catapano
mesh_terms: D000483:Alleles; D002097:C-Reactive Protein / Q000032:analysis; D019013:CD40 Antigens / Q000032:analysis; D017536:Carotid Artery, Common / Q000000981:diagnostic imaging*; D016893:Carotid Stenosis / Q000000981:diagnostic imaging* / Q000235:genetics / Q000276:immunology; D018932:Chemokine CCL2 / Q000032:analysis; D051546:Cyclooxygenase 2; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D015850:Interleukin-6 / Q000032:analysis; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics*; D008565:Membrane Proteins; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology*; D011110:Polymorphism, Genetic / Q000235:genetics*; D011446:Prospective Studies; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis; D011956:Receptors, Cell Surface / Q000032:analysis / Q000235:genetics*; D000683:Serum Amyloid P-Component / Q000032:analysis; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014463:Ultrasonography; D000099153:Pentraxins
chemical_list: D002097:C-Reactive Protein; D019013:CD40 Antigens; D018932:Chemokine CCL2; D051546:Cyclooxygenase 2; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D011956:Receptors, Cell Surface; D000683:Serum Amyloid P-Component; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D000099153:Pentraxins; C111835:CCL2 protein, human; C495345:TLR4 protein, human; C496540:PTGS2 protein, human