Tibbetts T A, Mendoza-Meneses M, O'Malley B W, Conneely O M
Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Biol Reprod. 1998 Nov;59(5):1143-52. doi: 10.1095/biolreprod59.5.1143.
The epithelial and stromal compartments of the uterus undergo significant estrogen- and progesterone (P4)-induced changes during the estrous cycle. While in the adult mouse, epithelial proliferation and stromal inflammation are induced by estrogen, P4 is antiproliferative in the epithelium and both proliferative and anti-inflammatory in the stroma. In light of these compartmentally varying roles, we have immunohistochemically examined estrogen and P4 regulation of the expression of their receptors (ER and PR) and their epithelial target gene lactoferrin (LF) in wild-type and PR null mutant mice. We demonstrate that estrogen exerts compartment-specific effects on the expression of ER, resulting in decreased levels of stromal and glandular epithelial (GE) ER and increased luminal epithelial (LE) and myometrial ER. Estrogen also has dual effects on PR expression, decreasing levels in the LE while at the same time increasing levels in the stroma and myometrium. Estrogen and P4 together mediate their effects in part through the ability of P4 to selectively inhibit myometrial ER expression while preserving GE expression. We also demonstrate a general negative feedback by P4 on PR expression that is most prominent in the GE. Finally, we demonstrate using the estrogen- and P4-responsive epithelial target gene LF that the differential regulation of PR in the glandular and luminal epithelium results in different functional responses of these compartments to P4. Together, our data indicate that the pleiotropic effects of estrogen and P4 in the adult mouse uterus are mediated by complex hormonal interregulation of ER and PR in specific uterine compartments.
在发情周期中，子宫的上皮和基质部分会经历由雌激素和孕酮（P4）诱导的显著变化。在成年小鼠中，雌激素可诱导上皮增殖和基质炎症，而P4对上皮具有抗增殖作用，对基质则既有增殖作用又有抗炎作用。鉴于这些不同的作用，我们通过免疫组织化学方法研究了野生型和PR基因敲除突变小鼠中雌激素和P4对其受体（ER和PR）表达以及上皮靶基因乳铁蛋白（LF）的调控。我们发现，雌激素对ER的表达具有组织特异性影响，导致基质和腺上皮（GE）中ER水平降低，而腔上皮（LE）和子宫肌层中ER水平升高。雌激素对PR表达也有双重影响，降低LE中的PR水平，同时增加基质和子宫肌层中的PR水平。雌激素和P4共同作用，部分是通过P4选择性抑制子宫肌层ER表达而保留GE表达的能力来介导的。我们还证明了P4对PR表达具有普遍的负反馈作用，这在GE中最为明显。最后，我们利用雌激素和P4反应性上皮靶基因LF证明，腺上皮和腔上皮中PR的差异调节导致这些组织对P4产生不同的功能反应。总之，我们的数据表明，成年小鼠子宫中雌激素和P4的多效性作用是由特定子宫组织中ER和PR的复杂激素相互调节介导的。
