A promoter polymorphism in human interleukin-32 modulates its expression and influences the risk and the outcome of epithelial cell-derived thyroid carcinoma

Year: 2013

Authors: Plantinga T.S., Costantini I., Heinhuis B., Huijbers A., Semango G., Kusters B., Netea M.G., Hermus A.R.M.M., Smit J.W.A., Dinarello C.A., Joosten L.A.B., Netea-Maier R.T.

Autors Affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre, Geert Grooteplein 8, Nijmegen, 6525 GA, Netherlands; Division of Endocrinology, Radboud University Nijmegen Medical Centre, Geert Grooteplein 8, Nijmegen, 6525 GA, Netherlands; Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Radboud University Nijmegen Medical Centre, Geert Grooteplein 8, Nijmegen, 6525 GA, Netherlands; Radboud Institute for Oncology, Radboud University Nijmegen Medical Centre, Geert Grooteplein 8, Nijmegen, 6525 GA, Netherlands; Department of Pathology, Radboud University Nijmegen Medical Centre, Geert Grooteplein 8, Nijmegen, 6525 GA, Netherlands; Department of Pathology, Maastricht University Medical Centre, PO Box 5800, 6202 AZ, Maastricht, Netherlands

Abstract: Interleukin (IL)-32 is an intracellular proinflammatory mediatorthat strongly modulates the inflammatory reaction. Recent studieshave suggested the involvement of IL-32 in the pathogenesisof malignancies. We aimed to assess whether a known germ-linepolymorphism in the IL32 promoter modulates IL-32 expression, and whether it influences susceptibility and/or outcome ofepithelial cell-derived thyroid carcinoma (TC). In this study, IL32 genotype was assessed in 139 TC patients and 138 healthycontrols and was correlated with TC susceptibility and clinicaloutcome. Furthermore, IL-32 messenger RNA expression andprotein were assessed in TC tissues and functional consequencesof genetic variants of IL32 were studied in a model of humanprimary immune cells. Results demonstrate substantial IL-32expression in TC tumor tissue. Lipopolysaccharide (LPS) stimulationof primary immune cells revealed 2-fold higher expressionof IL-32? but not IL-32ß, in cells homozygous for the ancient Tallele. Furthermore, production of LPS-induced cytokines wasincreased in cells bearing this T allele. Genetic analysis revealedthat the ancient T allele was overrepresented in TC patients withodds ratio (95% confidence interval) = 1.71 (1.06-2.75). In addition, the cumulative radioactive iodine (RAI) dose received aftertotal thyroidectomy was significantly higher in TC patients bearingthe ancient T allele. In conclusion, individuals bearing geneticvariants of IL32 that lead to an increased IL-32? gene expressionand higher production of proinflammatory cytokines have higherrisk for developing epithelial cell-derived TC. Subsequently, theyrequire higher dosages of RAI to achieve successful tumor remission. These data suggest an important role of IL-32 in the pathogenesisof TC.

Journal/Review: CARCINOGENESIS

Volume: 34 (7)      Pages from: 1529  to: 1535

KeyWords: Interleukin 10; Interleukin 1beta; Interleukin 32; interleukin 32 beta; interleukin 32 gamma; interleukin 6; lipopolysaccharide; messenger RNA; radioactive iodine; tumor necrosis factor alpha; unclassified drug, adult; allele; article; cancer susceptibility; carcinoma cell; cell stimulation; controlled study; correlation analysis; cytokine production; epithelium cell; female; gene dosage; gene expression; genetic analysis; genetic association; genetic variability; genotype; germ line; human; human cell; human tissue; immunocompetent cell; major clinical study; male; priority journal; promoter region; protein expression; single nucleotide polymorphism; thyroid carcinoma; thyroidectomy; tumor regression, Adult; Alleles; Case-Control Studies; Epithelial Cells; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Immunohistochemistry; Interleukins; Iodine Radioisotopes; Lipopolysaccharides; Male; Middle Aged; Odds Ratio; Polymorphism, Genetic; Promoter Regions, Genetic; Risk Factors; Thyroid Neoplasms; Thyroidectomy
DOI: 10.1093/carcin/bgt092

Citations: 33
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