title: No association between tumor necrosis factor-alpha production and gene polymorphisms among inbred rat strains.
abstract: Differences in spontaneous allograft acceptance after liver transplantation among inbred rat strains might be explained by variation in the local production of TNF-alpha as a potent mediator of the inflammatory response. In this study, we hypothesize that nucleotide differences in the rat Tnf gene influence TNF-alpha protein expression. As such, polymorphisms in the Tnf gene may also provide a possible explanation for differences in survival of allogeneic liver grafts among inbred rat strains. We therefore investigated the capacity of mononuclear cells to produce TNF-alpha in response to a mitogenic stimulus and the Tnf locus was sequenced in six different inbred rat strains. Among the six strains (AUG, BN, DA, LEW, PVG and WF), 44 nucleotide differences including 36 single nucleotide polymorphisms (SNPs), five simple sequence length polymorphisms, two deletions and one insertion, were found in the Tnf gene. Although, the inbred rat strains differed significantly in mean levels of maximum TNF-alpha production (P = 0.001), no associations were found with nucleotide differences within the Tnf gene. In conclusion, our results indicate that differential in vitro TNF-alpha responses among inbred rat strains are not associated with nucleotide differences within non-coding regulatory regions of the rat TNF-alpha gene. Without an established relationship between polymorphisms and expression of the TNF-alpha gene, it is preliminary to address a possible association of Tnf gene polymorphisms with rat liver allograft survival.
authors.affiliation: Department of Surgery, Erasmus MC Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands. h.w.tilanus@erasmusmc.nl
authors.forename: Michiel C
authors.initials: MC
authors.lastname: Warlé
authors.forename: Luc J W
authors.initials: LJ
authors.lastname: van der Laan
authors.forename: Johannes G
authors.initials: JG
authors.lastname: Kusters
authors.forename: Raymond G J
authors.initials: RG
authors.lastname: Pot
authors.forename: Wim C J
authors.initials: WC
authors.lastname: Hop
authors.forename: Katja C A
authors.initials: KC
authors.lastname: Segeren
authors.forename: Jan N M
authors.initials: JN
authors.lastname: Ijzermans
authors.forename: Herold J
authors.initials: HJ
authors.lastname: Metselaar
authors.forename: Hugo W
authors.initials: HW
authors.lastname: Tilanus
mesh_terms: D000818:Animals; D006085:Graft Survival / Q000235:genetics / Q000276:immunology*; D016031:Liver Transplantation / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics*
chemical_list: D014409:Tumor Necrosis Factor-alpha