Abstract 1423: Proinflammatory activity of type II interleukin 1 receptor, a decoy receptor.

We have previously demonstrated that type II interleukin 1 receptor (IL1R2), an IL-1 decoy receptor, plays a dual role on regulation of inflammatory signaling, i.e., IL1R2 inhibits the exogenous interleukin 1 (IL-1) signaling on the one hand but activates intracellular IL-1α and its downstream proinflammatory cytokines. To have a better understanding of the proinflammatory activity of IL1R2, we modulated the intracellular IL1R2 levels by ectopic expression or siRNA silencing techniques. In the present study, our results showed that ectopic expression of IL1R2 in HaCaT cells, an immortalized cell line of human keratinocyte, significantly enhanced the expression of IL-6, MMP-1, and VEGF-A. Since T4R2 cells, a tumorigenic cell line derived from HaCaT cells by long-term exposure to inorganic arsenic, expressed a significant amount of IL1R2, we therefore silenced the expression of IL1R2 in T4R2 cells by RNAi technique. Our results consistently showed that silencing of IL1R2 in T4R2 cells decreased expression of IL-6, MMP-1, and VEGF-A. Meanwhile, our results demonstrated that the intracellular levels of IL1R2 are closely associated with migration ability of HaCaT cells. Moreover, IL1R2 silencing reduced the growth rate of T4R2 cells in nude mice. The conditioned medium harvested from T4R2 cells was able to stimulate migration, proliferation, and tube formation of cultured endothelial cells, whereas the angiogenesis activity of conditioned medium harvested from IL1R2 silenced T4R2 cells was significantly suppressed. Furthermore, the enhanced migration ability of endothelial cells culturing in T4R2 conditioned medium was suppressed by antibodies against VEGF-A and IL-6. We also demonstrated that tumors derived from T4R2 cells contained higher levels of CD31 positive cells as compared to those derived from IL1R2 silenced T4R2 cells, indicating more blood vessels formed in T4R2 tumor tissues. Mechanistically, our present studies showed that IL1R2 may work together with cFos and bind to Ap-1 site of promoters of IL-6 and VEGF-A. Taken together, we revealed that intracellular IL1R2 acts as a proinflammatory factor and hence enhances the expression of several inflammatory cytokines involving in angiogenesis and tumor malignancy. Citation Format: Ai-Chung Mar, Hui-Ju Lee, Te-Chang Lee. Proinflammatory activity of type II interleukin 1 receptor, a decoy receptor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1423. doi:10.1158/1538-7445.AM2013-1423