1,25-Dihydroxy vitamin D(3) inhibits LPS-mediated inflammatory responses in endometriosis.

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 D(3) (1,25(OH)(2)D(3)), the biologically active form of VD, and its analog TEI-9647 (25-dehydro-1α-hydroxyvitamin D(3)-26,23-lactone). RESULTS: Our results revealed that 1,25(OH)(2)D(3) significantly reversed LPS-induced cell proliferation, migration, and inflammatory factor production in EESCs and Ishikawa cells, and induced apoptosis. Additionally, 1,25(OH)(2)D(3) inhibited the expression and nuclear translocation of phosphorylated p65 in LPS-activated EESCs and Ishikawa cells. Furthermore, 1,25(OH)(2)D(3) 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)(2)D(3) 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)(2)D(3) 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.