Abstract

Interleukin-1 receptor type 2 (IL1R2) acts as a decoy receptor of exogenous IL-1; however, its intracellular activity is poorly understood. We previously demonstrated that IL1R2 intracellularly activates the expression of several proinflammatory cytokines and affects cell migration. In this study, we found that intracellular IL1R2 expression was increased in human colorectal cancer cells (CRCs) compared with normal colon cells. We also observed that the mRNA levels of IL1R2 were highly correlated with IL-6 in tumor tissues of CRC patients. By modulating its expression in CRC cells, we verified that enhanced IL1R2 expression transcriptionally activated the expression of IL-6 and VEGF-A. Conditioned medium harvested from IL1R2-overexpressing CRC cells contained higher levels of IL-6 and VEGF-A than that from vector control cells and significantly enhanced the proliferation, migration, and tube formation of cultured endothelial cells. We further demonstrated a positive association of intracellular IL1R2 levels with tumor growth and microvessel density in xenograft mouse models. These results revealed that IL1R2 activates the expression of angiogenic factors. Mechanistically, we revealed that IL1R2 complexes with c-Fos and binds to the AP-1 site at the IL-6 and VEGF-A promoters. Together, these results reveal a novel function of intracellular IL1R2 that acts with c-Fos to enhance the transcription of IL-6 and VEGF-A, which promotes angiogenesis in CRC.

Highlights

  • Enhanced Interleukin-1 receptor type 2 (IL1R2) expression has frequently been observed in tumors, but its function is unclear

  • We previously observed that IL1R2 overexpression causes increased IL-6 mRNA levels in human urothelial cells [17]; we analyzed the IL-6 mRNA levels in 40 cancer cells (CRCs) tumor specimens by quantitative real time PCR (qPCR)

  • We observed a significant correlation between IL1R2 and IL-6 in CRC patients, implying that IL1R2 influences the development of human CRC by affecting key inflammatory and angiogenic factors

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Summary

Background

Enhanced IL1R2 expression has frequently been observed in tumors, but its function is unclear. We further demonstrated a positive association of intracellular IL1R2 levels with tumor growth and microvessel density in xenograft mouse models These results revealed that IL1R2 activates the expression of angiogenic factors. We showed that the ectopic expression of IL1R2 activates intracellular IL-1␣ signaling and increases the transcription of IL-6, IL-8, and collagen and the migration of human urothelial cells [17]. Consistent with these results, we observed a dose-dependent increase of intracellular IL1R2, IL-6, and VEGF-A levels, as well as tumorigenesis in human keratinocyte cells exposed long term to sodium arsenite. Because angiogenesis is critical for CRC development and metastasis [2], we conducted experiments to elucidate whether and how intracellular IL1R2 acts as an oncogenic and angiogenic factor in CRC

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