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

作者：Plantinga Theo S^*; Costantini Irene; Heinhuis Bas; Huijbers Angelique; Semango George; Kusters Benno; Netea Mihai G; Hermus Ad R M M; Smit Jan W A; Dinarello Charles A; Joosten Leo A B; Netea Maier Romana T

来源：Carcinogenesis, 2013, 34(7): 1529-1535.

DOI：10.1093/carcin/bgt092

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 cellderived 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-32, but not IL-32, 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 (1.062.75). 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-32 gene expression and higher production of proinflammatory cytokines have higher risk for developing epithelial cellderived 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.

• 出版日期2013-7