Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, Yale University, New Haven, CT, USA.
Mol Hum Reprod. 2021 Mar 24;27(4). doi: 10.1093/molehr/gaab016.
Endometriosis is a widespread gynecologic condition affecting up to 15% of women of reproductive age. The Janus kinase/signal transducer and activator of transcription (JAK/STAT3) pathway is upregulated in endometriosis and is a therapeutic target. Here we sought to determine the effect of Tofacitinib, a JAK inhibitor in widespread clinical use, on JAK/STAT signaling in endometriosis and lesion growth. Endometriosis was surgically induced in C57BL/6 mice using homologous uterine horn transplantation. Lesions were allowed to form over 4 weeks followed by Tofacitinib (10 mg/kg) or vehicle administered by oral gavage over 4 weeks. Tofacitinib treatment in vivo led to endometriosis lesion regression and reduced adhesion burden compared to vehicle treatment. In vitro studies on Ishikawa cells showed that Tofacitinib reduced hypoxia-inducible factor 1α and vascular endothelial growth factor mRNA levels at 12 and 24 h. Western blot analysis showed that Tofacitinib effectively reduced STAT3 phosphorylation in Ishikawa cells and human primary stromal and epithelial cells from eutopic endometrium of patients with and without endometriosis. This study suggests that the inhibition of JAK/STAT signaling using Tofacitinib may be a viable method for the treatment of endometriosis.
子宫内膜异位症是一种广泛存在的妇科疾病，影响着多达 15%的育龄妇女。Janus 激酶/信号转导子和转录激活子（JAK/STAT3）通路在子宫内膜异位症中被上调，是一个治疗靶点。在这里，我们试图确定托法替尼（一种广泛应用于临床的 JAK 抑制剂）对子宫内膜异位症和病变生长中 JAK/STAT 信号的影响。使用同源子宫角移植术在 C57BL/6 小鼠中诱导子宫内膜异位症。允许病变形成 4 周后，通过口服灌胃给予托法替尼（10mg/kg）或载体 4 周。与载体处理相比，体内给予托法替尼治疗导致子宫内膜异位症病变消退，并减少粘连负担。在 Ishikawa 细胞的体外研究中，托法替尼在 12 和 24 小时降低了缺氧诱导因子 1α 和血管内皮生长因子的 mRNA 水平。Western blot 分析表明，托法替尼可有效降低 Ishikawa 细胞以及来自有或无子宫内膜异位症的患者在位子宫内膜的基质和上皮细胞中 STAT3 的磷酸化。这项研究表明，使用托法替尼抑制 JAK/STAT 信号可能是治疗子宫内膜异位症的一种可行方法。
