Suppression of Matrix Metalloproteinase-9 by Prostaglandin E2 in Peritoneal Macrophage Is Associated with Severity of Endometriosis

Abstract

Decreased phagocytotic ability of macrophages has been reported to be associated with the severity of endometriosis, although the underlying mechanism remains uncharacterized. Expression and secretion of matrix metalloproteinase (MMP)-9 by macrophages is a means to degrade the extracellular matrix of cells that are designated for phagocytosis. Here, we describe the regulation of MMP-9 expression and activity in peritoneal macrophages of women with endometriosis. Results demonstrated that peritoneal macrophages isolated from women with endometriosis have decreased levels of protein and enzyme activity of MMP-9. Treatment of macrophages with peritoneal fluid obtained from patients with severe endometriosis inhibited MMP-9 expression and gelatinase activity. Further investigation identified prostaglandin (PG) E 2 as the major factor in the peritoneal fluid that inhibited MMP-9 activity. The inhibitory effect of PGE 2 was mediated via the EP2/EP4-dependent PKA pathway. Furthermore, expression of tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproteinase-2, and RECK in macrophages was not affected by treatment with PGE 2 , indicating the effect of PGE 2 on suppressing MMP-9 activity was not mediated by up-regulation of its inhibitor. Our results suggest that decreased phagocytotic capability of peritoneal macrophage in patients with endometriosis may be caused by PGE 2 -mediated decreases in MMP-9 expression. Endometriosis is a common gynecological disorder with a complex, multifactorial etiology that causes chronic pelvic pain, dysmenorrhea, and even infertility. The prevalence of this disease is ϳ10 to 15% among women of reproductive age. The underlying pathophysiological mechanism is still enigmatic. Although retrograde menstruation has been suggested to be the crucial constituent in the development of endometriosis, 1 factors allowing the implantation and propagation of endometriotic lesions are primarily unclear. Aberrant production of steroids by ectopic endometriotic lesions and alteration/ dysfunction of the immune system may lead to the development of endometriosis.2-5 During the development of endometriosis, immune cells are recruited into the peritoneal cavity. Among these immune cells, macrophages are the dominant cell type in the peritoneal cavity and are involved in phagocytosis and inflammation, especially in cleaning the retrograded endometrial debris.6,7 Peritoneal macrophages isolated from patients with endometriosis were found to have phenotypic and functional alterations leading to poor phagocytotic capacity, which is highly associated with severity of endometriosis. 4,8 Nevertheless, the mechanism of suppressed phagocytotic capability of macrophages in endometriosis is poorly understood.Matrix metalloproteinases (MMPs), also called matrixins, are proteinases that participate in extracellular matrix degradation.9 Based on substrate specificity, sequence similarity, and domain organization, vertebrate MMPs can be divided into six groups such as collagenases, gelatinases, stromel...

CD82 gene suppression in endometrial stromal cells leads to increase of the cell invasiveness in the endometriotic milieu

“…The initial phase of endometriosis is an invasion event that requires ECM breakdown and repair of tissues, such as an increased activity of these enzymes (MMP1, MMP2, and MMP9;Bruner-Tran et al 2002, Wu et al 2005. Indeed, MMPs and TIMPs levels have been correlated to the development and progression of endometriosis (Wu et al 2005, Kang et al 2008.…”

Macrophages Are Alternatively Activated in Patients with Endometriosis and Required for Growth and Vascularization of Lesions in a Mouse Model of Disease

“…Interestingly, a heterogeneity in response to innate signals among the population has been demonstrated, suggesting that environmental signals result in diverse patterns of macrophage activation in different subjects. 10,11 Differences in macrophage activation in the peritoneal cavity could therefore be involved in the susceptibility/ resistance to endometriosis: a "permissive" macrophage activation would facilitate the survival of shed endometrial tissue via the production of trophic and anti-apoptotic signals, facilitate invasion of the mesothelial layer via interference with the balance between metalloproteinase and their inhibitors, 12 and could be later on required for neo-angiogenesis. In the current study, using an experimental mouse model, we verified the hypothesis that macrophage activation is involved in the establishment, survival, and spreading of ectopic lesions from shed endometrium.…”

Involvement of Prostaglandins in the Pathophysiology of Endometriosis

“…Reduced expression of any one of the scavenger receptors may result in loss of phagocytic ability of macrophages . Another work suggests that the expression and the enzymatic activity of MMP-9, a metalloproteinase that plays important roles in the scavenger activity of macrophages, is reduced by PGE 2 in peritoneal macrophages derived from endometriosis patients compared to controls (Wu et al, 2005a). Wu and coworkers also reported that this inhibitory effect of PGE 2 may be mediated via the EP2/EP4-dependent PKA pathway (Wu et al, 2005a).…”

“…Another work suggests that the expression and the enzymatic activity of MMP-9, a metalloproteinase that plays important roles in the scavenger activity of macrophages, is reduced by PGE 2 in peritoneal macrophages derived from endometriosis patients compared to controls (Wu et al, 2005a). Wu and coworkers also reported that this inhibitory effect of PGE 2 may be mediated via the EP2/EP4-dependent PKA pathway (Wu et al, 2005a). These data allow us to explain some of the disruptions observed in the endometriotic macrophage functions and provide a functional link between COX-2 overexpression and endometriosis development (Ota et al, 2001;Tamura et al, 2002;Wu et al, 2005b).…”