Nuclear factor-kappa B is constitutively activated in peritoneal endometriosis

Abstract

Red (active), black and white endometriotic lesions are characteristic of peritoneal endometriosis. The transcription factor nuclear factor-kappa B (NF-kappaB) activates proinflammatory, proliferative and antiapoptotic genes in many cell types. To determine whether NF-kappaB is activated in peritoneal endometriosis in women, and further ascertain the differential inflammatory status of endometriotic implants, NF-kappaB activation and intercellular adhesion molecule (ICAM)-1 expression were investigated in peritoneal endometriotic lesions according to their type. Furthermore, p65 and p50 subunits of active NF-kappaB dimers were evaluated in endometriotic lesions to gain some insight into NF-kappaB-implicated pathways. Thirty-six biopsies of peritoneal endometriotic lesions were analyzed. Constitutive NF-kappaB activation, involving p65- and p50-containing dimers, was demonstrated in peritoneal endometriotic lesions by electrophoretic mobility shift assays and supershift analyses, as well as NF-kappaB (p65) DNA-binding activity immunodetection assays. NF-kappaB activation and ICAM-1 expression (evaluated by immunoblotting) were significantly higher in red lesions than black lesions, whereas IkappaBalpha (NF-kappaB inhibitory protein) expression was constant, as shown by western blot analysis. This is the first study to demonstrate constitutive NF-kappaB activation in peritoneal endometriosis in women. NF-kappaB activation and ICAM-1 expression in red lesions confirm the more extensive inflammatory pattern of these lesions compared with black lesions. The involvement of p50/p65 dimers in NF-kappaB activation suggests implication of the classic NF-kappaB activation pathway, making it an attractive therapeutic target in endometriosis.

Dating Endometriotic Ovarian Cysts Based on the Content of Cyst Fluid and its Potential Clinical Implications

“…27,37,38 Increased oxidative stress resulting from iron overload also would result in nuclear factor kB activation, creating an environment favorable for increased proliferation, survival, angiogenesis, proinflammatory cytokine/chemokine production, and invasiveness. 18,[39][40][41] However, iron overload is known to contribute to fibrosis in the liver, 42 lung, 43 and the heart. 44 Although the natural history of endometriosis is still unclear, the consensus view is that the color of endometriotic lesions, possibly including ovarian endometriomas, is a rough proxy for the lesion age, with red-colored lesion being the younger ones that progressing to black color and finally to white.…”

Role of iron overload-induced macrophage apoptosis in the pathogenesis of peritoneal endometriosis

“…This iron accumulation in macrophages may severely compromise their functions. Excessive production of free radicals enhances the activity of nuclear factor kappa B (NFkB), which up-regulates the expression of multiple genes encoding pro-inflammatory cytokines, chemokines, adhesion molecules, growth factor, and angiogenic factor, supporting the inflammatory response, resistance to apoptosis, and cell proliferation in endometriotic lesions (González-Ramos et al 2007, Lousse et al 2009). The maintenance of high activity of p65 subunit of NFkB throughout the menstrual cycle owing to progesterone resistance has recently been demonstrated to stimulate an inflammatory response, which promotes the proliferation and survival of ectopic endometrial cell, thereby favoring the establishment and development of peritoneal endometriosis (González-Ramos et al 2012).…”

Endometrial-Peritoneal Interactions during Endometriotic Lesion Establishment

“…36 Moreover, two inhibitors of the NF-B pathway significantly reduced xenograft development in the nude mouse model of endometriosis. 37 The presence of numerous leukocytes in the xenografts 38 ( Figure 5) and an elevation of activated macrophages in the peritoneal environment of women with endometriosis 39 are further indicators of the inflammatory response in both the animal model and human disease. In the human microarray analysis, transcripts in GO categories "inflammatory response" and "response to wounding" were significantly over-represented (Table 3).…”