Cyclooxygenase-2 in Endometriosis

Abstract

Endometriosis (EMS) is the most common gynecological disease in women of reproductive age, and it is associated with chronic pelvic pain, dyspareunia and infertility. As a consequence of genetic, immune and environmental factors, endometriotic lesions have high cyclooxygenase (COX)-2 and COX-2-derived prostaglandin E₂ (PGE₂) biosynthesis compared with the normal endometrium. The transcription of the PTGS2 gene for COX-2 is associated with multiple intracellular signals, which converge to cause the activation of mitogen-activated protein kinases (MAPKs). COX-2 expression can be regulated by several factors, such as estrogen, hypoxia, proinflammatory cytokines, environmental pollutants, metabolites and metabolic enzymes, and platelets. High concentrations of COX-2 lead to high cell proliferation, a low level of apoptosis, high invasion, angiogenesis, EMS-related pain and infertility. COX-2-derived PGE₂ performs a crucial function in EMS development by binding to EP2 and EP4 receptors. These basic findings have contributed to COX-2-targeted treatment in EMS, including COX-2 inhibitors, hormone drugs and glycyrrhizin. In this review, we summarize the most recent basic research in detail and provide a short summary of COX-2-targeted treatment.

Keywords: COX-2; PGE2; endometriosis; estrogen; pain.

Figure 1

Multiple factors regulate COX-2 expression. Estrogen (E₂), omega-3 PUFA and IL-1β promote COX-2 expression through the NF-κB signaling pathway. IL-1β stimulates the phosphorylation of MERK, p38 and JNK, then CRE and NF-κB p65 bind to sites on the COX-2 promoter to increase COX-2 expression. In hypoxic conditions, activated HIF-1α will suppress DUSP2 expression directly, and then result in the hypersensitivity of COX-2 in response to proinflammatory stimuli (e.g. IL-1β). Elevated NGF markedly upregulates the expression of PTGS2/COX-2 via the PI3K/AKT signaling pathway. Environmental pollutants, for example HCB and CB126, are known to act via the AhR. These organic compounds have some biological effects mediated by the activation of the cytosolic AhR complex (AhR-dioxin-c-Src), and regulate PTGS2 transcription indirectly. The combination of organic compounds and AhR induces HSD17B7 expression and results in the upregulation of E₂, IL-6 and IL-8, which will further promote COX-2 expression.

Figure 2

The role of COX-2 in EMS. Overexpression of COX-2 has been demonstrated to be a master regulator in the progression of endometriosis. A high level of COX-2 can promote cell proliferation and suppress cell apoptosis via trans-activating multiple complex signaling pathways, which are triggered by PGE₂ and its receptors, EP2 and EP4. In addition, MMP-2/9 activity regulated by PGE₂ is be involved in angiogenesis, and ESC migration and invasion, via the intracellular MAPK, AKT and Wnt signaling pathways. COX-2 can induce COX-2⁺CD16^-NK cell (Granzyme B^lowPerforin^lowIFN-γ^lowCD16-NK cell) differentiation in the peritoneal fluids of patients with endometriosis, which is beneficial to the immune escape of endometriotic lesions. The COX-2/PGE₂/EP2-EP4 signaling decreases the threshold and enhances the excitability of nociceptor sensory fibers through TRPV1 and SCN11A, and contributes to EMS-associated pain. A high level of COX-2/PGE₂ and COX-2-induced inflammatory mediators increase uterine tone and contractions and cause pain. TCs are important in maintaining the structural and reproductive functional normality of the oviduct, while overproduced COX-2 may damage the functions of TCs, which will lead to infertility. The low production of COX-2 in cumulus cells is regarded as a possible mechanism of EMS-related infertility.

Figure 3

The anti-EMS strategy of targeted COX-2. There are three main types of anti-EMS drugs targeting COX-2: COX-2 inhibitors, hormone drugs and other drugs. They inhibit COX-2 expression in different ways. Treatment with COX‐2 inhibitors significantly decreases microvessel density and macrophage numbers, and is associated with decreased expression of VEGF and Flk-1. Combining the inhibition of COX-2 with peroxisome proliferator-activated receptor (PPAR)-γ agonists suppresses cell proliferation and induces apoptosis by decreasing the expression of p-Akt/Akt and p-eNOS/eNOS. GnRH-II decreases the COX-2 secretion of the ectopic, eutopic and normal ESC in EMS, and it can reverse the IL-1β-induced expression of COX-2 in ESCs. DNG, a selective PR agonist, downregulates the mRNA expression of CYP19A1, COX-2, mPGES-1, IL-8, IL-6, MCP-1, VEGF and NGF, and PGE2 production, as well as suppressing the development of endometriotic lesions and relieving EMS-associated pain. Glycyrrhizin is able to attenuate the expression of COX-2 and dramatically diminishes LPS-induced TLR4 expression and NF-κB activation in MEECs. As a result, it can inhibit the LPS-induced inflammatory response. Puerarin can inhibit the expression of P450arom and COX-2 in the ectopic endometrium, restrict the levels of E2 and PGE2, and block the positive feedback mechanism of E₂ synthesis.