Laboratory for Experimental Feto-Maternal Medicine, Department of Obstetrics and Fetal Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
J Reprod Immunol. 2011 Dec;92(1-2):33-44. doi: 10.1016/j.jri.2011.09.003. Epub 2011 Oct 21.
PCOS, a major cause of anovulatory sterility, is associated with obesity, insulin resistance and chronic inflammation. New evidence suggests that the immune system aggravates the clinical features of PCOS. Our aim was to study the immune, metabolic and endocrine features of a mouse model of PCOS elicited by androgenisation using dehydroepiandrosterone (DHEA). We observed a significant weight gain and insulin resistance in DHEA-androgenised mice, coupled with the formation of ovarian follicular cysts. DHEA up-regulated the expression of vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 in the granulosa cell layer of the majority of cysts, and VCAM-1 expression in the theca cell layer of all follicles and cysts. The expression of these markers was low in control tissue. Peritoneal cells from PCOS-mice showed enhanced production of inflammatory cytokines, suggesting an association between chronic inflammation and PCOS. In addition, DHEA-androgenisation induced the activation of CD4(+) cells both in vivo and in vitro, and their expression of the respective ligands for VCAM-1 and ICAM-1, VLA-4 and LFA-1, as assessed in vitro. CD4(+) cells were present in androgenised ovaries, especially in the granulosa cell layer of cysts with high VCAM-1 expression. Herein, we present novel evidence that the immune system is activated systemically and locally in a mouse model for PCOS. We propose that VCAM-1 is involved in aggravating PCOS symptoms by promoting leukocyte recruitment to the ovaries and perpetuating local inflammation. These findings offer novel therapeutic opportunities for PCOS, such as blockage of VCAM-1 expression.
多囊卵巢综合征（PCOS）是一种无排卵性不孕的主要原因，与肥胖、胰岛素抵抗和慢性炎症有关。新的证据表明，免疫系统会加重 PCOS 的临床特征。我们的目的是研究雄激素化脱氢表雄酮（DHEA）诱导的 PCOS 小鼠模型的免疫、代谢和内分泌特征。我们观察到 DHEA 雄激素化小鼠体重显著增加和胰岛素抵抗，同时伴有卵巢卵泡囊肿的形成。DHEA 上调了大多数囊肿颗粒细胞层中血管细胞黏附分子（VCAM）-1 和细胞间黏附分子（ICAM）-1 的表达，以及所有卵泡和囊肿的膜细胞层中 VCAM-1 的表达。这些标志物在对照组织中的表达水平较低。PCOS 小鼠的腹腔细胞表现出促炎细胞因子的产生增加，提示慢性炎症与 PCOS 之间存在关联。此外，DHEA 雄激素化在体内和体外均诱导 CD4+细胞的激活，并且它们在体外评估时表达各自的 VCAM-1 和 ICAM-1 配体，即 VLA-4 和 LFA-1。CD4+细胞存在于雄激素化的卵巢中，尤其是在高 VCAM-1 表达的囊肿颗粒细胞层中。在此，我们提供了新的证据表明免疫系统在 PCOS 的小鼠模型中全身和局部被激活。我们提出 VCAM-1 通过促进白细胞向卵巢募集并使局部炎症持续存在，从而加重 PCOS 症状。这些发现为 PCOS 提供了新的治疗机会，例如阻断 VCAM-1 的表达。
