Proposed Role of RGS1 in Modulating IL-1β-IL-1R1-IRAK4-TAK1 Signaling in Endometriotic Stromal Cells.

The pathology of endometriosis is associated with various inflammatory cytokines, including IL-1β, and recent studies have shown that spheroid cell cultures can be used to investigate the mechanisms of endometriosis-associated inflammation and cell proliferation more effectively than that of monolayer cell cultures. However, the detailed role of the IL-1β signaling pathway in endometriotic stromal cells in spheroid cell cultures remains unclear. This study investigated the role of the IL-1β pathway in the pathogenesis of endometriosis in spheroid cell cultures derived from ovarian endometrioma stromal cells (OESCs) and normal endometrial stromal cells (NESCs). Specimens were collected from 22 patients with and 11 patients without endometriosis. IL-6/IL-8 protein production was evaluated by ELISA, gene expression by real-time PCR, cell proliferation by WST-8 assay, and RGS1 expression by immunohistochemical staining. Spheroid OESCs showed elevated IL-6/IL-8 production and increased expression of inflammation-related genes compared with monolayer cell cultures. IL-1β promoted the proliferation of spheroid OESCs and upregulated endometriosis-associated gene expression, but did not promote the proliferation of spheroid NESCs. Spheroid OESCs also showed increased levels of IL-1R1 and NLRP3 mRNA. IRAK4, TAK1, and RGS inhibitors suppressed cell proliferation and IL-6/IL-8 production in spheroid OESCs treated with IL-1β. Additionally, RGS1 was highly expressed in OESCs. The IL-1β pathway is crucial for OESCs proliferation and IL-6/IL-8 production in spheroid culture. Thus, RGS1, IRAK4, and TAK1 may serve as novel therapeutic targets for endometriosis.