Regulation of Interleukin-8 Expression in Human Endometrial Endothelial Cells: A Potential Mechanism for the Pathogenesis of Endometriosis

Abstract

The elevation of the proinflammatory chemoattractant cytokine levels in ectopic and eutopic endometrium of endometriosis implies an inflammatory basis for this disease. The relationship between endothelial cells and leukocytes is likely to be important in the regulation of inflammatory mediators of endometriosis. The aim of this study was to describe the temporal and spatial expression of IL-8 in human endometrial endothelial cells (HEEC) in vivo and to compare the in vitro regulation of IL-8 expression by sex steroids in HEEC from women with or without endometriosis. Eutopic endometrial tissues and endometriosis implants were grouped according to menstrual cycle phase and examined by immunohistochemistry for IL-8 expression. Endothelial cells of endometriotic implants expressed higher IL-8 immunoreactivity compared with endothelial cells of eutopic endometrium from women with or without endometriosis (P < 0.02). For in vitro studies, HEEC were isolated from women with or without endometriosis and grown to preconfluence. The purity of cultured HEEC (90-95%) was confirmed by immunocytochemistry using endothelium-specific markers, CD31 and CD146. The effects of estradiol (5 x 10(-8) m), progesterone (10(-7) m), or both on IL-8 mRNA and protein levels were analyzed by RT-PCR and ELISA, respectively. Sex steroids reduced the expression of IL-8 mRNA and protein in HEEC from women without endometriosis. In contrast, both estradiol and progesterone stimulated IL-8 mRNA and protein expression in HEEC from women with endometriosis. We postulate that the stimulation of chemokine expression by sex steroids in HEEC of women with endometriosis may play a role in the inflammatory aspect of this disease.

Tumor Necrosis Factor-α Regulates Inflammatory and Mesenchymal Responses via Mitogen-Activated Protein Kinase Kinase, p38, and Nuclear Factor κB in Human Endometriotic Epithelial Cells

“…Primary cultures of endometriotic epithelial cells have been shown to produce IL-6, IL-8, and TNF-␣ (Bergqvist et al, 2000;Luk et al, 2005). MCP-1 and RAN-TES have also been found elevated in peritoneal fluid of women with endometriosis, and previously, their production has been reported to originate from stromal cells (Bersinger et al, 2006;Kalu et al, 2007).…”

Estradiol Attenuates Lipopolysaccharide-Induced CXC Chemokine Ligand 8 Production by Human Peripheral Blood Monocytes

“…The CXCL8 promoter contains C/EBP and NF-B-binding sites, and C/EBP and the p65 subunit of NF-B have been shown to cooperatively activate CXCL8 transcription through complex formation on the CXCL8 promoter (35). Recent studies suggest that E2/ER complexes may bind these transcription factors, thus changing their conformation and ability to bind DNA and activate transcription (34,36). It will be of considerable interest to determine whether C/EBP and/or NF-B binding to the CXCL8 promoter are altered in estradiol-treated monocytes.…”

Peripheral Biomarkers as Predictive Indicators of Endometriosis: A Prospective Case Control Study

“…[21] Chemokine IL-8 expression in endometrial endothelial cells is stimulated by sex steroids in women with endometriosis. [22] IL-8 enhances endometrial stromal cell metalloproteinase activity and invasive capability that degrade extracellular matrix to assist the endometrial cells invade the peritoneum and to built up an endometriotic lesion. [23] In our study level of serum IL-6 was higher in cases than controls but difference was statistically non-significant (Table 4).…”