Estrogen Promotes Pituitary Prolactinoma by Upregulating TLR4 / NF-κB/p38MAPK Pathway

Background: Prolactinomas have harmful effects on human health, and the pathogenesis is still unknown. Furthermore, the morbidity of women is much more than man, maybe related with estradiol level. Thus, it is important to reveal the pathogenesis and develop new therapeutic methods for prolactinomas.Methods: Immunofluorescence analysis or Immunohistochemistry analysis were performed on the ERβ, TLR4 and prolactin (PRL) expressions of pituitary gland in C57BL/6 mice and human prolactinoma specimen. In the present study, the role of TLR4 in prolactinoma was determined using estradiol-induced mice models in C57BL/6 wild-type (WT) and TLR4−/− mice. MMQ cells were treated with estradiol, fulvestrant, LPS or transfected with different TLR4 small interfering RNA, which to study ERβ, TLR4 and PRL expression in MMQ cells. Co‑immunoprecipitates analysis was used to investigate the interaction between ERβ and TLR4.Results: Immunofluorescence analysis or Immunohistochemistry analysis showed that PRL and TLR4 expression were co-located and increased in the pituitary gland of mice and human prolactinoma specimen compared with the control specimen. It was shown that PRL and TLR4 expression was co-located and increased significantly in the pituitary gland of estradiol-injected prolactinoma mice compared with the control mice. Knockout of TLR4 significantly inhibited tumor overgrowth, and PRL expression was decreased in estradiol-induced mice through regulating TLR4/NF‑κB/p38MAPK pathway. Estradiol promoted PRL expression through regulating TLR4/NF‑κB/p38MAPK pathway in vitro study, and pre-Inhibiting ERβ or TLR4 reverse the effect, while simultaneously activating ERβ and TLR4 enhanced PRL expression than activating single ERβ or TLR4. Furthermore, ERβ co-immunoprecipitates with endogenous TLR4 was assessed by co-immunoprecipitation analysis.Conclusions: These results suggest that estradiol promoted prolactinoma development by activating the TLR4/NF‑κB/ p38MAPK pathway through Erβ and TLR4 knockout inhibited the proliferation and secretion of prolactin in prolactinoma.