title: The tumor necrosis factor alpha -308 G/A polymorphism does not influence inflammation and coagulation response in human endotoxemia.
abstract: Tumor necrosis factor (TNF)-alpha plays a major role in the immune system. Release of proinflammatory cytokines, such as TNF-alpha and interleukin 6, by macrophages and other cells occurs in response to bacterial products. It has been reported that the TNF-alpha -308 G/A polymorphism in the TNF-alpha gene determines basal TNF-alpha levels. We hypothesized that it may also be associated with the degree of inflammatory response in a well-standardized model of systemic inflammation. Eighty-seven young men (age range, 19-35 years) received 2 ng/kg i.v. endotoxin (lipopolysaccharide [LPS]). The TNF-alpha promoter genotype was analyzed on a TaqMan genomic analyzer. Inflammation markers (interleukin 6, TNF-alpha), temperature, and coagulation markers (prothrombin fragment F1+2, D-dimer) were measured at 0, 2, 6, and 24 h after LPS infusion. Tumor necrosis factor-alpha plasma concentrations increased from a baseline 1.3 ng/L (range, 0.8-3.1 ng/L) before LPS infusion to a peak of 57.5 ng/L (range, 10.8-131.4 ng/L) at 2 h after LPS and then decreased continually to 10.8 ng/L (range, 4.7-16.5 ng/L) after 6 h and returned to baseline values after 24 h (1.9 ng/L [range, 1.1-3.9 ng/L]). We observed no significant differences in TNF-alpha baseline levels or in response to LPS after stratification of the data according to TNF-alpha genotype. Basal and peak values of selected inflammatory and coagulation markers were not different between wild-type TNF-alpha -308 individuals (GG) and carriers of the TNF-alpha -308 mutant allele (GA and AA). The TNF-alpha -308 G/A polymorphism does not contribute significantly to the individual variability of systemic TNF-alpha plasma concentrations after endotoxin challenge. Thus, if any, the impact of the TNF-alpha -308 G/A polymorphism on systemic endotoxin-triggered inflammation seems to be limited.
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria. florian.kovar@meduniwien.ac.at
authors.forename: Florian M
authors.initials: FM
authors.lastname: Kovar
authors.forename: Claudia
authors.initials: C
authors.lastname: Marsik
authors.forename: Tuende
authors.initials: T
authors.lastname: Cvitko
authors.forename: Oswald F
authors.initials: OF
authors.lastname: Wagner
authors.forename: Bernd
authors.initials: B
authors.lastname: Jilma
authors.forename: Georg
authors.initials: G
authors.lastname: Endler
mesh_terms: D000328:Adult; D001777:Blood Coagulation; D016207:Cytokines / Q000378:metabolism; D019446:Endotoxemia / Q000235:genetics*; D004731:Endotoxins / Q000378:metabolism; D005838:Genotype; D006801:Humans; D007107:Immune System; D007249:Inflammation / Q000235:genetics*; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008297:Male; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*
chemical_list: D016207:Cytokines; D004731:Endotoxins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha