Background: Endometriosis, a chronic immune-mediated inflammatory disease, remains elusive in its pathogenesis. Given vitamin D (VD)'s pivotal role in modulating innate and adaptive immune responses, we sought to elucidate how VD modulates inflammatory responses in endometriosis.
Materials and methods: We isolated primary human ectopic endometrial stromal cells (EESCs) from ectopic endometrium of ovarian endometrioma, alongside Ishikawa cells, and subjected them to treatment with lipopolysaccharide (LPS), a potent inducer of inflammation, alongside varying concentrations of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the biologically active form of VD, and its analog TEI-9647 (25-dehydro-1α-hydroxyvitamin D3-26,23-lactone).
Results: Our results revealed that 1,25(OH)2D3 significantly reversed LPS-induced cell proliferation, migration, and inflammatory factor production in EESCs and Ishikawa cells, and induced apoptosis. Additionally, 1,25(OH)2D3 inhibited the expression and nuclear translocation of phosphorylated p65 in LPS-activated EESCs and Ishikawa cells. Furthermore, 1,25(OH)2D3 counteracted LPS-induced suppression of VD receptor (VDR)/IκBα and enhancement of Toll-like receptor 4 (TLR4)/pyrin domain (PYD)-containing protein 3 (NLRP3) activation, while the addition of TEI-9647 reversed VD's regulatory effects on the NF-κB pathway. In vivo experimental results showed that 1,25(OH)2D3 significantly inhibited lesion growth, suppressed NF-κB pathway activation, and corresponding inflammatory phenotypes in a rat model of endometriosis.
Conclusions: Collectively, these results underscore the potential of 1,25(OH)2D3 as a therapeutic target for endometriosis via VDR-dependent endometrial homeostasis regulation, suppressing LPS-mediated inflammatory responses and NF-κB signaling pathway through VDR activation and IκBα stabilization.
Keywords: Endometriosis; NF-κB; Vitamin D; inflammation; lipopolysaccharides.