Endometriosis: Pathogenesis and Treatment 2014 Ed.

7. Inflammation and Cytokines in Endometriosis

Tomio Iwabe  and Tasuku Harada2

(1)

Department of Obstetrics and Gynecology, Faculty of Medicine, Sanin Rosai Hospital, Yonago, Japan

(2)

Department of Obstetrics and Gynecology, Faculty of Medicine, Tottori University, Yonago, Japan

Tomio Iwabe

Email: iwabe@saninh.rofuku.go.jp

Abstract

Endometriosis, a common disease among women of reproductive age, is characterized by the presence and growth of endometrial tissue (glands and stroma) outside the uterus. Dysmenorrhea and infertility common in endometriosis compromise the quality of life of reproductive age women. Despite a long history of clinical experience and experimental research, endometriosis remains an enigma, and its pathogenesis is still controversial. The peritoneal fluid (PF) of women with endometriosis contains an increased number of activated macrophages that secrete a variety of local products, such as growth factors and cytokines. In this chapter, we review the current understanding of the role of cytokines in the pathogenesis of endometriosis.

Keywords

AngiogenesisCytokinePeritoneal fluidRetrograde menstruationTranscriptional factor

7.1 Introduction

Endometriosis was first acknowledged more than about 100 years ago, and the usual definitions of this disease are based on histology and related to glands, stroma, hemosiderin, and fibromuscular metaplasia [1]. Endometriosis, which occurs in 10 % of reproductive age women, is characterized by the growth of endometrial-like tissue outside the uterus. Dysmenorrhea and infertility, which are common symptoms of endometriosis, compromise the quality of life. This disease is thought to be estrogen dependent. However, the pathogenesis of endometriosis is poorly understood despite decades of experimental and clinical study. Endometriosis is associated with infertility even among affected women who ovulate and have anatomically patent fallopian tubes. The exact mechanism by which endometriosis interferes with fertility is not known, but data suggest that an aberrant immunological mechanism is involved in its pathophysiology. An important general concept is that of endometriosis as a local pelvic inflammatory process with altered function of immune-related cells in the peritoneal environment. Supporting this concept are recent studies suggesting that the peritoneal fluid (PF) of women with endometriosis contains an increased number of activated macrophages that secrete a variety of local products, such as growth factors and cytokines. Therefore, secreted cytokines in chronic pelvic inflammation is a key factor in the pathogenesis of endometriosis [2].

7.2 Peritoneal Environment

7.2.1 Retrograde Menstruation

Retrograde menstruation, in which fragments of endometrium are refluxed through the fallopian tubes into the peritoneal cavity, occurs only in women and nonhuman primates and in a few exceptional species, such as the elephant and bat. Spontaneous endometriosis, which is clinically confirmed endometriosis in nature, has been reported only in humans and some primates, the rhesus macaque (Macaca mulatta), the Japanese macaque (Macaca fuscata), the pig-tailed macaque (Macaca nemestrina), and the Kenya baboon (Papio doguera) [3]. The reproductive organs of women are anatomically similar to that of female baboons; therefore these nonhuman primates are thought to be an adequate animal experimental model. Patients with endometriosis almost always have patent tubes; thus blood and endometrial fragments are able to pass out of the uterus by way of the tubes (Fig. 7.1). Cyclic and retrograde menstruation are common phenomena in both humans and these animals. Several studies suggest that retrograde menstruation strongly relates to endometriosis. Shorter cycles and heavier and longer menstrual flow often occur in women with endometriosis [4]. From the above observation, retrograde menstruation is one of the most important factors in the pathophysiology of endometriosis.

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Fig. 7.1

Laparoscopic findings in pelvic cavity during menstrual period. (a) Retrograde menstruation from fimbria. (b) Cul-de-sac

The most widely accepted hypothesis for endometriosis is Sampson’s theory of retrograde menstruation [5]. Retrograde menstruation occurs in 76–90 % of investigated women, and endometrial cells have been observed in the peritoneal fluid of 59–79 % of women during menstruation or the early follicular phase; however, endometriosis was diagnosed in only 10 % of this population [67]. Endometriosis was hypothesized to be caused by decreased clearance of peritoneal fluid in endometrial cells due to reduced natural killer (NK) activity and/or decreased macrophage activity [8]. However, the development of endometriosis cannot be explained by this phenomenon. Recently, Khan et al. reported that the menstrual blood of women with endometriosis is more frequently contaminated with Escherichia coli than that of the controls and corresponds to higher levels of endotoxin in the menstrual fluid. Consequently, endotoxin levels are high in the PF due to reflux of menstrual blood into the pelvis. The colony formation of E. coli and endotoxin levels in the menstrual fluid was markedly higher in women with red lesion in r-ASRM stage I–II endometriosis patients than in women with endometrioma of stage III–IV endometriosis [9]. We also reported LPS (endotoxin)-promoted proliferation and invasion of endometriotic stromal cells via upregulation of cyclooxygenase 2 (COX2) and prostaglandin E2 (PGE2) [10]. These findings, including that of bacterial contamination, would be a suitable area for future research into the pathophysiology of endometriosis.

7.2.2 Peritoneal Fluid

Peritoneal fluid (PF) containing immune-related cells is often seen in the vesico-uterine cavity or the pouch of Douglas during gynecologic surgery. PF bathes the pelvic cavity, uterus, fallopian tubes, and ovaries and may be a major player controlling the peritoneal microenvironment that influences the development and progression of endometriosis and endometriosis-associated infertility.

The peritoneal cavity is normally empty except for a thin film of fluid that keeps surfaces moist. Peritoneal fluid arises primarily from two sources: plasma transudate and ovarian exudate. Other sources of peritoneal fluid are tubal fluid, retrograde menstruation, and immune cell secretions. Peritoneal fluid depends on follicular activity, corpus luteum vascularity, and hormonal production. The volume of PF within the peritoneal cavity varies during the menstrual cycle, reaching a peak of 20 mL at the time of ovulation [11].

Changes in fluid volume and the presence of various cells, hormones, and other compounds during normal menstrual cycles and in pathologic conditions have been described. Syrop and Halme analyzed PF volume in 426 patients and found that women with endometriosis had a greater PF volume than fertile controls, patients with adhesive disease, or those with unexplained infertility [12]. The PF volume in women with unexplained infertility was also higher than in controls. Therefore, increased PF volume may be commonly associated not only with endometriosis but also with long-lasting, unexplained infertility.

PF contains various free-floating cells, including macrophages, mesothelial cells, lymphocytes, eosinophils, and mast cells. Normally, PF contains leukocytes in concentrations of 0.5–2.0 × 106 mL−1, of which approximately 85 % are macrophages. Halme et al. postulated that peritoneal macrophage activation might be a central contributor to the pathogenesis of endometriosis [13]. Activated macrophages in the peritoneal cavity of women with endometriosis are potent producers of cytokines. Thus, PF contains a rich cocktail of cytokines. The cytokines are multifunctional proteins whose biological properties suggest a key role in hematopoiesis, immunity, infectious disease, tumorigenesis, homeostasis, tissue repair, and cellular development and growth.

7.3 Cytokines

7.3.1 Cytokines in Peritoneal Fluid

Cytokines, a large family of more than 100 low molecular weight proteins that function as growth and differentiation factors and immune cell modulators, also play a major role in the regulation of immune and inflammatory responses. Immune cell activation results in a burst and cascade of inflammatory cytokines. These cytokines have pleiotropic and redundant activities culminating in the recruitment of numerous cell types to the site of inflammation.

The development of enzyme-linked immunosorbent assay has made it possible to measure a number of cytokines in the PF of women with endometriosis. These include interleukin-1 (IL-1) [14], IL-4 [15], IL-5 [16], IL-6 [1721], IL-8 [2224], IL-10 [202526], IL-12 [2728], IL-13 [29], IL-17 [30], IL-23 [31], IL-33 [32], interferon γ (INFγ) [19], tumor necrosis factor α (TNFα) [1421], RANTES [33], monocyte chemotactic protein-1 (MCP-1) [3436], macrophage colony-stimulating factor (MCSF) [37], transforming growth factor β (TGFβ) [38], and vascular endothelial growth factor (VEGF) [3940]. A number of studies report that the level of many cytokines is increased in the PF of women with endometriosis. Cytokines may regulate the actions of leukocytes in the PF or could act directly on the ectopic endometrium, where they may play various roles in the pathogenesis and pathophysiology of endometriosis.

7.3.2 Source of Cytokines

Increased levels of cytokines in the PF of women with endometriosis may reflect increased synthesis of cytokines by the peritoneal macrophages, lymphocytes, ectopic endometrial implants, and/or mesothelial cells of the peritoneum, all of which are capable of cytokine production [4142]. The main source of cytokines is thought to be the macrophages, which originate in bone marrow, circulate as monocytes, and then migrate to various body cavities.

7.3.2.1 Macrophages

Macrophages are main regulators of the innate response to injured, infected, and neoplastic tissues. The peritoneal macrophages (PMs) are the major resident cells in the peritoneal cavity. They kill cells, such as retrograde endometrial tissues, and their presence is commonly associated with an inflammatory process. Most studies revealed increased cell numbers and activity of PMs in cases of endometriosis, although some studies did not [4344]. The increased number of PMs in women with endometriosis may indicate that the presence of endometrial tissue in the peritoneal cavity represents a foreign entity and needs to be removed. Activated PMs might synthesize and secrete different cytokines into the PF including various cytokines and growth factors.

7.3.2.2 T-Lymphocytes

T-lymphocytes are also implicated in the pathogenesis of endometriosis. T-helper cells can be classified into two subsets: type 1 (Th1) and type 2 (Th2). Th1 cells produce IL-2, IL-12, and INFγ, which are potent inducers of cell-mediated immunity. Th2 cells produce mainly IL-4, IL-5, IL-10, and IL-13, which are involved in the suppression of cell-mediated immunity. Hsu et al. investigated the expression of Th1 (IL-2 and INFγ) and Th2 (IL-4 and IL-10) cytokines in the peripheral blood monocytes and PF from patients with endometriosis [15]. They found that cytokine secretion by Th1 and Th2 cells is altered in women with endometriosis. The shift in the balance of Th1/Th2 toward the Th2 arm may contribute to the derangement of an immunologic defense mechanism in endometriosis. Interleukin-10 is well known to be an anti-inflammatory cytokine in regulating inflammatory responses. We also observed that IL-10 expression levels in endometriotic stromal cells were lower than in endometrial stromal cells [26].

7.3.2.3 Others

Recent studies suggest that endometriotic implants also produce cytokines [4546]. We demonstrated that endometriotic cells constitutively express IL-6 mRNA and produce IL-6 protein and that adding TNFα stimulated IL-6 gene and protein expression in a dose-dependent manner [47]. When we compared IL-6 production by macrophages and endometriotic stromal cells in patients with endometriosis, similar levels of IL-6 were found to be produced in stromal cells derived from an endometrioma and by macrophages under basal- and TNFα-stimulated conditions.

Numerous leukocytes are harbored in both stromal and intraepithelial parts of normal eutopic endometrium. In women with endometriosis, the member of lymphocytes is increased both in eutopic and ectopic endometria. We postulated that immune cells, such as leukocytes or lymphocytes, and endometriotic tissue interacted via the paracrine mechanism on the source of the cytokines. Therefore, they may contribute to cytokine production in PF and be involved in cellular growth and inflammatory reaction. The findings suggest that endometriotic tissue may be another important source of this cytokine.

7.3.3 Role of Cytokines

The pathogenesis of endometriosis is still a matter of debate, despite extensive research efforts since Sampson’s landmark article in 1927 [5]. Sampson’s theory of retrograde menstruation, which describes endometrial cells that may attach, implant, and grow, seems plausible because peritoneal lesions are most frequently found in the ovaries and the posterior cul-de-sac where regurgitated menstrual material pools.

One study demonstrated that endometrium can attach to the mesothelial surface of the peritoneum in vitro [48]. The authors described that in all cases of adhesion to intact mesothelium, the endometrium was attached via stromal cells. Another theory, the metaplasia theory, is also attractive since it can explain some rare cases of endometriosis, such as those with the absence of menstruation (Rokitansky–Kuster–Hauser syndrome) [49]. A recent in vitro study supports the metaplasia theory [50]. Unfortunately, neither theory can explain all cases of endometriosis.

7.3.3.1 Implantation of Endometrium

Recent studies demonstrated increased IL-6 production by endometriotic cells in both basal- and cytokine-stimulated conditions compared with their normal counterpart [45]. Tseng et al. examined eutopic endometrium from patients with endometriosis and found an increased basal- and IL-1β-stimulated production of IL-6 compared with patients without endometriosis [46]. This is an important aspect for recent investigation because it suggests that endometrial cells of women who develop endometriosis may function differently from those who do not.

In order to implant and grow, endometrial cells must establish cell–cell or cell–extracellular matrix (ECM) interactions with the peritoneal lining. In these circumstances, cell adhesion molecules are of great importance [51]. A recent report clearly showed that endometrial stromal cells are the critical cells in endometrial attachment to the mesothelial surface of the peritoneum and that endometrial epithelial cells fail to attach to the mesothelium [48]. Most of these interactions between endometrial cells and ECM are mediated by the integrin family of cell surface receptors, which are capable of transducing intracellular signals. It has also been suggested that cellular▪adhesion itself stimulates chemokine expression [52].

Garcia-Velasco and Arici showed that increasing the dose of IL-8 stimulates endometrial stromal cells’ ability to adhere to an ECM protein, fibronectin [53]. They also showed that the adhesion of endometrial stromal cells to different ECM proteins induces variable levels of IL-8 gene expression and protein secretion and that this event is integrin-mediated [54]. IL-8 may be relevant for the attachment of endometrial implants in the pathogenesis of endometriosis.

According to Sampson’s theory of retrograde menstruation, deficient cellular immunity, in particular impaired natural killer (NK) cell function, is one of the etiological factors that could contribute to the survival and implantation of refluxed endometrial cells. Several investigators showed a decrease in NK cell activity in the PF of women with endometriosis compared with women without endometriosis [85556]. This observation suggests that the clearing mechanism of retrograde menstruated endometrial cells may be impaired in women with endometriosis because of a defect in the local immune defense system. Oosterlynck et al. found increased TGFβ activity in the PF of women with endometriosis [37]. Transforming growth factor β may be a cytokine that inhibits NK activity in the PF of women with endometriosis.

Intercellular adhesion molecule (ICAM)-1-mediated cell–cell adhesion is essential for various immunological functions, including NK cell-mediated cytotoxicity against endometrium. Recently, Somigliana et al. reported that soluble intercellular adhesion molecules (sICAM)-1 were constitutively shed from the surface of endometrial stromal cells obtained from patients with endometriosis into the culture medium [57]. The enhanced release of sICAM may allow the endometrial stromal cells of patients with endometriosis to escape immunosurveillance and, therefore, to implant in ectopic sites. More interestingly, sICAM-1 production from the macrophages of patients with endometriosis was upregulated by INFγ and IL-6 [58].

Interleukin-12 acts on T and NK cells, inducing cytokine production (primarily INFγ), enhancing NK cell cytotoxic activity, and favoring the generation of T-helper 1 response [5960]. Concentrations of IL-12 in the PF are low regardless of the presence or absence of endometriosis, but they are detectable [26]. The administration of IL-12 was recently shown to significantly prevent ectopic endometrial implantation in a murine model of endometriosis [61]. A direct growth inhibitory effect on endometrial cells seems unlikely since endometrial cells do not express receptors for IL-12. A potential explanation for these results is that IL-12 may enhance the growth and augment the cytolytic activity of both NK and T cells. These data support the idea that manipulation of cytokine activity in PF is a novel management approach to controlling the establishment of endometriosis.

7.3.3.2 Angiogenesis

Angiogenesis seldom occurs in adult organs with normal tissues under physiologic conditions. The endometrium represents an exception: the tightly regulated fluctuation of ovarian steroids, estrogen and progesterone concentrations, cyclically triggers the remodeling of the organ vasculature, with angiogenesis and lymphangiogenesis. Angiogenesis, which is the process of generating new capillary blood vessels, occurs in a variety of normal and pathologic processes. It consists of the following steps: dissolution of the basement membrane by the protease derived from vascular endothelial cells, migration and proliferation of the endothelial cells, and formation of the capillary tube [62]. Each step is regulated by various angiogenic factors. Neovascularization is likely to be required for the implant to grow beyond 2–3 mm during tumor growth [63]. An angiogenic mechanism could be involved in the pathogenesis of endometriosis. We can postulate that further outgrowth of these ectopic endometrial implants will depend on new capillary growth according to several studies that indicate that tumors are angiogenesis dependent [64].

Vascular endothelial growth factor (VEGF) is a heparin-binding growth factor of 30–46 KDa, which is active as a disulfide-linked homodimer and is a potent mitogen, morphogen, and chemoattractant for endothelial cells. The angiogenic activity of PF, as well as levels of VEGF in PF, is elevated in women with endometriosis [3865]. McLaren et al. demonstrated that PF macrophages are the principal source of the angiogenic growth factor, VEGF, and that the anti-VEGF antibody abolished the enhanced endothelial cell proliferation induced by a conditioned medium from macrophages isolated from the peritoneal cavity of women with endometriosis [39]. McLaren’s study suggests that activated macrophages are a major source of VEGF in endometriosis and that estradiol and progesterone directly regulate this expression. Since endometriosis is characterized by pronounced vascularization within and surrounding the ectopic tissue, elevated levels of the potent angiogenic growth factor, VEGF, in the PF and the presence of VEGF-positive macrophages within the ectopic tissue are clinically important in this disease. VEGF-induced angiogenesis may therefore be a critical aspect of the pathophysiology of endometriosis.

IL-8, which is a chemoattractant for neutrophils and an angiogenic agent, induces the proliferation of human melanoma and glioma cells [6667]. Arici et al. reported that IL-8 is produced in the human endometrium in vivo, mainly in glandular cells, and that IL-8 induces proliferation of endometrial stromal cell as a potential autocrine growth factor [6869]. We demonstrated that IL-8 exerts its growth-promoting actions in endometriotic as well as in normal endometrial cells [2470]. TNFα, a secretory product of activated macrophages and a potent inducer of new blood vessel growth, also stimulates proliferation of endometriotic stromal cells. These angiogenic cytokines may play a role in the angiogenesis of endometriosis.

Hypoxia is the stimulus that triggers vessel remodeling in injured and regenerating tissues as well as in tumors. It elicits an adaptive response, which is largely mediated by the hypoxia-inducible transcription factor-1 alpha (HIF1α), under hypoxic conditions. HIF1α translocates to the nucleus where it enhances and accelerates the transcription of genes with appropriate response elements, including angiopoietin 2 (Ang-2), CXCL12, and VEGF [7173].

In experimental models of endometriosis, early phases of lesion establishment are characterized by a transient hypoxia, which results in the upregulation of HIF1α, with downstream expression of VEGF [7475]. Limited ischemia of the endometrium in the early and middle secretory phase occurs: the event is apparently associated with the upregulated expression of VEGF in the late secretory phase of the menstrual cycle in endometriotic women [76]. Interestingly, endometrial fragments from women in which a transient ischemia had been induced by repeated clamping/ unclamping of the uterine artery transplanted onto the chick embryo chorioallantoic membrane demonstrated higher VEGF expression and better survival: this mechanism could facilitate implantation and establishment of the endometrium at ectopic sites [77]. Moreover, response to ischemia is likely to play a role in established lesions of endometriotic patients: the relative expression of HIF1α and VEGF differs at various sites within endometriotic lesions, possibly accounting for some of their heterogeneous histological characteristics [78].

7.3.3.3 Progression and Infiltration

Surrey and Halme demonstrated a direct stimulatory effect of the cell-free fraction of PF samples derived from patients with endometriosis on the proliferation of normal uterine endometrial cells in a short-term culture, indicating that factors in the PF are involved in the progression of endometriosis [79]. Several cytokines, such as IL-8 and TNFα, have growth-promoting effects on endometrial and endometriotic cells [246970]. These findings suggest that elevated PF levels of cytokines promote the progression and spread of endometriotic implants in the peritoneal cavity.

We revealed that PF levels of IL-8 significantly enhanced the proliferation of stromal cells derived from ovarian endometriomas [24]. Expression of IL-8 receptor type A (CXCR3A) mRNA was detected in endometriotic stromal cells. These results suggest that IL-8 may promote the progression of endometriosis [70]. We tested the hypothesis that TNFα elevated in PF of patients with endometriosis may contribute to the progression of endometriosis by inducing the production of IL-8. Gene and protein expression of IL-8 in the stromal cells of endometriotic tissues are upregulated by TNFα, and TNFα also stimulated the proliferation of the endometriotic stromal cells. This stimulatory effect of TNFα was abolished by adding either anti-TNFα antibody or anti-IL-8 antibody. Therefore, the action of TNFα on stromal cells may occur by mediating the proliferative effects of IL-8. The expression of type I and type II receptors for TNFα was observed in endometriotic stromal cells. This evidence suggests that TNFα action mediated by IL-8 may not only be an initiating factor that facilitates adhesion of endometrial cells to the peritoneum, but may also contribute to the development and progression of endometriosis.

We found that the extent of superficial red endometriotic lesions was related to increased levels of IL-6, IL-8, and TNFα in the PF [21]. Red lesions, such as red flame-like lesions, gland-like lesions, and red vesicles, were classified as active lesions of endometriosis because angiogenesis is more pronounced in red lesions than in black or white lesions and because early red lesions invade the ECM. Thus, cytokines may play a role in the early stage of endometriosis.

Hepatocyte growth factor (HGF) was originally characterized as a potent mitogen for adult hepatocytes. HGF is known as a mesenchymal (stromal)-derived pleiotropic growth factor that elicits mitogenic and morphogenic activities on various types of epithelial cells, usually as a paracrine factor [8081]. In normal uterine endometrium, stromal-derived HGF promotes proliferation, migration, and lumen formation of endometrial epithelial cells [82]. Overexpression of Met, the receptor for HGF, was observed in several malignant tumors, such as uterine endometrium and ovary [83]. We also showed that the peritoneum and endometriotic stromal cells may be major sources of HGF in peritoneal fluid. Endometrial and endometriotic stromal cells expressed the Met receptor, which was activated by endogenous and exogenous HGF [84]. HGF enhanced stromal cell proliferation and invasion. We also demonstrated that the HGF-stimulated stromal cell invasion was due in part to the induction of urokinase-type plasminogen activator, a member of the extracellular proteolysis system. HGF increased in PF and produced by endometrial stromal cells may induce critical changes in morphology of mesothelial cells and then enhance the endometrial cell attachment and invasion.

7.3.3.4 Infertility

Pelvic endometriosis is frequently associated with infertility even if affected women ovulate and have functional, patent tubes. The exact mechanism by which endometriosis interferes with fertility is not fully understood. A recent study suggests that cytokines are related to infertility in women with endometriosis [2]. Since the ovaries and fallopian tubes are bathed in PF, substances present in PF have the potential to impact greatly on the reproductive function by affecting tubal motility, ovum pickup, or ovulation. It is speculated that a substance or substances from endometriotic tissues enter the PF, interfering with the reproductive process. Interleukin-6, a pleiotropic cytokine produced by a variety of cell types, plays a pivotal role as a mediator of numerous physiologic and pathogenic processes. It has also been suggested that IL-6 has important functions in reproductive physiology, including the regulation of ovarian steroid production, folliculogenesis, and early events related to implantation [85]. We demonstrated that the addition of human recombinant IL-6 to culture medium suppressed the rate of blastocyst formation of mouse embryos, suggesting that increased IL-6 in the PF of endometriosis patients may contribute to infertility by adversely affecting embryonic development [86]. Recently, Banerjee J et al. showed that IL-6 caused the deterioration in morphology of the microtubule and chromosomal alignment in metaphase-II mouse oocytes [87]. IL-6, generated in the process of oxidative stress, directly affects the quality of the oocyte and may contribute to infertility.

We used a steroidogenic human granulosa-like tumor cell line, KGN cells, as a model for granulosa cells collected during the follicular phase [88]. We demonstrate that IL-6 may reduce aromatase activity and E2 production via the MAPK signal pathway in human granulosa cells [89]. The results may support the notion that IL-6 is related to impaired estrogen biosynthesis in patients with endometriosis.

Half of the cause of infertility is the male factor. The key predictors of fertilization capability are sperm count and motility. We showed that IL-6 and sIL-6R significantly reduced the percentage of motile and rapidly moving sperm [90]. The inhibition of sperm motility by IL-6 may be involved in the infertility of at least some patients with endometriosis who have highly elevated levels of IL-6 in PF. PF diffusing into the tubal and endometrial environment may affect the sperm and their interaction with the oocyte and embryo development. Many authors have demonstrated that the PF of patients with endometriosis has detrimental effects on several steps of the reproductive process.

These findings suggest that endometriotic implants, which can produce various cytokines, may contribute to reduced fecundity in patients with endometriosis. The role of PF and cytokines in the pathophysiology of endometriosis-associated infertility is summarized in Fig. 7.2. However, data on cytokines and their role in infertility are still incomplete, and future investigation that can reveal the critical roles of cytokines is still needed.

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Fig. 7.2

Pathophysiology of endometriosis-associated infertility

7.3.4 Signal Transduction in Endometriotic Cells

Signal transduction is defined as the response of a cell to the application of an external stimulus. Numerous factors, including cytokines, hormonal factors, genetic predisposition, environmental toxins, and immunological dysfunction, may contribute to the aberrant progression of endometriotic tissue.

7.3.4.1 MAPK Pathway

Many studies have demonstrated that MAPK is involved directly in regulating the pathogenesis of endometriosis [9193]. MAPK pathways seem to play a pivotal role as intracellular and extracellular signal transducers in endometriotic cells. In the MAPK pathway, the activation of p38, c-jun N-terminal kinase (JNK), and ERK1/2 is important for inflammatory cytokine secretion in endometriotic stromal cells. The most extensively studied mitogen-activated protein kinase (MAPK) pathway is the extracellular signal-regulated kinase (ERK) pathway in which the MAPKKK is Raf, the MAPKK is MEK, and the MAPK is ERK. The activation of the MAPK pathway induced by TNFα through Ras, Raf, MEK, and ERK also affected the activation of AP-1 (Fig. 7.3). We showed that TNFα induced the activation of the signal molecule ERK1/2 of the MAPK cascade in endometriotic cells [94].

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Fig. 7.3

Signal transduction of MAPK pathway

Recent studies have shown that p38 mitogen-activated protein kinase (p38 MAPK), an intracellular signal-transducing molecule, plays an important role in the regulation of a variety of inflammatory responses, including expression of proinflammatory cytokines, leukocyte adhesion, and chemotaxis. A number of studies indicated that the p38 MAPK pathway might play an important role in the development and progression of endometriosis [94]. Increased p38 MAPK activation in eutopic and ectopic endometrium indicated that p38 MAPK might be one of the main factors regulating the inflammatory process in endometriosis [9597]. Yoshino et al. revealed that FR 167653, a p38 mitogen-activated protein kinase inhibitor, inhibits the development of endometriosis, possibly by suppressing peritoneal inflammatory status [98]. Zhou et al. also demonstrated that SB203580, a p38 mitogen-activated protein kinase inhibitor, may suppress the development of EM by inhibiting the expression of proinflammatory cytokines and proteolytic factors. p38 MAPK might play a key role in the progression of endometriosis [99]. These findings suggest that estrogen might to some extent exert its effects on the endometrium through the p38 MAPK pathway.

Many studies have demonstrated that MAPK is involved directly in regulating the pathogenesis of endometriosis. MAPK pathways seem to play a pivotal role as intracellular and extracellular signal transducers in the pathogenesis of endometriosis.

7.3.4.2 NF-kappaB Pathway

Nuclear factor-kappaB (NF-κB) is a family of transcription factors modulating hundreds of genes involved in inflammation, cell proliferation, apoptosis, invasion, angiogenesis, and other cell processes [100]. Therefore, accurate monitoring of NF-κB activation in target cells is crucial to investigating its signal transduction. NF-κB is composed of homo- and heterodimers of five members of the Rel family including p50, p52, p65, RelB, and c-Rel. NF-κB dimers are sequestered in the cytosol of unstimulated cells via noncovalent interactions with a class of inhibitor proteins, called IkBs. NF-κB is normally bound to IκB in cytosol; this binding prevents its movement into the nucleus. Proinflammatory stimuli activate the IκB kinase (IKK) complex and NF-κB essential modulator. Activated IKK phosphorylates IκB, resulting in its polyubiquitination and degradation. The degradation of IκB exposes the nuclear localization signal of NF-κB, resulting in the translocation of the p50/p65 NF-κB dimer to the nucleus in which it can be bound to NF-κB recognition elements in the promoter of proinflammatory cytokines such as TNFα, IL-6, and IL-8 (Fig. 7.4). We demonstrated that NF-κB activation has been involved in the induction of IL-8 in endometriotic tissues [101].

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Fig. 7.4

Signal transduction of NF-κB pathway

Multiple publications have strongly suggested participation of the NF-κB pathway in endometriosis pathophysiology. In vitro studies have shown positive regulation of growth factors and proinflammatory and antiapoptotic proteins mediated by NF-κB activation in human endometrial and endometriotic cells [102103]. In vivo research in animal models treated with NF-κB inhibitors has revealed reduction of endometriosis development by diminishing inflammation and cell proliferation and inducing apoptosis of endometriotic cells [104105]. Constitutive activation of NF-κB was shown to be increased in red endometriotic lesions relative to black endometriotic lesions in women, and iron-mediated NF-κB activation in pelvic macrophages and endometriotic cells has been proposed as a possible mechanism contributing to endometriosis establishment and maintenance [106]. Thus, NF-κB pathways seem to play a pivotal role in the pathophysiology of endometriosis.

TAK1, a serine/threonine kinase, is an essential intracellular signaling component in inflammatory signaling pathways [107]. TAK1 has proven to be a crucial factor in regulating inflammatory responses by controlling production and function of various other cytokines. An accumulation of evidence suggests that TAK1 plays an important role as a second messenger in the activation of NF-κB, p38, and JNK. The activation of TAK1, which works on the TNFα-inducible phosphorylation of both the NF-κB and MAPK pathways, may be indispensable for inflammatory response and progression of endometriosis. TAK1 has been widely accepted as a regulator of the rapid activation of JNK/p38 MAPKs and IκB kinase signaling pathways in response to cellular stimuli (Fig. 7.5).

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Fig. 7.5

Mechanism of signal transduction by the TAK1 cascade

We showed that TNFα and its downstream TAK1, which are key mediators for NF-κB and MAPK pathways, may be involved in the pathogenesis of endometriosis [108].

7.4 Conclusion

Pathogenesis of endometriosis is very complex, so various factors and directions of studies were needed. Cytokines, which are produced by many cell types in PF, play a diverse role in constructing the peritoneal environment that induces the development and progression of endometriosis. Intense basic research into the specific role of these cells and soluble factors may improve our understanding of endometriosis and result in novel therapeutic modalities for endometriosis.

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