1,25-Dihydroxy vitamin D3 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 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.