The association between progestins, nuclear receptors expression and inflammation in endometrial stromal cells from women with endometriosis

Abstract

Endometriosis is an inflammatory disease and nuclear receptors play a crucial role in mediating the inflammatory response. In endometrial stromal cells (ESC), nuclear receptors expression can be influenced by the local environment. Progestins are first-line, on-label treatments of endometriosis that may have direct effects on endometriotic lesions through these nuclear receptors. Therefore, we investigated whether there was an association between nuclear receptors expression and the influence of progestins on inflammatory cytokines production in a preliminary, in vitro study with primary cultures. ESC from endometrial biopsies of six subjects with histologically confirmed endometriosis were treated for 6 h with medium alone or with TNF-α (10 or 100 ng/ml) in the presence of dienogest (DNG), medroxyprogesterone acetate (MPA) and norethisterone acetate (NETA) 10–5 M. The progestin-mediated change in IL6, IL8 and MCP-1 mRNA transcription was measured, as was the PRA, PRB, GR, AR and MCR protein expression. The change (medium versus TNF-α 10 ng/ml and medium versus TNF-α 100 ng/ml) in IL6 mRNA transcription was positively associated with the change in PRB, but not PRA with both DNG and NETA treatment. The change in IL8 mRNA was negatively associated with AR expression in the presence of NETA. The change in MCP-1 mRNA expression was positively associated with GR expression and negatively associated with MCR after MPA treatment. The associations between the change in cytokines mRNA expression and nuclear receptors protein expression in response to progestins activity may indirectly suggest different activities of these compounds at a local level worthy of further investigations.

Chinese abstract

子宫内膜异位症（以下简称内异症）是一种炎性疾病, 核受体在介导炎性应答时起重要作用。在子宫内膜基质细胞（ESC）中, 核受体表达受局部环境的影响。孕激素是内异症符合说明书的一线治疗, 可能通过核受体对内异症病灶直接起作用。因此, 我们通过一项体外原代细胞培养的初步研究, 探讨核受体表达与孕激素对炎性细胞因子产生的影响是否有关联。6名组织学证实为内异症的受试者进行子宫内膜活检取ESC, 在地诺孕素（DNG）、醋酸甲羟孕酮（MPA）和醋酸炔诺酮（NETA）10-5M作用下单独用培养基培养6h, 或加入TNF-α （10或100ng/ml）培养。检测到孕激素介导的IL6, IL8和MCP-1 mRNA转录的改变, 以及PRA, PRB, GR, AR和MCR蛋白表达。IL6 mRNA转录的改变（培养基 vs. TNF-α 10 ng/ml vs. 100 ng/ml）与DNG和NETA培养下PRB（而非PRA）的改变呈正相关。NETA存在条件下IL8 mRNA的改变与AR表达呈负相关。MPA存在条件下MCP-1 mRNA表达的改变与GR呈相关, MCR呈负相关。孕激素作用下细胞因子mRNA的表达与核受体蛋白表达的关系可能间接说明这些化合物在局部水平发挥不同的作用, 值得进一步的研究。

Keywords:

• Androgen receptor
• dienogest
• medroxyprogesterone acetate
• norethisterone acetate
• progesterone receptors

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

All authors deny any financial relationship with biotechnology manufacturers, pharmaceutical companies and other commercial entities in relation to this original research.