Basal and Steroid Hormone-Regulated Expression of CXCR4 in Human Endometrium and Endometriosis

Abstract

Endometriosis is associated with activation of local and systemic inflammatory mechanisms, including increased levels of chemokines and other proinflammatory cytokines. We have previously reported increased gene expression of chemokine receptor 4 (CXCR4), the receptor for CXCL12, in lesions of the rat model of endometriosis. The CXCR4-CXCL12 axis has been shown to have both immune (HIV infection, lymphocyte chemotaxis) and nonimmune functions, including roles in tissue repair, angiogenesis, invasion, and migration. There is evidence indicating that these mechanisms are also at play in endometriosis; therefore, we hypothesized that activation of the CXCR4-CXCL12 axis could be responsible, at least in part, for the survival and establishment of endometrial cells ectopically. Immunohistochemistry (IHC) showed that CXCR4 protein levels were significantly higher in endometriotic lesions compared to the endometrium of controls. Next, we determined basal gene and protein expression of CXCR4 and CXCL12 and regulation by estradiol (E2) and/or progesterone (P4) in endometrial cell lines using quantitative polymerase chain reaction (qPCR), and Western blots. Basal CXCR4 gene expression levels were higher in epithelial versus stromal cells; conversely, CXCL12 was expressed at higher levels in stromal vs epithelial cells. CXCR4 gene expression was significantly downregulated by ovarian steroid hormones in endometrial epithelial. These data suggest that steroid modulation of CXCR4 is defective in endometriosis, although the specific mechanism involved remains to be elucidated. These findings have implications for future therapeutic strategies specifically targeting the inflammatory component in endometriosis.

Endometriosis with an aberrant immunophenotype: Challenging differential diagnosis of glandular lesions in the pelvic lymph nodes

“…32 ). These data are consistent with results published by Ruiz et al who also found significantly higher CXCR4 expression in endometriotic lesions compared to normal endometrium 33 . In 2012 Ji published that macrophages act as a direct structure contributor to lymphatic endothelial walls or secrete a vascular endothelial growth factor (VEGF) to initiate lymphangiogenesis in inflamed or tumor tissues 34 .…”

Bone Marrow Stem Cell Chemotactic Activity Is Induced by Elevated CXCl12 in Endometriosis

“…40 Microarray studies that show the increased mRNA expression of both CXCR4 and CXCL12 in endometriotic lesions further support our results. 1,35 Bone marrow (BM) contains multiple cell types including mesenchymal stem cells, which have the capacity to differentiate into a number of numerous types of cells.…”

“…These results are in agreement with the previous reports, 11,24,34,35 which described the upregulation of CXCR4 in both ectopic and eutopic endometrium of patients with endometriosis, as well as in endometriotic lesions in a rat model of endometriosis 34 and the peritoneal fluid from endometriosis patients. [36][37][38] More recently, it is been reported that the activation of the CXCR4-CXCL12 signaling axis is involved in the pathophysiology of endometriosis by promoting invasion and growth of endometrial cells ectopically 39,40 and is responsible for the survival of human secretory phase endometrial stromal cells by the inhibition of autophagy. 41 We demonstrated previously that E2 treatment at physiological levels induced the expression of both CXCR4 and CXCL12 in mBMCs and in human endometrial stromal cells (hESCs), respectively, and enhanced the chemoattraction activity of Figure 1.…”

HDAC1 and HDAC2 are Differentially Expressed in Endometriosis

“…Compared to EEC, Hs832cT cells have a lower ER1/ER2 ratio and lower PR protein levels (Bello et al, unpublished data). Steroid hormone treatments were conducted as described by Ruiz et al 23 …”