Endometriosis, one of the most frequently occurring gynecological
disorders, is estrogen dependent and is often associated with
immunological changes. These include increased macrophage activation
...and infiltration into the endometriotic implants themselves as well as
the peritoneal cavity where the implants often develop. Despite the
critical role estrogens play in the development of endometriosis, the
biochemical mechanisms of their action remain unclear. In the
present study we report that estradiol (E2) enhances
endometriotic cell responsiveness to the proinflammatory cytokine
interleukin-1β by up-regulating interleukin-1-induced monocyte
chemotactic protein-1 (MCP-1) expression at the level of both protein
secretion and messenger ribonucleic acid (mRNA) synthesis, whereas
progesterone had no significant effects. According to mRNA half-life
experiments, E2 action does not seem to be due to increased
MCP-1 mRNA stability but, rather, to a higher level of transcription,
as shown by run-on analysis. Interestingly, immunohistochemical
analysis of MCP-1 expression in endometriotic tissue showed intense
immunostaining in both epithelial glands and stroma regardless of the
menstrual cycle phase, which is consistent with the cell culture data
and indicates that MCP-1 expression is not subject to cyclic variation.
The findings of the present study for the first time provide evidence
that E2 up-regulates, although in an indirect way, the
expression of a potent chemotactic and activating factor by ectopic
endometrial cells, which may occur locally in the inflammatory site and
contribute to peritoneal macrophage recruitment and activation, and
reveal a new means of E2 action in the pathophysiology of
endometriosis.
PROBLEM: Endometriosis is associated with a chronic inflammatory process, and the increased number of activated peritoneal macrophages is one of the major hallmarks of this process. The medical ...treatment of the disease, which is based on the creation of an hypoestrogenic milieu unfavorable to the growth of endometriotic lesions, is often associated with a reduced peritoneal inflammation. The aim of this study was to investigate the ability of current therapeutic agents to modulate, through a direct mechanism, the expression by endometriotic cells of monocyte chemotactic protein‐1 (MCP‐1), a chemokine endowed with the potent faculty of recruiting and activating macrophages. METHOD OF STUDY: Cells were stimulated with interleukin‐1 beta (IL‐1β) to induce MCP‐1 expression. MCP‐1 protein secretion and mRNA steady‐state levels were evaluated by ELISA and northern blot, respectively. RESULTS: Our results show that danazol concentrations (10−7–10−5 M), taking into account the therapeutic levels found in the plasma of treated patients, inhibited MCP‐1 protein and mRNA steady‐state levels in endometriotic cells, whereas buserelin acetate (0.1–10 ng/mL), a GnRH agonist, had no significant effect. Dexamethasone, an anti‐inflammatory glucocorticoid, used at concentrations varying between 10−12 and 10−6 M, also displayed a dose‐dependent inhibitory action. CONCLUSIONS: These results put into prominence the capability of danazol to directly inhibit the expression of a potent monocyte chemotactic and activating factor by ectopic endometrial cells shedding more light on the mechanisms underlying the clinical effects of hormonal therapeutic agents used in the treatment of endometriosis.
The study of misplaced endometrial cells, which abnormally implant and grow outside the uterine cavity, is of considerable interest for the understanding of the pathophysiology of endometriosis. ...However, endometriotic cells, particularly epithelial cells, required for primary cell culture are not easily available. We report here the characterization of an endometriotic cell line immortalized after infection of primary endometriotic cell cultures with simian virus 40. Transformed cells express T-antigen, and blot hybridization analysis showed that the viral genome is present as an episome. Cytogenetic analysis revealed a polyploid karyotype with numerical and structural rearrangements involving mainly the same chromosomes (6, 10, 11, 15, and 17). The cell line has been maintained in culture for over 80 passages and was still proliferating without any noticeable change in the biological properties investigated. Transformed endometriotic cells expressed both progesterone and estradiol receptors and were stimulated by these ovarian hormones to secrete monocyte chemotactic protein-1, a factor that may play an important role in the recruitment and activation of peritoneal macrophages. In addition, this response was enhanced in interleukin-1-treated cells. Taken together, these findings support the view that this cell line may be an interesting tool for the study of the pathophysiology of endometriosis.
Transgenic mice expressing T antigen (Tag) in pancreatic beta cells establish systemic tolerance toward this self-protein. A study characterized this self-tolerance in two families of rat insulin ...promoter (RIP)-Tag mice, expressing different levels of Tag protein.
PDF
