title: A promoter polymorphism in human interleukin-32 modulates its expression and influences the risk and the outcome of epithelial cell-derived thyroid carcinoma.
abstract: Interleukin (IL)-32 is an intracellular proinflammatory mediator that strongly modulates the inflammatory reaction. Recent studies have suggested the involvement of IL-32 in the pathogenesis of malignancies. We aimed to assess whether a known germ-line polymorphism in the IL32 promoter modulates IL-32 expression, and whether it influences susceptibility and/or outcome of epithelial cell-derived thyroid carcinoma (TC). In this study, IL32 genotype was assessed in 139 TC patients and 138 healthy controls and was correlated with TC susceptibility and clinical outcome. Furthermore, IL-32 messenger RNA expression and protein were assessed in TC tissues and functional consequences of genetic variants of IL32 were studied in a model of human primary immune cells. Results demonstrate substantial IL-32 expression in TC tumor tissue. Lipopolysaccharide (LPS) stimulation of primary immune cells revealed 2-fold higher expression of IL-32γ, but not IL-32β, in cells homozygous for the ancient T allele. Furthermore, production of LPS-induced cytokines was increased in cells bearing this T allele. Genetic analysis revealed that the ancient T allele was overrepresented in TC patients with odds ratio (95% confidence interval) = 1.71 (1.06-2.75). In addition, the cumulative radioactive iodine (RAI) dose received after total thyroidectomy was significantly higher in TC patients bearing the ancient T allele. In conclusion, individuals bearing genetic variants of IL32 that lead to an increased IL-32γ gene expression and higher production of proinflammatory cytokines have higher risk for developing epithelial cell-derived TC. Subsequently, they require higher dosages of RAI to achieve successful tumor remission. These data suggest an important role of IL-32 in the pathogenesis of TC.
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre, Geert Grooteplein 8, Nijmegen, 6525 GA, The Netherlands.
authors.forename: Theo S
authors.initials: TS
authors.lastname: Plantinga
authors.forename: Irene
authors.initials: I
authors.lastname: Costantini
authors.forename: Bas
authors.initials: B
authors.lastname: Heinhuis
authors.forename: Angelique
authors.initials: A
authors.lastname: Huijbers
authors.forename: George
authors.initials: G
authors.lastname: Semango
authors.forename: Benno
authors.initials: B
authors.lastname: Kusters
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.forename: Ad R M M
authors.initials: AR
authors.lastname: Hermus
authors.forename: Jan W A
authors.initials: JW
authors.lastname: Smit
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Romana T
authors.initials: RT
authors.lastname: Netea-Maier
mesh_terms: D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D007378:Interleukins / Q000235:genetics* / Q000378:metabolism; D007457:Iodine Radioisotopes / Q000008:administration & dosage / Q000627:therapeutic use; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013965:Thyroidectomy
chemical_list: C496971:IL32 protein, human; D007378:Interleukins; D007457:Iodine Radioisotopes; D008070:Lipopolysaccharides