**3.4 Prostaglandins as immune and inflammatory mediators in endometriosis**

Immune dysfunction has been proposed to play an important role in endometriosis (Dmowski W.P. & Braun, 2004; Vinatier et al., 1996). Peritoneal macrophages may play a key role in this respect, and may control the function of other immune cells. One of the altered mechanisms involved in the implantation and propagation of endometrial tissues ectopically is the decrease of the phagocytic ability of peritoneal macrophages (Chuang et al., 2009).

In their earlier studies, Braun and coworkers reported that the decrease in peritoneal macrophages cytotoxic function is controlled by PG synthesis (Braun et al., 1992) (Figure 2). To elucidate the molecular mechanism implicated in the reduced phagocytic ability of peritoneal macrophages in endometriosis, recent *in vitro* and *in vivo* studies demonstrated that PGE2, via the EP2 receptor-dependent signaling pathway, inhibits the expression of the scavenger receptor CD36 in peritoneal macrophages. Reduced expression of any one of the scavenger receptors may result in loss of phagocytic ability of macrophages (Chuang et al., 2010). 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 PGE2 in peritoneal macrophages derived from endometriosis patients compared to controls (Wu et al., 2005a). Wu and coworkers also reported that this inhibitory effect of PGE2 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).

There is abundant evidence demonstrating that endometriosis is accompanied by inflammatory reactions in the peritoneum, resulting in abnormal levels of a variety of cytokines, chemokines and pro-inflammatory factors in the peritoneal fluid (Gazvani & Templeton, 2002; Lousse et al., 2010). It is also well known, that the number of macrophages is increased in the peritoneal fluid of endometriosis patients and that they are in a hyperactive state (Halme & Surrey, 1990; Raiter-Tenenbaum et al., 1998). Production of inflammatory cytokines by these macrophages such as monocyte chemoattractant protein (MCP)-1, IL-1β, TNF-α and IL-6 is also increased in peritoneal fluid (Wu et al., 2007). As well, we found that the release of PGE2 by peritoneal macrophages was 100-fold higher in advanced endometriosis patients than in controls (Raiter-Tenenbaum et al., 1998).

It has also been demonstrated that the overexpression of COX-2 is markedly induced by IL-1β, TNF-α and MIF and that these pro-inflammatory agents strongly stimulate the production of PGE2 (Carli et al., 2009; Wu et al., 2002) (Figure 2). However, not only the overexpression of COX-2 increases the production of PGE2, but also a decrease in the deactivating enzyme 15-PGDH was found, showing an imbalance between eicosanoid biosynthesis and degradation in endometriosis patients compared with controls (Lousse et al., 2010). As a result, the concentration of PGE2 in the peritoneal fluid is elevated in patients with endometriosis, which leads to a more severe pathological process.

2002); as it happens with aromatase, a positive feedback loop is established in which COX-2 activity and PGE2 production are favored, giving the characteristic inflammation site of

Immune dysfunction has been proposed to play an important role in endometriosis (Dmowski W.P. & Braun, 2004; Vinatier et al., 1996). Peritoneal macrophages may play a key role in this respect, and may control the function of other immune cells. One of the altered mechanisms involved in the implantation and propagation of endometrial tissues ectopically is the decrease of the phagocytic ability of peritoneal macrophages (Chuang et

In their earlier studies, Braun and coworkers reported that the decrease in peritoneal macrophages cytotoxic function is controlled by PG synthesis (Braun et al., 1992) (Figure 2). To elucidate the molecular mechanism implicated in the reduced phagocytic ability of peritoneal macrophages in endometriosis, recent *in vitro* and *in vivo* studies demonstrated that PGE2, via the EP2 receptor-dependent signaling pathway, inhibits the expression of the scavenger receptor CD36 in peritoneal macrophages. Reduced expression of any one of the scavenger receptors may result in loss of phagocytic ability of macrophages (Chuang et al., 2010). 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 PGE2 in peritoneal macrophages derived from endometriosis patients compared to controls (Wu et al., 2005a). Wu and coworkers also reported that this inhibitory effect of PGE2 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

There is abundant evidence demonstrating that endometriosis is accompanied by inflammatory reactions in the peritoneum, resulting in abnormal levels of a variety of cytokines, chemokines and pro-inflammatory factors in the peritoneal fluid (Gazvani & Templeton, 2002; Lousse et al., 2010). It is also well known, that the number of macrophages is increased in the peritoneal fluid of endometriosis patients and that they are in a hyperactive state (Halme & Surrey, 1990; Raiter-Tenenbaum et al., 1998). Production of inflammatory cytokines by these macrophages such as monocyte chemoattractant protein (MCP)-1, IL-1β, TNF-α and IL-6 is also increased in peritoneal fluid (Wu et al., 2007). As well, we found that the release of PGE2 by peritoneal macrophages was 100-fold higher in

advanced endometriosis patients than in controls (Raiter-Tenenbaum et al., 1998).

with endometriosis, which leads to a more severe pathological process.

It has also been demonstrated that the overexpression of COX-2 is markedly induced by IL-1β, TNF-α and MIF and that these pro-inflammatory agents strongly stimulate the production of PGE2 (Carli et al., 2009; Wu et al., 2002) (Figure 2). However, not only the overexpression of COX-2 increases the production of PGE2, but also a decrease in the deactivating enzyme 15-PGDH was found, showing an imbalance between eicosanoid biosynthesis and degradation in endometriosis patients compared with controls (Lousse et al., 2010). As a result, the concentration of PGE2 in the peritoneal fluid is elevated in patients

**3.4 Prostaglandins as immune and inflammatory mediators in endometriosis** 

development (Ota et al., 2001; Tamura et al., 2002; Wu et al., 2005b).

endometriosis (Figure 2).

al., 2009).

Macrophages synthesize and liberate PGE2, VEGF, MIF, IL-1β, TNF-α; all of these factors stimulate the expression and/or activity of COX-2 producing higher concentrations of PGE2. The high levels of PGE2 stimulate the expression of the angiogenic factor VEGF and the steroidogenic capacity of endometriotic cells by the upregulation of StAR and aromatase, which augments the byosinthesis of estrogen. E2 and PGE2 further induce FGF-9 expresion to stimulate endometriotic cell proliferation. As a result, angiogenesis and cell proliferation are augmented while apoptosis is inhibited. Moreover, PGE2 suppresses the phagocytic ability of macrophages, which fail to phagocytase the retrograde endometrial tissue and allow the implantation and proliferation of endometriotic lesion.

**A:** androstenedione; **AA**: arachidonic acid; **Arom:** aromatase P450; **COX-2**: cyclooxygenase-2; **E2**: estradiol; **IL-1β**: interleukin 1β; **MIF**: macrophage migration inhibitory factor; **PGE2**: prostaglandin E2; **StAR**: steroidogenic acute regulatory protein; **TNF-α**: tumor necrosis factor α; **VEGF**: vascular endothelial growth factor; **FGF-9**: fibroblast growth factor-9.

Fig. 2. Peritoneal environment in endometriosis
