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      The Role of Tumor Necrosis Factor α in the Biology of Uterine Fibroids and the Related Symptoms

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          Abstract

          Uterine fibroids (UFs) are the most common benign tumors of the female genital tract. The incidence of UFs has been estimated at 25–80% depending on selected population. The pathophysiology of UFs remains poorly understood. The transformation of smooth muscle cells of the uterus into abnormal, immortal cells, capable of clonal division, is the main component of all pathways leading to UF tumor formation and tumor necrosis factor α (TNF-α) is believed to be one of the key factors in this field. TNF-α is a cell signaling protein involved in systemic inflammation and is one of the cytokines responsible for the acute phase reaction. This publication presents current data about the role of tumor necrosis factor α in the biology of UFs and the related symptoms. TNF-α is an extremely important cytokine associated with the biology of UFs, UF-related symptoms and complaints. Its concentration has been proven to be elevated in women with clinically symptomatic UFs. The presented data suggest the presence of an “inflammation-like” state in women with UFs where TNF-α is a potent inflammation inducer. The origin of numerous symptoms reported by women with UFs can be traced back to the TNF-α influence. Nevertheless, our knowledge on this subject remains limited and TNF-α dependent pathways in UF pathophysiology should be investigated further.

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          Most cited references186

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          Adipose tissue, adipokines, and inflammation.

          White adipose tissue is no longer considered an inert tissue mainly devoted to energy storage but is emerging as an active participant in regulating physiologic and pathologic processes, including immunity and inflammation. Macrophages are components of adipose tissue and actively participate in its activities. Furthermore, cross-talk between lymphocytes and adipocytes can lead to immune regulation. Adipose tissue produces and releases a variety of proinflammatory and anti-inflammatory factors, including the adipokines leptin, adiponectin, resistin, and visfatin, as well as cytokines and chemokines, such as TNF-alpha, IL-6, monocyte chemoattractant protein 1, and others. Proinflammatory molecules produced by adipose tissue have been implicated as active participants in the development of insulin resistance and the increased risk of cardiovascular disease associated with obesity. In contrast, reduced leptin levels might predispose to increased susceptibility to infection caused by reduced T-cell responses in malnourished individuals. Altered adipokine levels have been observed in a variety of inflammatory conditions, although their pathogenic role has not been completely clarified.
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            TNF-mediated inflammatory disease.

            JR Bradley (2008)
            TNF was originally described as a circulating factor that can cause necrosis of tumours, but has since been identified as a key regulator of the inflammatory response. This review describes the known signalling pathways and cell biological effects of TNF, and our understanding of the role of TNF in human disease. TNF interacts with two different receptors, designated TNFR1 and TNFR2, which are differentially expressed on cells and tissues and initiate both distinct and overlapping signal transduction pathways. These diverse signalling cascades lead to a range of cellular responses, which include cell death, survival, differentiation, proliferation and migration. Vascular endothelial cells respond to TNF by undergoing a number of pro-inflammatory changes, which increase leukocyte adhesion, transendothelial migration and vascular leak and promote thrombosis. The central role of TNF in inflammation has been demonstrated by the ability of agents that block the action of TNF to treat a range of inflammatory conditions, including rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease and psoriasis. The increased incidence of infection in patients receiving anti-TNF treatment has highlighted the physiological role of TNF in infectious diseases. 2007 Pathological Society of Great Britain and Ireland
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              Macrophages: master regulators of inflammation and fibrosis.

              Macrophages are found in close proximity with collagen-producing myofibroblasts and indisputably play a key role in fibrosis. They produce profibrotic mediators that directly activate fibroblasts, including transforming growth factor-beta1 and platelet-derived growth factor, and control extracellular matrix turnover by regulating the balance of various matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases. Macrophages also regulate fibrogenesis by secreting chemokines that recruit fibroblasts and other inflammatory cells. With their potential to act in both a pro- and antifibrotic capacity, as well as their ability to regulate the activation of resident and recruited myofibroblasts, macrophages and the factors they express are integrated into all stages of the fibrotic process. These various, and sometimes opposing, functions may be performed by distinct macrophage subpopulations, the identification of which is a growing focus of fibrosis research. Although collagen-secreting myofibroblasts once were thought of as the master "producers" of fibrosis, this review will illustrate how macrophages function as the master "regulators" of fibrosis. Copyright Thieme Medical Publishers.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                04 December 2018
                December 2018
                : 19
                : 12
                : 3869
                Affiliations
                [1 ]Second Department of Obstetrics and Gynecology, The Center of Postgraduate Medical Education, 01-809 Warsaw, Poland
                [2 ]Department of Biochemistry and Clinical Chemistry, Department of Pharmacogenomics, Medical University of Warsaw, 02-097 Warsaw, Poland; mdwlodarczyk@ 123456gmail.com
                [3 ]Students’ Scientific Association at the I Department of Obstetrics and Gynecology, Medical University of Warsaw, 02-015 Warsaw, Poland; zgliczynska.magda@ 123456gmail.com
                [4 ]Department of Obstetrics and Gynecological Nursing, Faculty of Health Sciences, Medical University of Gdansk, 80-210 Gdansk, Poland; krzysztof.lukaszuk@ 123456invicta.pl
                [5 ]INVICTA Fertility and Reproductive Center, 80-172 Gdansk, Poland
                [6 ]Department of Gynecological Endocrinology, Poznan University of Medical Sciences, 60-513 Poznan, Poland; blazejmeczekalski@ 123456yahoo.com
                [7 ]Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland; ch.kobierzycki@ 123456gmail.com
                [8 ]Department of Obstetrics and Gynecology Pro-Familia Hospital, 35-001 Rzeszów, Poland; tomasz.lozinski@ 123456pro-familia.pl
                [9 ]First Department of Obstetrics and Gynecology, The Center of Postgraduate Medical Education, 01-004 Warsaw, Poland; grzegorz.jakiel1@ 123456o2.pl
                Author notes
                [* ]Correspondence: michal.ciebiera@ 123456gmail.com ; Tel.: +48-607-155-177
                Author information
                https://orcid.org/0000-0001-5780-5983
                Article
                ijms-19-03869
                10.3390/ijms19123869
                6321234
                30518097
                a3727058-9a56-4290-8f5d-1f1a381d6b5d
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 18 October 2018
                : 28 November 2018
                Categories
                Review

                Molecular biology
                uterine fibroid,leiomyoma,tumor,tumor necrosis factor α,cytokine,growth factor,inflammation,clinical symptoms,pathophysiology,therapy

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