Laboratory for Reproductive Immunology, Hospital & Institute of Obstetrics and Gynecology, IBS, Fudan University Shanghai Medical College, Shanghai 200011, China.
Hum Reprod. 2012 Jul;27(7):2107-16. doi: 10.1093/humrep/des132. Epub 2012 May 4.
Chemokine CXCL8 (also known as IL-8) has been identified as a potential regulator of endometrial stromal cells (ESCs), but it is unclear how CXCL8 regulates the survival of ESCs in the pathogenesis of endometriosis.
We assessed the secretion of CXCL8 by enzyme-linked immunosorbent assays and the expression of its receptors, CXCR1 and CXCR2, by in-cell Western assay and immunohistochemistry. The effects of CXCL8 on the activation or expression of various cell mediators were also investigated by in-cell Western assay. The effects of CXCL8 on the proliferation, growth and apoptosis of ESCs in vitro were assessed by BrdU assays, cell counts and annexin V labeling, respectively.
Secretion of CXCL8 and expression of CXCR1 in the eutopic ESCs from women with endometriosis were significantly higher than that in control ESCs, but the expression of CXCR2 showed no significant difference between these two cell types. CXCL8 stimulated proliferation and growth and reduced apoptosis of ESCs in an autocrine manner, and these effects were abolished by anti-human CXCL8 and CXCR1 neutralizing antibodies and by a PI3K/Akt inhibitor. Moreover, CXCL8 up-regulated the expression of the anti-apoptotic proteins, survivin and Bcl-2, inhibited the expression of the Phosphatase and tensin homolog (PTEN) and activated the phosphorylation of Akt.
This study suggests that CXCL8 and CXCR1 are involved in the pathogenesis of endometriosis by up-regulating proliferation and growth and restricting apoptosis in ESCs by activating the PTEN/Akt pathway and mediating the expression of survivin and Bcl-2.
趋化因子 CXCL8（也称为 IL-8）已被确定为子宫内膜基质细胞（ESCs）的潜在调节剂，但尚不清楚 CXCL8 如何调节子宫内膜异位症发病过程中 ESCs 的存活。
我们通过酶联免疫吸附试验评估 CXCL8 的分泌，通过细胞内 Western 测定和免疫组织化学评估其受体 CXCR1 和 CXCR2 的表达。还通过细胞内 Western 测定研究了 CXCL8 对各种细胞介质的激活或表达的影响。通过 BrdU 测定、细胞计数和 Annexin V 标记分别评估 CXCL8 对体外 ESCs 增殖、生长和凋亡的影响。
子宫内膜异位症患者在位 ESCs 中 CXCL8 的分泌和 CXCR1 的表达明显高于对照组 ESCs，但这两种细胞类型中 CXCR2 的表达无显著差异。CXCL8 以自分泌方式刺激 ESCs 的增殖、生长并减少其凋亡，这些作用被抗人 CXCL8 和 CXCR1 中和抗体以及 PI3K/Akt 抑制剂所阻断。此外，CXCL8 上调了抗凋亡蛋白 survivin 和 Bcl-2 的表达，抑制了磷酸酶和张力蛋白同源物（PTEN）的表达，并激活了 Akt 的磷酸化。
本研究表明，CXCL8 和 CXCR1 通过激活 PTEN/Akt 通路并介导 survivin 和 Bcl-2 的表达，上调 ESCs 的增殖和生长并限制其凋亡，从而参与子宫内膜异位症的发病机制。
