Macrophage-derived IL-1β stimulates Wnt signaling and growth of colon cancer cells: a crosstalk interrupted by vitamin D3

Abstract

Tumor-associated macrophages mediate the link between inflammation and cancer progression. Here, we showed that macrophage-derived soluble factors induce canonical Wnt signaling in colon cancer cells and promote their growth. Tumor cells induced the release of interleukin (IL)-1β from macrophages, which induced phosphorylation of GSK3β, stabilized β-catenin, enhanced T-cell factor (TCF)-dependent gene activation and induced the expression of Wnt target genes in tumor cells. Neutralization experiments using anti-IL-1β-specific antibodies, or silencing of IL-1β in THP1 macrophages, showed that IL-1β was required for macrophages to induce Wnt signaling and to support the growth of tumor cells. Constitutive activation of signal transducer and activator of transcription (STAT)1 in THP1 macrophages was essential for the induction of IL-1β and thus for the activation of β-catenin signaling in tumor cells. Vitamin D₃, an effective chemopreventive agent, interrupted this crosstalk by blocking the constitutive activation of STAT1 and the production of IL-1β in macrophages, and therefore—in a vitamin D receptor-dependent manner—inhibited the ability of macrophages to activate Wnt signaling in colon carcinoma cells. Our data therefore established that vitamin D₃ exerts its chemopreventive activity by interrupting a crosstalk between tumor epithelial cells and the tumor microenvironment.