Involvement of the nuclear factor-κB pathway in the pathogenesis of endometriosis.
TL;DR: In this article, the role of NF-κB in the pathogenesis of endometriosis has been evaluated using a literature search conducted in PubMed to identify all relevant citations, highlighting the important role of NGF in the pathwayophysiology of Endometria.
About: This article is published in Fertility and Sterility.The article was published on 2010-11-01. It has received 135 citations till now. The article focuses on the topics: Endometriosis & Proinflammatory cytokine.
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TL;DR: Endometriosis is estrogen-dependent, manifests during reproductive years and is associated with pain and infertility, while lesion eradication is considered a fertility-enhancing procedure, the benefit on reproductive performance is moderate.
Abstract: Endometriosis is defined as the presence of endometrial-type mucosa outside the uterine cavity. Of the proposed pathogenic theories (retrograde menstruation, coelomic metaplasia and Mullerian remnants), none explain all the different types of endometriosis. According to the most convincing model, the retrograde menstruation hypothesis, endometrial fragments reaching the pelvis via transtubal retrograde flow, implant onto the peritoneum and abdominal organs, proliferate and cause chronic inflammation with formation of adhesions. The number and amount of menstrual flows together with genetic and environmental factors determines the degree of phenotypic expression of the disease. Endometriosis is estrogen-dependent, manifests during reproductive years and is associated with pain and infertility. Dysmenorrhoea, deep dyspareunia, dyschezia and dysuria are the most frequently reported symptoms. Standard diagnosis is carried out by direct visualization and histologic examination of lesions. Pain can be treated by excising peritoneal implants, deep nodules and ovarian cysts, or inducing lesion suppression by abolishing ovulation and menstruation through hormonal manipulation with progestins, oral contraceptives and gonadotropin-releasing hormone agonists. Medical therapy is symptomatic, not cytoreductive; surgery is associated with high recurrence rates. Although lesion eradication is considered a fertility-enhancing procedure, the benefit on reproductive performance is moderate. Assisted reproductive technologies constitute a valid alternative. Endometriosis is associated with a 50% increase in the risk of epithelial ovarian cancer, but preventive interventions are feasible.
1,174 citations
TL;DR: The disease process is reviewed from theories regarding origin to the molecular basis for disease sequelae and a thorough understanding of the histopathogenesis and pathophysiology of endometriosis is essential to the development of novel diagnostic and treatment approaches for this debilitating condition.
1,066 citations
Cites background from "Involvement of the nuclear factor-κ..."
...17b-HSD-2 Hydroxysteroid dehydrogenase (47) BCL-2 Antiapoptosis (31) CYP19 Aromatase enzyme (102) HOXA10 Transcription factor (103) IL-6 Cytokine (82) KRAS Oncogene (30) MMP 3,7 Matrix metalloproteinases (65) NF-KB Transcription factor (104) PGE2 Prostaglandin (105) PTEN Tumor suppressor gene (30) TGF-B Cytokine (61) TNF-a Cytokine (81)...
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12 Feb 2014
TL;DR: This review examines existing theories on the initiation and propagation of different types of endometriotic lesions, as well as critically appraises the myriad of biologically relevant evidence that support or oppose each of the proposed theories.
Abstract: Endometriosis is a common, chronic inflammatory disease defined by the presence of extrauterine endometrial tissue. The aetiology of endometriosis is complex and multifactorial, where several not fully confirmed theories describe its pathogenesis. This review examines existing theories on the initiation and propagation of different types of endometriotic lesions, as well as critically appraises the myriad of biologically relevant evidence that support or oppose each of the proposed theories. The current literature suggests that stem cells, dysfunctional immune response, genetic predisposition, and aberrant peritoneal environment may all be involved in the establishment and propagation of endometriotic lesions. An orchestrated scientific and clinical effort is needed to consider all factors involved in the pathogenesis of this multifaceted disease and to propose novel therapeutic targets to reach effective treatments for this distressing condition.
313 citations
Cites background from "Involvement of the nuclear factor-κ..."
...The inhibition of the apoptosis of endometrial cells may also be mediated by the transcriptional activation of genes that normally promotes inflammation, angiogenesis, and cell proliferation [54]....
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TL;DR: Endometriosis is classically defined as a chronic, gynaecological disease characterised by endometrial-like tissue present outside of the uterus and is thought to arise by retrograde menstruation as discussed by the authors.
244 citations
TL;DR: In this review, recent advances that have illuminated the origin and pathogenesis of endometriosis and have provided new avenues for research that promise to improve the early diagnosis and management of endometricriosis are summarized.
Abstract: Recent molecular genetic findings on endometriosis and normal endometrium suggest a modified model in which circulating epithelial progenitor or stem cells intended to regenerate uterine endometrium after menstruation may become overreactive and trapped outside the uterus. These trapped epithelium-committed progenitor cells form nascent glands through clonal expansion and recruit polyclonal stromal cells, leading to the establishment of deep infiltrating endometriosis. Once formed, the ectopic tissue becomes subject to immune surveillance, resulting in chronic inflammation. The inflammatory response orchestrated by nuclear factor-κB signaling is exacerbated by aberrations in the estrogen receptor-β and progesterone receptor pathways, which are also affected by local inflammation, forming a dysregulated inflammation-hormonal loop. Glandular epithelium within endometriotic tissue harbors cancer-associated mutations that are frequently detected in endometriosis-related ovarian cancers. In this review, we summarize recent advances that have illuminated the origin and pathogenesis of endometriosis and have provided new avenues for research that promise to improve the early diagnosis and management of endometriosis.
159 citations
References
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TL;DR: The transcription factor NF-κB has attracted widespread attention among researchers in many fields based on its unusual and rapid regulation, the wide range of genes that it controls, its central role in immunological processes, the complexity of its subunits, and its apparent involvement in several diseases.
Abstract: ▪ Abstract The transcription factor NF-κB has attracted widespread attention among researchers in many fields based on the following: its unusual and rapid regulation, the wide range of genes that it controls, its central role in immunological processes, the complexity of its subunits, and its apparent involvement in several diseases. A primary level of control for NF-κB is through interactions with an inhibitor protein called IκB. Recent evidence confirms the existence of multiple forms of IκB that appear to regulate NF-κB by distinct mechanisms. NF-κB can be activated by exposure of cells to LPS or inflammatory cytokines such as TNF or IL-1, viral infection or expression of certain viral gene products, UV irradiation, B or T cell activation, and by other physiological and nonphysiological stimuli. Activation of NF-κB to move into the nucleus is controlled by the targeted phosphorylation and subsequent degradation of IκB. Exciting new research has elaborated several important and unexpected findings that...
5,833 citations
TL;DR: This article showed that NF-kappaB provides a mechanistic link between inflammation and cancer, and is a major factor controlling the ability of both pre-neoplastic and malignant cells to resist apoptosis-based tumour-surveillance mechanisms.
Abstract: Nuclear factor-kappaB (NF-kappaB) transcription factors and the signalling pathways that activate them are central coordinators of innate and adaptive immune responses. More recently, it has become clear that NF-kappaB signalling also has a critical role in cancer development and progression. NF-kappaB provides a mechanistic link between inflammation and cancer, and is a major factor controlling the ability of both pre-neoplastic and malignant cells to resist apoptosis-based tumour-surveillance mechanisms. NF-kappaB might also regulate tumour angiogenesis and invasiveness, and the signalling pathways that mediate its activation provide attractive targets for new chemopreventive and chemotherapeutic approaches.
3,157 citations
TL;DR: The choice between life and death is one of the major events in regulation of the immune system and a major regulator of such life or death decisions is the transcription factor NF-κB as mentioned in this paper.
Abstract: The choice between life and death is one of the major events in regulation of the immune system. T cells that specifically recognize viral or bacterial antigens are selected to survive and proliferate in response to infection, whereas those that are self-reactive are eliminated via apoptosis. Even the survival of alloreactive T cells requires their proper costimulation and, when infection subsides, the activated T cells are eliminated. A major regulator of such life or death decisions is the transcription factor NF-κB. However, NF-κB cannot function alone. A variety of mechanisms exist to modulate its activity and thereby affect the ultimate outcome of a cell's fate.
2,543 citations
TL;DR: Results strongly suggest that the classical and alternative pathways to NF-κB activation have distinct regulatory functions, one that is mostly involved in innate immunity and the other in adaptive immunity.
2,393 citations
"Involvement of the nuclear factor-κ..." refers background in this paper
...The noncanonical pathway is related to lymphoid organogenesis, B-cell maturation, and humoral immunity, and it has a slow response time (over hours and days), ensuring long-lasting NF-kB activity (30, 42, 43)....
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...The NF-kB–dependent activation of proinflammatory genes, such as RANTES, ICAM-1, IL-1, or TNF-a, may provide positive feedback to the pathway, thus self-perpetuating macrophage recruitment and the inflammatory response in the peritoneal cavity of endometriosis patients (31, 33, 43, 58, 75, 76)....
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...Fertility and Sterility as a repressor because it lacks a transcription activation domain (32, 43)....
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TL;DR: This work has shown that crosstalk constitutes a decision-making process that determines the consequences of NF-κB and IKK activation and, ultimately, cell fate.
Abstract: Nuclear factor (NF)-kappaB and inhibitor of NF-kappaB kinase (IKK) proteins regulate many physiological processes, including the innate- and adaptive-immune responses, cell death and inflammation. Disruption of NF-kappaB or IKK function contributes to many human diseases, including cancer. However, the NF-kappaB and IKK pathways do not exist in isolation and there are many mechanisms that integrate their activity with other cell-signalling networks. This crosstalk constitutes a decision-making process that determines the consequences of NF-kappaB and IKK activation and, ultimately, cell fate.
2,169 citations
"Involvement of the nuclear factor-κ..." refers background in this paper
...These cell processes are involved in the development of endometriosis and other diseases (9, 14, 17, 29, 30)....
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...The noncanonical pathway is related to lymphoid organogenesis, B-cell maturation, and humoral immunity, and it has a slow response time (over hours and days), ensuring long-lasting NF-kB activity (30, 42, 43)....
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...Modulation of NF-kB is cell type–specific and interacts with other pathways, providing a complex variety of cellular responses (29, 30)....
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...013 Copyright a2010 American S adhesion, invasion, and angiogenesis in many cell types (29, 30)....
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