Abstract

In this study, LPS-induced inflammatory responses in BEAS-2B human bronchial epithelial cells and human umbilical vein endothelial cell (HUVEC)s were found to be prevented by Dickkopf-1 (DKK-1), a secreted Wnt antagonist, and LGK974, a small molecular inhibitor of the Wnt secretion. LPS-induced IκB degradation and NF-κB nuclear translocation as well as the expressions of pro-inflammatory genes including IL-6, IL-8, TNF- α, IL-1β, MCP-1, MMP-9, COX-2 and iNOS, were all suppressed by DKK-1 and LGK974 in a dose-dependent manner. The suppressive effects of LGK974 on NF-κB, IκB, and pro-inflammatory gene expression were rescued by ectopic expression of β-catenin, suggesting that the anti-inflammatory activity of LGK974 is mediated by modulation of the Wnt/β-catenin pathway and not by unrelated side effects. When Wnt recombinant proteins were treated to cells, Wnt3a and Wnt5a significantly induced pro-inflammatory gene expressions, while Wnt7a and Wnt10b showed little effects. It was also found that Wnt3a and Wnt5a expressions were significantly induced by LPS treatment. Consistently, knockdown of Wnt3a and Wnt5a blocked LPS-induced inflammatory responses, while treatment of recombinant Wnt3a and Wnt5a proteins rescued the inhibition of inflammatory responses by LGK974. Findings of this study showed that DKK-1 and LGK974 suppress LPS-induced inflammatory response by modulating Wnt/β-catenin pathway.

Highlights

  • Dickkopf-1 (DKK-1), among which DKK-1 prevents Wnt signaling by binding and inducing the internalization of lipoprotein receptor-related protein 6 (LRP6) while others act by binding and sequestering Wnt[4]

  • We hypothesized that LPS might enhance Wnt ligand secretion or maturation. To test this hypothesis we tested whether the treatment of cells with DKK-1, a secreted Wnt antagonist that is well-known to induce the internalization of LRP6 on cell surface to prevent their association with Wnt ligands[13], blocks LPS-induced Wnt signaling

  • These data clearly show that DKK-1 suppressed LPS-induced activation of the Wnt/β-catenin signaling in BEAS-2B human bronchial epithelial cells, and suggest that the treatment of LPS induces secretion of Wnts, which may act via autocrine or paracrine fashion to induce Wnt/β-catenin signaling

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Summary

Introduction

Dickkopf-1 (DKK-1), among which DKK-1 prevents Wnt signaling by binding and inducing the internalization of LRP6 while others act by binding and sequestering Wnt[4]. Diverse chemical inhibitors of the Wnt pathway, including a Wnt secretion inhibitor, Fzd antagonist, Axin stabilizer, Dvl inhibitor and inhibitor of β-catenin/Tcf interaction, are being developed as anti-cancer drug candidates[6]. LGK974, a small-molecule inhibitor of PORCN which was developed as an anti-tumor drug candidate, has been shown to be effective in tumor models of murine breast cancer, human head and neck squamous cell carcinoma[8] and glioblastoma[9]. LPS-induced inflammatory response was found to be prevented by DKK-1, a secreted Wnt antagonist. These results suggest that secreted Wnt may act via autocrine or paracrine fashion in LPS-induced inflammatory response, so we examined the effects of LGK974, a small molecular inhibitor of Wnt secretion, on LPS-induced inflammatory response

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