Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells

Abstract

Endometriosis is estrogen-dependent disorder. Two theories provide the explanations for the increased estrogen production. One is the feed-forward loop model linking inflammation and estrogen production. The more recent model evokes the tissue hypoxia resulting from endometrial debris detached and then regurgitated to the peritoneal cavity. Both models tacitly assume that everything occurs within the endometriotic stromal cells, seemingly without the need for exogenous factors. This study was undertaken to investigate as whether platelets may be responsible for local estrogen overproduction. We employed in vitro experimentation that evaluated the 17β-estradiol (e 2) levels in endometriotic stromal cells treated with activated platelets, and the genes and protein expression levels of StAR, HSD3B2, aromatase, and HSD17B1, as well as their upstream genes/proteins such as nf-κB, TGF-β1, HIF-1α, SF-1 and phosphorylated CREB. In addition, we conducted 2 animal experimentations using platelet depletion/infusion and also neutralization of NF-κB and tGf-β1, followed by immunohistochemistry analysis of involved in StAR, HSD3B2, aromatase, and HSD17B1, as well as SF-1 and p-CREB. We found that treatment of endometriotic stromal cells by activated platelets increase the e 2 production by 4.5 fold, and concomitant with increased gene and protein expression of StAR, HSD3B2, aromatase, and HSD17B1, the four genes/enzymes important to estrogen synthesis, along with their upstream genes HIF-1α, SF-1 and phosphorylated CREB. Moreover, platelets activate these genes through the activation of NF-κB and/or TGF-β1, and antagonism of either signaling pathway can abolish the induction of the 4 genes and thus increased estrogen production. The two animal experimentations confirmed these changes. Thus, platelets increase the E 2 production in endometriotic stromal cells through upregulation of StAR, HSD3B2, aromatase, and HSD17B1 via the activation of NF-κB and/or TGF-β1. These findings provide a yet another compelling piece of evidence that endometriotic lesions are indeed wounds undergoing repeated tissue injury and repair. They strongly indicate that non-hormonal therapeutics for endometriosis is theoretically viable, with antiplatelet therapy being one promising avenue. Endometriosis, defined as the deposition and growth of endometrium-like tissues outside the uterine cavity, is a common disorder affecting about 6-10% of women of reproductive age 1. As a major contributor to pelvic pain and infertility 2 impacting negatively on women's quality of life 3 , a source of anxiety and depression 4 and a leading cause of gynecological hospitalization in the United States 5 and likely in many other parts of the world, endometriosis is frequently viewed as an enigmatic disease due to its elusive pathogenesis and pathophysiology 6,7. Consequently, its effective treatment remains a challenge 2,8. Endometriosis has been viewed as a ultimate hormonal disease 9 , featuring estrogen-dependent growth and maintenance of ectopic endometrium as well as ...

Platelets and Regulatory T Cells May Induce a Type 2 Immunity That Is Conducive to the Progression and Fibrogenesis of Endometriosis

“…In fact, endometriotic stromal cells themselves can secrete platelet-activating molecules (94). Activated platelets can induce estrogen production in endometriotic stromal cells (97,98), which, in turn, may induce TSLP secretion (30). Through activation of DCs, TSLP can promote Th2 cell differentiation and propagate a type 2 immune response (16).…”

The Pathogenesis of Adenomyosis vis-à-vis Endometriosis

“…More remarkably, activated platelets can activate HIF-1α in endometrial and endometriotic stromal cells, effectively generating a state of hypoxia [97]. In fact, activated platelets can also upregulate the gene expression of StAR, SF-1 and aromatase, increasing the estrogen production significantly in endometriotic stromal cells [98]. Thus, the increased estrogen levels may induce an ERα-mediated OT/OTR system, enhancing uterine peristalsis.…”

A Brief Analysis of Tissue-Resident NK Cells in Pregnancy and Endometrial Diseases: The Importance of Pharmacologic Modulation

“…They then were able to explore the most relevant miRNA in endometriosis [148][149][150]. This information is critical since directed therapies depending on endometriosis may provide new elements to control the inflammatory disease and aid in fertilization [148][149][150][151][152][153][154][155][156][157][158][159][160][161][162][163][164][165][166]. In addition, exosomes contain miRNA and other proteins.…”

“…Other therapies involve platelet-rich plasma in the uterine cavity and the use of different stem cells [149][150][151][152][153][154][155]. The goal of the platelet-rich plasma is related to local TGFβ release and consequently promote NK differentiation [149][150][151][152][153][154][155]. There have not been conclusive studies using this therapy and other therapies involving various stem cells and allostimulation [155].…”