ER‐α36 is involved in calycosin inhibition of IL‐6 production in macrophages

Abstract The tumour microenvironment (TME) is crucial for tumour development and progression. Tumour‐associated macrophages (TAMs) in the TME can promote tumour progression and metastasis by releasing cytokines, such as IL‐6. Calycosin, a phytoestrogen that is one of the active compounds in Radix Astragali , has been shown to inhibit tumour growth and metastasis. However, the underlying mechanism by which calycosin inhibits tumour growth remains unclear. Thus, this study aimed to investigate the effect of calycosin on IL‐6 production in peripheral blood mononuclear cell (PBMC)‐ and THP‐1‐derived macrophages and explore its potential mechanisms using co‐immunoprecipitation, western blotting, immunofluorescence, chromatin immunoprecipitation and luciferase assays. We found that calycosin treatment substantially upregulated the expression of ER‐α36, a variant of the ER, and reduced IL‐6 production in macrophages. Mechanistically, ER‐α36 physically interacted with NF‐κBp65 and retained p65 in the cytoplasm to attenuate NF‐κB function as an IL‐6 transcriptional inducer. In conclusion, our result indicated that calycosin inhibited IL‐6 production by enhancing ER‐α36 expression and its interaction with p65, which attenuated NF‐κB function as an IL‐6 inducer. Therefore, calycosin can be developed as an effective agent for cancer therapy by targeting TAMs.