Macrophages and Immune Responses in Uterine Fibroids

Alessandro Zannotti, Stefania Greco, Pamela Pellegrino, Federica Giantomassi, Giovanni Delli Carpini, Gaia Goteri, Andrea Ciavattini, Pasquapina Ciarmela, Alessandro Zannotti, Stefania Greco, Pamela Pellegrino, Federica Giantomassi, Giovanni Delli Carpini, Gaia Goteri, Andrea Ciavattini, Pasquapina Ciarmela

Abstract

Uterine fibroids represent the most common benign tumors of the uterus. They are considered a typical fibrotic disorder. In fact, the extracellular matrix (ECM) proteins-above all, collagen 1A1, fibronectin and versican-are upregulated in this pathology. The uterine fibroids etiology has not yet been clarified, and this represents an important matter about their resolution. A model has been proposed according to which the formation of an altered ECM could be the result of an excessive wound healing, in turn driven by a dysregulated inflammation process. A lot of molecules act in the complex inflammatory response. Macrophages have a great flexibility since they can assume different phenotypes leading to the tissue repair process. The dysregulation of macrophage proliferation, accumulation and infiltration could lead to an uncontrolled tissue repair and to the consequent pathological fibrosis. In addition, molecules such as monocyte chemoattractant protein-1 (MCP-1), granulocyte macrophage-colony-stimulating factor (GM-CSF), transforming growth factor-beta (TGF-β), activin A and tumor necrosis factor-alfa (TNF-α) were demonstrated to play an important role in the macrophage action within the uncontrolled tissue repair that contributes to the pathological fibrosis that represents a typical feature of the uterine fibroids.

Keywords: ECM; inflammatory process; macrophages; pathological fibrosis; tissue repair; uterine fibroids.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Illustration of the promoters of fibroid growth. The blue net represents the typical extracellular matrix (ECM) proteins: collagen 1A1, fibronectin and versican. The abundant ECM in uterine fibroids (approximately 50% more than the corresponding myometrium) was suggested to represent a reservoir for the other promoters of fibroid growth.
Figure 2
Figure 2
Illustration of the role of the macrophages and their highly flexible programming in tissue repair and fibrosis in several organs. Macrophages, because of their high flexibility, can play a key regulatory role in every stage that characterizes the tissue repair and fibrosis from the promotion to the resolution of the inflammation leading to the wound closure. The figure shows the principal events and principal molecules: chemokines, Matrix metalloproteinases, tumor necrosis factor-alfa (TNF-α), platelet-derived growth factor (PDGF), transforming growth factor-beta 1 (TGF-β1), insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor-alfa (VEGF-α), programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2), interleukin-10 (IL-10) involved in the process, highlighting the different phenotypic states that the macrophages can assume in the process. The blue net represents the extracellular matrix (ECM) that is produced by myofibroblasts after that fibroblasts or other cellular types differentiated into them.
Figure 3
Figure 3
Illustration of the macrophages’ (yellow in the figure) role in uterine fibroids. Monocyte chemoattractant protein-1 (MCP-1) takes part in the regulation of the macrophages’ infiltration. The granulocyte macrophage-colony-stimulating factor (GM-CSF) is considered the most important growth factor for macrophage proliferation. GM-CSF can establish regulatory interactions with the transforming growth factor-beta (TGF-β), which was shown to be the most important growth factor secreted by macrophages. In uterine fibroids, TGF-β is overexpressed and it contributes to myofibroblast differentiation. Macrophages also secrete activin A, an immuno-regulator belonging to the TGF-β family. Activin A develops a pro-fibrotic action leading to the expression of the extracellular matrix (ECM) proteins (represented by the blue net in the figure), which are overexpressed in uterine fibroids. Activin A mRNA expression in uterine fibroids is upregulated by the tumor necrosis factor-alfa (TNF-α), an inflammatory mediator mainly produced by macrophages. On the right, above the image that portrays the myofibroblasts, the uterine fibroids (red in the figure) with the myometrium (pink in the figure), the endometrium (brown in the figure), the macrophages (yellow in the figure) and the overexpressed ECM proteins (blue net in the figure) are represented. The blood vessels within endometrium are also represented (red lines in the figure).
Figure 4
Figure 4
Macrophages in uterine fibroids. (a) Illustration of uterus showing the macrophage density in uterine fibroids pathology. (b) Enlargement of the detail showing the macrophage density in uterine fibroids pathology. Macrophages (yellow in the figure) predominantly localize inside uterine fibroids (red in the figure) and in the myometrium tissue (pink in the figure) next to them. Autologous distant myometrium shows low levels of macrophage infiltration. The macrophage density is higher also in the endometrium (brown in the figure) next to uterine fibroids than in the autologous endometrium far from uterine fibroid nodules. The extracellular matrix (ECM) around and within the uterine fibroids is also represented (blue net in the figure). The blood vessels within endometrium are also represented (red lines in the figure).
Figure 5
Figure 5
Illustration of the possible phase mechanism of leiomyoma development proposed by our group. Cellular leiomyoma is considered as the first step in the tumoral transformation. In fact, cellular leiomyoma shows higher levels of macrophage (yellow in the figure) infiltration and an increased number of inflammatory cells. This aspect could represent a response to an inflammatory stimulus that leads some cellular leiomyoma cells to myofibroblast differentiation with the consequent upregulation of the typical extracellular matrix (ECM) proteins. In fact, usual leiomyoma shows a larger amount of ECM proteins and low levels of macrophage infiltration. So, usual leiomyoma could be considered as the late-phase tumor. The blue net represents the typical ECM proteins: collagen 1A1, fibronectin and versican. The red color represents the uterine fibroids (light red for cellular leiomyoma histotype and dark red for usual leiomyoma histotype). The pink color represents the myometrium; the brown color represents the endometrium. The blood vessels within endometrium are also represented (red lines in the figure).

References

    1. McEvoy A., Sabir S. Physiology, Pregnancy Contractions. StatPearls; Treasure Island, FL, USA: 2021.
    1. Valente R., Malesani M.G. Dizionario Medico. Larousse; Paris, France: 1984. p. 928.
    1. Gentile F. Enciclopedia Italiana. Volume 16. Grolier; New Delhi, India: 1987. p. 271.
    1. Day Baird D., Dunson D.B., Hill M.C., Cousins D., Schectman J.M. High cumulative incidence of uterine leiomyoma in black and white women: Ultrasound evidence. Am. J. Obstet. Gynecol. 2003;188:100–107. doi: 10.1067/mob.2003.99.
    1. Stewart E.A. Uterine fibroids. Lancet. 2001;357:293–298. doi: 10.1016/S0140-6736(00)03622-9.
    1. Buttram V.C., Jr., Reiter R.C. Uterine leiomyomata: Etiology, symptomatology, and management. Fertil. Steril. 1981;36:433–445.
    1. Eldar-Geva T., Meagher S., Healy D.L., MacLachlan V., Breheny S., Wood C. Effect of intramural, subserosal, and submucosal uterine fibroids on the outcome of assisted reproductive technology treatment. Fertil. Steril. 1998;70:687–691. doi: 10.1016/S0015-0282(98)00265-9.
    1. Evans P., Brunsell S. Uterine fibroid tumors: Diagnosis and treatment. Am. Fam. Physician. 2007;75:1503–1508.
    1. Marsh E.E., Bulun S.E. Steroid hormones and leiomyomas. Obstet. Gynecol. Clin. N. Am. 2006;33:59–67. doi: 10.1016/j.ogc.2005.12.001.
    1. Okolo S. Incidence, aetiology and epidemiology of uterine fibroids. Best Pract. Res. Clin. Obstet. Gynaecol. 2008;22:571–588. doi: 10.1016/j.bpobgyn.2008.04.002.
    1. Islam M.S., Protic O., Stortoni P., Grechi G., Lamanna P., Petraglia F., Castellucci M., Ciarmela P. Complex networks of multiple factors in the pathogenesis of uterine leiomyoma. Fertil. Steril. 2013;100:178–193. doi: 10.1016/j.fertnstert.2013.03.007.
    1. Ciarmela P., Islam M.S., Reis F.M., Gray P.C., Bloise E., Petraglia F., Vale W., Castellucci M. Growth factors and myometrium: Biological effects in uterine fibroid and possible clinical implications. Hum. Reprod. Update. 2011;17:772–790. doi: 10.1093/humupd/dmr031.
    1. Lethaby A., Puscasiu L., Vollenhoven B. Preoperative medical therapy before surgery for uterine fibroids. Cochrane Database Syst. Rev. 2017;11:CD000547. doi: 10.1002/14651858.CD000547.pub2.
    1. Angioni S., D’Alterio M.N., Daniilidis A. Highlights on Medical Treatment of Uterine Fibroids. Curr. Pharm. Des. 2021 doi: 10.2174/1381612826666210101152820.
    1. Friedman A.J., Hoffman D.I., Comite F., Browneller R.W., Miller J.D. Treatment of leiomyomata uteri with leuprolide acetate depot: A double-blind, placebo-controlled, multicenter study. The Leuprolide Study Group. Obstet. Gynecol. 1991;77:720–725.
    1. Schlaff W.D., Zerhouni E.A., Huth J.A., Chen J., Damewood M.D., Rock J.A. A placebo-controlled trial of a depot gonadotropin-releasing hormone analogue (leuprolide) in the treatment of uterine leiomyomata. Obstet. Gynecol. 1989;74:856–862.
    1. Stovall T.G., Muneyyirci-Delale O., Summitt R.L., Jr., Scialli A.R. GnRH agonist and iron versus placebo and iron in the anemic patient before surgery for leiomyomas: A randomized controlled trial. Leuprolide Acetate Study Group. Obstet. Gynecol. 1995;86:65–71. doi: 10.1016/0029-7844(95)00102-W.
    1. Carbonell J.L., Acosta R., Perez Y., Garces R., Sanchez C., Tomasi G. Treatment of Uterine Myoma with 2.5 or 5 mg Mifepristone Daily during 3 Months with 9 Months Posttreatment Followup: Randomized Clinical Trial. ISRN Obstret. Gynecol. 2013;2013:649030. doi: 10.1155/2013/649030.
    1. Chwalisz K., Larsen L., Mattia-Goldberg C., Edmonds A., Elger W., Winkel C.A. A randomized, controlled trial of asoprisnil, a novel selective progesterone receptor modulator, in women with uterine leiomyomata. Fertil. Steril. 2007;87:1399–1412. doi: 10.1016/j.fertnstert.2006.11.094.
    1. Wiehle R.D., Goldberg J., Brodniewicz T., Jarus-Dziedzic K., Jabiry-Zieniewicz Z. Effects of a new progesterone receptor modulator, CDB-4124, on fibroid size and uterine bleeding. Obstet. Gynecol. 2008;3:17–20.
    1. Levens E.D., Potlog-Nahari C., Armstrong A.Y., Wesley R., Premkumar A., Blithe D.L., Blocker W., Nieman L.K. CDB-2914 for uterine leiomyomata treatment: A randomized controlled trial. Obstret. Gynecol. 2008;111:1129–1136. doi: 10.1097/AOG.0b013e3181705d0e.
    1. Nieman L.K., Blocker W., Nansel T., Mahoney S., Reynolds J., Blithe D., Wesley R., Armstrong A. Efficacy and tolerability of CDB-2914 treatment for symptomatic uterine fibroids: A randomized, double-blind, placebo-controlled, phase IIb study. Fertil. Steril. 2011;95:767–772.e2. doi: 10.1016/j.fertnstert.2010.09.059.
    1. Donnez J., Tatarchuk T.F., Bouchard P., Puscasiu L., Zakharenko N.F., Ivanova T., Ugocsai G., Mara M., Jilla M.P., Bestel E. Ulipristal acetate versus placebo for fibroid treatment before surgery. N. Engl. J. Med. 2012;366:409–420. doi: 10.1056/NEJMoa1103182.
    1. Donnez J., Tomaszewski J., Vázquez F., Bouchard P., Lemieszczuk B., Baró F., Nouri K., Selvaggi L., Sodowski K., Bestel E. Ulipristal acetate versus leuprolide acetate for uterine fibroids. N. Engl. J. Med. 2012;366:421–432. doi: 10.1056/NEJMoa1103180.
    1. Blithe D.L., Nieman L.K., Blye R.P., Stratton P., Passaro M. Development of the selective progesterone receptor modulator CDB-2914 for clinical indications. Steroids. 2003;68:1013–1017. doi: 10.1016/S0039-128X(03)00118-1.
    1. Attardi B.J., Burgenson J., Hild S.A., Reel J.R., Blye R.P. CDB-4124 and its putative monodemethylated metabolite, CDB-4453, are potent antiprogestins with reduced antiglucocorticoid activity: In vitro comparison to mifepristone and CDB-2914. Mol. Cell. Endocrinol. 2002;188:111–123. doi: 10.1016/S0303-7207(01)00743-2.
    1. Del Forno S., Degli Esposti E., Salucci P., Leonardi D., Iodice R., Arena A., Raimondo D., Paradisi R., Seracchioli R. Liver function, tolerability and satisfaction during treatment with ulipristal acetate in women with fibroids: A single center experience. Gynecol. Endocrinol. 2020;36:445–447. doi: 10.1080/09513590.2019.1680626.
    1. Ciarmela P., Carrarelli P., Islam M.S., Janjusevic M., Zupi E., Tosti C., Castellucci M., Petraglia F. Ulipristal acetate modulates the expression and functions of activin a in leiomyoma cells. Reprod. Sci. 2014;21:1120–1125. doi: 10.1177/1933719114542019.
    1. Frasca C., Arena A., Degli Esposti E., Raimondo D., Del Forno S., Moro E., Zanello M., Mabrouk M., Seracchioli R. First Impressions Can Be Deceiving: Surgical Outcomes of Laparoscopic Myomectomy in Patients Pretreated with Ulipristal Acetate. J. Minim. Invasive Gynecol. 2020;27:633–638. doi: 10.1016/j.jmig.2019.04.026.
    1. Friedman A.J., Rein M.S., Harrison-Atlas D., Garfield J.M., Doubilet P.M. A randomized, placebo-controlled, double-blind study evaluating leuprolide acetate depot treatment before myomectomy. Fertil. Steril. 1989;52:728–733. doi: 10.1016/S0015-0282(16)61022-1.
    1. Islam M.S., Protic O., Giannubilo S.R., Toti P., Tranquilli A.L., Petraglia F., Castellucci M., Ciarmela P. Uterine leiomyoma: Available medical treatments and new possible therapeutic options. J. Clin. Endocrinol. Metab. 2013;98:921–934. doi: 10.1210/jc.2012-3237.
    1. Wallach E.E., Vlahos N.F. Uterine myomas: An overview of development, clinical features, and management. Obstret. Gynecol. 2004;104:393–406. doi: 10.1097/01.AOG.0000136079.62513.39.
    1. Kim T., Purdy M.P., Kendall-Rauchfuss L., Habermann E.B., Bews K.A., Glasgow A.E., Khan Z. Myomectomy associated blood transfusion risk and morbidity after surgery. Fertil. Steril. 2020;114:175–184. doi: 10.1016/j.fertnstert.2020.02.110.
    1. Flynn M., Jamison M., Datta S., Myers E. Health care resource use for uterine fibroid tumors in the United States. Am. J. Obstet. Gynecol. 2006;195:955–964. doi: 10.1016/j.ajog.2006.02.020.
    1. Zepiridis L.I., Grimbizis G.F., Tarlatzis B.C. Infertility and uterine fibroids. Best Pract. Res. Clin. Obstret. Gynaecol. 2016;34:66–73. doi: 10.1016/j.bpobgyn.2015.12.001.
    1. Kurman R., Ellenson L., Ronnett B. Blaustein’s Pathology of the Female Genital Tract. Int. J. Gynecol. Pathol. 2016 doi: 10.1007/1978-1001-4614-3165-1007.
    1. Rosai J., Ackerman L. Rosai and Ackerman’s Surgical Pathology. 10th ed. Elsevier; Amsterdam, The Netherlands: 2012. pp. 1508–1513.
    1. Avritscher R., Iyer R.B., Ro J., Whitman G. Lipoleiomyoma of the uterus. AJR Am. J. Roentgenol. 2001;177:856. doi: 10.2214/ajr.177.4.1770856.
    1. Myles J.L., Hart W.R. Apoplectic leiomyomas of the uterus. A clinicopathologic study of five distinctive hemorrhagic leiomyomas associated with oral contraceptive usage. Am. J. Surg. Pathol. 1985;9:798–805. doi: 10.1097/00000478-198511000-00003.
    1. Ciarmela P., Islam M.S., Lamanna P., Tranquilli A.L., Castellucci M. Healthy and pathological changes of myometrium: Pregnant myometrium, uterine fibroids and leiomyosarcoma. Rev. Argent. Anatomía Clínica. 2012;4:7–13. doi: 10.31051/1852.8023.v4.n1.13945.
    1. Toledo G., Oliva E. Smooth muscle tumors of the uterus: A practical approach. Arch. Pathol. Lab. Med. 2008;132:595–605. doi: 10.5858/2008-132-595-SMTOTU.
    1. Leppert P.C., Catherino W.H., Segars J.H. A new hypothesis about the origin of uterine fibroids based on gene expression profiling with microarrays. Am. J. Obstret. Gynecol. 2006;195:415–420. doi: 10.1016/j.ajog.2005.12.059.
    1. Malik M., Norian J., McCarthy-Keith D., Britten J., Catherino W.H. Why leiomyomas are called fibroids: The central role of extracellular matrix in symptomatic women. Semin. Reprod. Med. 2010;28:169–179. doi: 10.1055/s-0030-1251475.
    1. Gelse K., Pöschl E., Aigner T. Collagens-structure, function, and biosynthesis. Adv. Drug Deliv. Rev. 2003;55:1531–1546. doi: 10.1016/j.addr.2003.08.002.
    1. Fujita M. Histological and biochemical studies of collagen in human uterine leiomyomas. Hokkaido J. Med. Sci. 1985;60:602–615.
    1. Arici A., Sozen I. Transforming growth factor-beta3 is expressed at high levels in leiomyoma where it stimulates fibronectin expression and cell proliferation. Fertil. Steril. 2000;73:1006–1011. doi: 10.1016/S0015-0282(00)00418-0.
    1. Norian J.M., Malik M., Parker C.Y., Joseph D., Leppert P.C., Segars J.H., Catherino W.H. Transforming growth factor beta3 regulates the versican variants in the extracellular matrix-rich uterine leiomyomas. Reprod. Sci. 2009;16:1153–1164. doi: 10.1177/1933719109343310.
    1. Stewart E.A., Friedman A.J., Peck K., Nowak R.A. Relative overexpression of collagen type I and collagen type III messenger ribonucleic acids by uterine leiomyomas during the proliferative phase of the menstrual cycle. J. Clin. Endocrinol. Metab. 1994;79:900–906.
    1. Giuliani A., Greco S., Pacile S., Zannotti A., Delli Carpini G., Tromba G., Giannubilo S.R., Ciavattini A., Ciarmela P. Advanced 3D Imaging of Uterine Leiomyoma’s Morphology by Propagation-based Phase-Contrast Microtomography. Sci. Rep. 2019;9:10580. doi: 10.1038/s41598-019-47048-0.
    1. Walker C.L., Stewart E.A. Uterine fibroids: The elephant in the room. Science. 2005;308:1589–1592. doi: 10.1126/science.1112063.
    1. Hulboy D.L., Rudolph L.A., Matrisian L.M. Matrix metalloproteinases as mediators of reproductive function. Mol. Hum. Reprod. 1997;3:27–45. doi: 10.1093/molehr/3.1.27.
    1. Ohara N. Sex steroidal modulation of collagen metabolism in uterine leiomyomas. Clin. Exp. Obstet. Gynecol. 2009;36:10.
    1. Protic O., Toti P., Islam M.S., Occhini R., Giannubilo S.R., Catherino W.H., Cinti S., Petraglia F., Ciavattini A., Castellucci M., et al. Possible involvement of inflammatory/reparative processes in the development of uterine fibroids. Cell Tissue Res. 2016;364:415–427. doi: 10.1007/s00441-015-2324-3.
    1. Flake G.P., Andersen J., Dixon D. Etiology and pathogenesis of uterine leiomyomas: A review. Environ. Health Perspect. 2003;111:1037–1054. doi: 10.1289/ehp.5787.
    1. Kiechle-Schwarz M., Sreekantaiah C., Berger C.S., Pedron S., Medchill M.T., Surti U., Sandberg A.A. Nonrandom cytogenetic changes in leiomyomas of the female genitourinary tract. A report of 35 cases. Cancer Genet. Cytogenet. 1991;53:125–136. doi: 10.1016/0165-4608(91)90124-D.
    1. Rein M.S., Friedman A.J., Barbieri R.L., Pavelka K., Fletcher J.A., Morton C.C. Cytogenetic abnormalities in uterine leiomyomata. Obstet. Gynecol. 1991;77:923–926.
    1. Meloni A.M., Surti U., Contento A.M., Davare J., Sandberg A.A. Uterine leiomyomas: Cytogenetic and histologic profile. Obstet. Gynecol. 1992;80:209–217.
    1. Cha P.C., Takahashi A., Hosono N., Low S.K., Kamatani N., Kubo M., Nakamura Y. A genome-wide association study identifies three loci associated with susceptibility to uterine fibroids. Nat. Genet. 2011;43:447–450. doi: 10.1038/ng.805.
    1. Ligon A.H., Scott I.C., Takahara K., Greenspan D.S., Morton C.C. PCOLCE deletion and expression analyses in uterine leiomyomata. Cancer Genet. Cytogenet. 2002;137:133–137. doi: 10.1016/S0165-4608(02)00547-2.
    1. Ptacek T., Song C., Walker C.L., Sell S.M. Physical mapping of distinct 7q22 deletions in uterine leiomyoma and analysis of a recently annotated 7q22 candidate gene. Cancer Genet. Cytogenet. 2007;174:116–120. doi: 10.1016/j.cancergencyto.2006.11.018.
    1. Velagaleti G.V., Tonk V.S., Hakim N.M., Wang X., Zhang H., Erickson-Johnson M.R., Medeiros F., Oliveira A.M. Fusion of HMGA2 to COG5 in uterine leiomyoma. Cancer Genet. Cytogenet. 2011;202:11–16. doi: 10.1016/j.cancergencyto.2010.06.002.
    1. Mäkinen N., Mehine M., Tolvanen J., Kaasinen E., Li Y., Lehtonen H.J., Gentile M., Yan J., Enge M., Taipale M. MED12, the mediator complex subunit 12 gene, is mutated at high frequency in uterine leiomyomas. Science. 2011;334:252–255. doi: 10.1126/science.1208930.
    1. Nezhad M.H., Drieschner N., Helms S., Meyer A., Tadayyon M., Klemke M., Belge G., Bartnitzke S., Burchardt K., Frantzen C. 6p21 rearrangements in uterine leiomyomas targeting HMGA1. Cancer Genet. Cytogenet. 2010;203:247–252. doi: 10.1016/j.cancergencyto.2010.08.005.
    1. Sandberg A.A. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: Leiomyoma. Cancer Genet. Cytogenet. 2005;158:1–26. doi: 10.1016/j.cancergencyto.2004.08.025.
    1. El-Gharib M.N., Elsobky E.S. Cytogenetic aberrations and the development of uterine leiomyomata. J. Obstet. Gynaecol. Res. 2010;36:101–107. doi: 10.1111/j.1447-0756.2009.01099.x.
    1. Mehine M., Kaasinen E., Makinen N., Katainen R., Kampjarvi K., Pitkanen E., Heinonen H.R., Butzow R., Kilpivaara O., Kuosmanen A., et al. Characterization of uterine leiomyomas by whole-genome sequencing. N. Engl. J. Med. 2013;369:43–53. doi: 10.1056/NEJMoa1302736.
    1. Mehine M., Makinen N., Heinonen H.R., Aaltonen L.A., Vahteristo P. Genomics of uterine leiomyomas: Insights from high-throughput sequencing. Fertil. Steril. 2014;102:621–629. doi: 10.1016/j.fertnstert.2014.06.050.
    1. Marsh E.E., Lin Z., Yin P., Milad M., Chakravarti D., Bulun S.E. Differential expression of microRNA species in human uterine leiomyoma versus normal myometrium. Fertil. Steril. 2008;89:1771–1776. doi: 10.1016/j.fertnstert.2007.05.074.
    1. Navarro A., Yin P., Monsivais D., Lin S.M., Du P., Wei J.J., Bulun S.E. Genome-Wide DNA Methylation Indicates Silencing of Tumor Suppressor Genes in Uterine Leiomyoma. PLoS ONE. 2012;7:e33284. doi: 10.1371/journal.pone.0033284.
    1. Wei L.H., Torng P.L., Hsiao S.M., Jeng Y.M., Chen M.W., Chen C.A. Histone Deacetylase 6 Regulates Estrogen Receptor α in Uterine Leiomyoma. Reprod. Sci. 2011;18:755–762. doi: 10.1177/1933719111398147.
    1. Yang Q., Mas A., Diamond M.P., Al-Hendy A. The Mechanism and Function of Epigenetics in Uterine Leiomyoma Development. Reprod. Sci. 2016;23:163–175. doi: 10.1177/1933719115584449.
    1. Wang T., Zhang X., Obijuru L., Laser J., Aris V., Lee P., Mittal K., Soteropoulos P., Wei J.J. A micro-RNA signature associated with race, tumor size, and target gene activity in human uterine leiomyomas. Genes Chromosomes Cancer. 2007;46:336–347. doi: 10.1002/gcc.20415.
    1. Liu J., Matsuo H., Xu Q., Chen W., Wang J., Maruo T. Concentration-dependent effects of a selective estrogen receptor modulator raloxifene on proliferation and apoptosis in human uterine leiomyoma cells cultured in vitro. Hum. Reprod. 2007;22:1253–1259. doi: 10.1093/humrep/del515.
    1. Georgieva B., Milev I., Minkov I., Dimitrova I., Bradford A.P., Baev V. Characterization of the uterine leiomyoma microRNAome by deep sequencing. Genomics. 2012;93:275–281. doi: 10.1016/j.ygeno.2012.03.003.
    1. Ciebiera M., Wlodarczyk M., Zgliczynski S., Lozinski T., Walczak K., Czekierdowski A. The Role of miRNA and Related Pathways in Pathophysiology of Uterine Fibroids-From Bench to Bedside. Int. J. Mol. Sci. 2020;21:3016. doi: 10.3390/ijms21083016.
    1. Nothnick W.B. Non-coding RNAs in Uterine Development, Function and Disease. Adv. Exp. Med. Biol. 2016;886:171–189. doi: 10.1007/978-94-017-7417-8_9.
    1. Baranov V.S., Osinovskaya N.S., Yarmolinskaya M.I. Pathogenomics of Uterine Fibroids Development. Int. J. Mol. Sci. 2019;20:6151. doi: 10.3390/ijms20246151.
    1. McWilliams M.M., Chennathukuzhi V.M. Recent Advances in Uterine Fibroid Etiology. Semin. Reprod. Med. 2017;35:181–189. doi: 10.1055/s-0037-1599090.
    1. Mallik S., Maulik U. MiRNA-TF-gene network analysis through ranking of biomolecules for multi-informative uterine leiomyoma dataset. J. Biomed. Inf. 2015;57:308–319. doi: 10.1016/j.jbi.2015.08.014.
    1. Ciarmela P., Bloise E., Gray P.C., Carrarelli P., Islam M.S., De Pascalis F., Severi F.M., Vale W., Castellucci M., Petraglia F. Activin-A and myostatin response and steroid regulation in human myometrium: Disruption of their signalling in uterine fibroid. J. Clin. Endocrinol. Metab. 2011;96:755–765. doi: 10.1210/jc.2010-0501.
    1. Moro E., Degli Esposti E., Borghese G., Manzara F., Zanello M., Raimondo D., Gava G., Arena A., Casadio P., Meriggiola M.C., et al. The Impact of Hormonal Replacement Treatment in Postmenopausal Women with Uterine Fibroids: A State-of-the-Art Review of the Literature. Medicina (Kaunas) 2019;55:549. doi: 10.3390/medicina55090549.
    1. Sozen I., Arici A. Interactions of cytokines, growth factors, and the extracellular matrix in the cellular biology of uterine leiomyomata. Fertil. Steril. 2002;78:1–12. doi: 10.1016/S0015-0282(02)03154-0.
    1. Ciarmela P., Wiater E., Vale W. Activin-A in myometrium: Characterization of the actions on myometrial cells. Endocrinology. 2008;149:2506–2516. doi: 10.1210/en.2007-0692.
    1. Ciarmela P., Wiater E., Smith S.M., Vale W. Presence, actions, and regulation of myostatin in rat uterus and myometrial cells. Endocrinology. 2009;150:906–914. doi: 10.1210/en.2008-0880.
    1. Hatthachote P., Gillespie J.I. Complex interactions between sex steroids and cytokines in the human pregnant myometrium: Evidence for an autocrine signaling system at term. Endocrinology. 1999;140:2533–2540. doi: 10.1210/endo.140.6.6785.
    1. Litovkin K.V., Domenyuk V.P., Bubnov V.V., Zaporozhan V.N. Interleukin-6-174G/C polymorphism in breast cancer and uterine leiomyoma patients: A population-based case control study. Exp. Oncol. 2007;29:295–298.
    1. Kurachi O., Matsuo H., Samoto T., Maruo T. Tumor necrosis factor-α expression in human uterine leiomyoma and its down-regulation by progesterone. J. Clin. Endocrinol. Metab. 2001;86:2275–2280. doi: 10.1210/jc.86.5.2275.
    1. Syssoev K.A., Kulagina N.V., Chukhlovin A.B., Morozova E.B., Totolian A.A. Expression of mRNA for chemokines and chemokine receptors in tissues of the myometrium and uterine leiomyoma. Bull. Exp. Biol. Med. 2008;145:84–89. doi: 10.1007/s10517-008-0038-1.
    1. Sozen I., Olive D.L., Arici A. Expression and hormonal regulation of monocyte chemotactic protein-1 in myometrium and leiomyomata. Fertil. Steril. 1998;69:1095–1102. doi: 10.1016/S0015-0282(98)00072-7.
    1. Nair S., Al-Hendy A. Adipocytes enhance the proliferation of human leiomyoma cells via TNF-α proinflammatory cytokine. Reprod. Sci. 2011;18:1186–1192. doi: 10.1177/1933719111408111.
    1. Bodner-Adler B., Bodner K., Kimberger O., Czerwenka K., Leodolter S., Mayerhofer K. Expression of matrix metalloproteinases in patients with uterine smooth muscle tumors: An immunohistochemical analysis of MMP-1 and MMP-2 protein expression in leiomyoma, uterine smooth muscle tumor of uncertain malignant potential, and leiomyosarcoma. J. Soc. Gynecol. Investig. 2004;11:182–186. doi: 10.1016/j.jsgi.2003.09.004.
    1. Wolanska M., Sobolewski K., Bańkowski E., Jaworski S. Matrix metalloproteinases of human leiomyoma in various stages of tumor growth. Gynecol. Obstet. Investig. 2004;58:14–18. doi: 10.1159/000077177.
    1. Bogusiewicz M., Stryjecka-Zimmer M., Postawski K., Jakimiuk A.J., Rechberger T. Activity of matrix metalloproteinase-2 and-9 and contents of their tissue inhibitors in uterine leiomyoma and corresponding myometrium. Gynecol. Endocrinol. 2007;23:541–546. doi: 10.1080/09513590701557416.
    1. Walker C.L., Hunter D., Everitt J.I. Uterine leiomyoma in the Eker rat: A unique model for important diseases of women. Genes Chromosomes Cancer. 2003;38:349–356. doi: 10.1002/gcc.10281.
    1. Cook J.D., Walker C.L. The Eker rat: Establishing a genetic paradigm linking renal cell carcinoma and uterine leiomyoma. Curr. Mol. Med. 2004;4:813–824. doi: 10.2174/1566524043359656.
    1. Andersen J., Barbieri R.L. Abnormal gene expression in uterine leiomyomas. J. Soc. Gynecol. Investig. 1995;2:663–672. doi: 10.1177/107155769500200501.
    1. Maruo T., Ohara N., Wang J., Matsuo H. Sex steroidal regulation of uterine leiomyoma growth and apoptosis. Hum. Reprod. Update. 2004;10:207–220. doi: 10.1093/humupd/dmh019.
    1. Sadan O., Van Iddekinge B., Van Gelderen C.J., Savage N., Becker P.J., Van Der Walt L.A., Robinson M. Oestrogen and progesterone receptor concentrations in leiomyoma and normal myometrium. Ann. Clin. Biochem. 1987;24:263–267. doi: 10.1177/000456328702400304.
    1. Kim J.J., Sefton E.C. The role of progesterone signaling in the pathogenesis of uterine leiomyoma. Mol. Cell. Endocrinol. 2011;358:223–231. doi: 10.1016/j.mce.2011.05.044.
    1. Brandon D.D., Bethea C.L., Strawn E.Y., Novy M.J., Burry K.A., Harrington M.S., Erickson T.E., Warner C., Keenan E.J., Clinton G.M. Progesterone receptor messenger ribonucleic acid and protein are overexpressed in human uterine leiomyomas. Am. J. Obstet. Gynecol. 1993;169:78–85. doi: 10.1016/0002-9378(93)90135-6.
    1. Marelli G., Codegoni A.M., Bizzi A. Estrogen and progesterone receptors in leiomyomas and normal uterine tissues during reproductive life. Acta Eur. Fertil. 1989;20:19–22.
    1. Viville B., Charnock-Jones D.S., Sharkey A.M., Wetzka B., Smith S.K. Distribution of the A and B forms of the progesterone receptor messenger ribonucleic acid and protein in uterine leiomyomata and adjacent myometrium. Hum. Reprod. 1997;12:815–822. doi: 10.1093/humrep/12.4.815.
    1. Ying Z., Weiyuan Z. Dual actions of progesterone on uterine leiomyoma correlate with the ratio of progesterone receptor A:B. Gynecol. Endocrinol. 2009;25:520–523. doi: 10.1080/09513590902972117.
    1. Fujimoto J., Hirose R., Ichigo S., Sakaguchi H., Li Y., Tamaya T. Expression of progesterone receptor form A and B mRNAs in uterine leiomyoma. Tumor Biol. 1998;19:126–131. doi: 10.1159/000029983.
    1. Protic O., Islam M.S., Greco S., Giannubilo S.R., Lamanna P., Petraglia F., Ciavattini A., Castellucci M., Hinz B., Ciarmela P. Activin A in Inflammation, Tissue Repair, and Fibrosis: Possible Role as Inflammatory and Fibrotic Mediator of Uterine Fibroid Development and Growth. Semin. Reprod. Med. 2017;35:499–509. doi: 10.1055/s-0037-1607265.
    1. Kisseleva T., Brenner D.A. Mechanisms of fibrogenesis. Exp. Biol. Med. 2008;233:109–122. doi: 10.3181/0707-MR-190.
    1. Hinz B., Phan S.H., Thannickal V.J., Prunotto M., Desmouliere A., Varga J., De Wever O., Mareel M., Gabbiani G. Recent developments in myofibroblast biology: Paradigms for connective tissue remodeling. Am. J. Pathol. 2012;180:1340–1355. doi: 10.1016/j.ajpath.2012.02.004.
    1. Hinz B. Formation and function of the myofibroblast during tissue repair. J. Investig. Derm. 2007;127:526–537. doi: 10.1038/sj.jid.5700613.
    1. Wynn T.A. Cellular and molecular mechanisms of fibrosis. J. Pathol. 2008;214:199–210. doi: 10.1002/path.2277.
    1. Kacperczyk J., Bartnik P., Romejko-Wolniewicz E., Dobrowolska-Redo A. Postmyomectomic Uterine Rupture Despite Cesarean Section. Anticancer Res. 2016;36:1011–1013.
    1. Wynn T.A., Barron L. Macrophages: Master regulators of inflammation and fibrosis. Semin. Liver Dis. 2010;30:245–257. doi: 10.1055/s-0030-1255354.
    1. Mosser D.M., Edwards J.P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 2008;8:958–969. doi: 10.1038/nri2448.
    1. Lech M., Anders H.J. Macrophages and fibrosis: How resident and infiltrating mononuclear phagocytes orchestrate all phases of tissue injury and repair. Biochim. Biophys. Acta. 2013;1832:989–997. doi: 10.1016/j.bbadis.2012.12.001.
    1. Davies L.C., Jenkins S.J., Allen J.E., Taylor P.R. Tissue-resident macrophages. Nat. Immunol. 2013;14:986–995. doi: 10.1038/ni.2705.
    1. Galli S.J., Borregaard N., Wynn T.A. Phenotypic and functional plasticity of cells of innate immunity: Macrophages, mast cells and neutrophils. Nat. Immunol. 2011;12:1035–1044. doi: 10.1038/ni.2109.
    1. Jenkins S.J., Ruckerl D., Cook P.C., Jones L.H., Finkelman F.D., van Rooijen N., MacDonald A.S., Allen J.E. Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation. Science. 2011;332:1284–1288. doi: 10.1126/science.1204351.
    1. Jenkins S.J., Ruckerl D., Thomas G.D., Hewitson J.P., Duncan S., Brombacher F., Maizels R.M., Hume D.A., Allen J.E. IL-4 directly signals tissue-resident macrophages to proliferate beyond homeostatic levels controlled by CSF-1. J. Exp. Med. 2013;210:2477–2491. doi: 10.1084/jem.20121999.
    1. Berse B., Brown L.F., Van de Water L., Dvorak H.F., Senger D.R. Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors. Mol. Biol. Cell. 1992;3:211–220. doi: 10.1091/mbc.3.2.211.
    1. Chujo S., Shirasaki F., Kondo-Miyazaki M., Ikawa Y., Takehara K. Role of connective tissue growth factor and its interaction with basic fibroblast growth factor and macrophage chemoattractant protein-1 in skin fibrosis. J. Cell Physiol. 2009;220:189–195. doi: 10.1002/jcp.21750.
    1. Rappolee D.A., Mark D., Banda M.J., Werb Z. Wound macrophages express TGF-alpha and other growth factors in vivo: Analysis by mRNA phenotyping. Science. 1988;241:708–712. doi: 10.1126/science.3041594.
    1. Shimokado K., Raines E.W., Madtes D.K., Barrett T.B., Benditt E.P., Ross R. A significant part of macrophage-derived growth factor consists of at least two forms of PDGF. Cell. 1985;43:277–286. doi: 10.1016/0092-8674(85)90033-9.
    1. Willenborg S., Lucas T., van Loo G., Knipper J.A., Krieg T., Haase I., Brachvogel B., Hammerschmidt M., Nagy A., Ferrara N., et al. CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair. Blood. 2012;120:613–625. doi: 10.1182/blood-2012-01-403386.
    1. Murray P.J., Wynn T.A. Protective and pathogenic functions of macrophage subsets. Nat. Rev. Immunol. 2011;11:723–737. doi: 10.1038/nri3073.
    1. Ramachandran P., Iredale J.P., Fallowfield J.A. Resolution of liver fibrosis: Basic mechanisms and clinical relevance. Semin. Liver Dis. 2015;35:119–131. doi: 10.1055/s-0035-1550057.
    1. Khalil N., Bereznay O., Sporn M., Greenberg A.H. Macrophage production of transforming growth factor beta and fibroblast collagen synthesis in chronic pulmonary inflammation. J. Exp. Med. 1989;170:727–737. doi: 10.1084/jem.170.3.727.
    1. Said E.A., Dupuy F.P., Trautmann L., Zhang Y., Shi Y., El-Far M., Hill B.J., Noto A., Ancuta P., Peretz Y., et al. Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. Nat. Med. 2010;16:452–459. doi: 10.1038/nm.2106.
    1. Shouval D.S., Biswas A., Goettel J.A., McCann K., Conaway E., Redhu N.S., Mascanfroni I.D., Al Adham Z., Lavoie S., Ibourk M., et al. Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function. Immunity. 2014;40:706–719. doi: 10.1016/j.immuni.2014.03.011.
    1. Zigmond E., Bernshtein B., Friedlander G., Walker C.R., Yona S., Kim K.W., Brenner O., Krauthgamer R., Varol C., Muller W., et al. Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis. Immunity. 2014;40:720–733. doi: 10.1016/j.immuni.2014.03.012.
    1. Wynn T.A., Ramalingam T.R. Mechanisms of fibrosis: Therapeutic translation for fibrotic disease. Nat. Med. 2012;18:1028–1040. doi: 10.1038/nm.2807.
    1. Tidball J.G. Regulation of muscle growth and regeneration by the immune system. Nat. Rev. Immunol. 2017;17:165–178. doi: 10.1038/nri.2016.150.
    1. Arnold L., Henry A., Poron F., Baba-Amer Y., van Rooijen N., Plonquet A., Gherardi R.K., Chazaud B. Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. J. Exp. Med. 2007;204:1057–1069. doi: 10.1084/jem.20070075.
    1. Saini J., McPhee J.S., Al-Dabbagh S., Stewart C.E., Al-Shanti N. Regenerative function of immune system: Modulation of muscle stem cells. Ageing Res. Rev. 2016;27:67–76. doi: 10.1016/j.arr.2016.03.006.
    1. Martinez F.O., Gordon S. The M1 and M2 paradigm of macrophage activation: Time for reassessment. F1000Prime Rep. 2014;6:13. doi: 10.12703/P6-13.
    1. Stables M.J., Shah S., Camon E.B., Lovering R.C., Newson J., Bystrom J., Farrow S., Gilroy D.W. Transcriptomic analyses of murine resolution-phase macrophages. Blood. 2011;118:e192–e208. doi: 10.1182/blood-2011-04-345330.
    1. Varga T., Mounier R., Horvath A., Cuvellier S., Dumont F., Poliska S., Ardjoune H., Juban G., Nagy L., Chazaud B. Highly Dynamic Transcriptional Signature of Distinct Macrophage Subsets during Sterile Inflammation, Resolution, and Tissue Repair. J. Immunol. 2016;196:4771–4782. doi: 10.4049/jimmunol.1502490.
    1. Varga T., Mounier R., Patsalos A., Gogolak P., Peloquin M., Horvath A., Pap A., Daniel B., Nagy G., Pintye E., et al. Macrophage PPARgamma, a Lipid Activated Transcription Factor Controls the Growth Factor GDF3 and Skeletal Muscle Regeneration. Immunity. 2016;45:1038–1051. doi: 10.1016/j.immuni.2016.10.016.
    1. Heredia J.E., Mukundan L., Chen F.M., Mueller A.A., Deo R.C., Locksley R.M., Rando T.A., Chawla A. Type 2 innate signals stimulate fibro/adipogenic progenitors to facilitate muscle regeneration. Cell. 2013;153:376–388. doi: 10.1016/j.cell.2013.02.053.
    1. Takeda N., O’Dea E.L., Doedens A., Kim J.W., Weidemann A., Stockmann C., Asagiri M., Simon M.C., Hoffmann A., Johnson R.S. Differential activation and antagonistic function of HIF-{alpha} isoforms in macrophages are essential for NO homeostasis. Genes Dev. 2010;24:491–501. doi: 10.1101/gad.1881410.
    1. Gondin J., Theret M., Duhamel G., Pegan K., Mathieu J.R., Peyssonnaux C., Cuvellier S., Latroche C., Chazaud B., Bendahan D., et al. Myeloid HIFs are dispensable for resolution of inflammation during skeletal muscle regeneration. J. Immunol. 2015;194:3389–3399. doi: 10.4049/jimmunol.1401420.
    1. Oishi Y., Manabe I. Macrophages in inflammation, repair and regeneration. Int. Immunol. 2018;30:511–528. doi: 10.1093/intimm/dxy054.
    1. Holness C.L., Simmons D.L. Molecular cloning of CD68, a human macrophage marker related to lysosomal glycoproteins. Blood. 1993;81:1607–1613. doi: 10.1182/blood.V81.6.1607.1607.
    1. Miura S., Khan K.N., Kitajima M., Hiraki K., Moriyama S., Masuzaki H., Samejima T., Fujishita A., Ishimaru T. Differential infiltration of macrophages and prostaglandin production by different uterine leiomyomas. Hum. Reprod. 2006;21:2545–2554. doi: 10.1093/humrep/del205.
    1. Deshmane S.L., Kremlev S., Amini S., Sawaya B.E. Monocyte chemoattractant protein-1 (MCP-1): An overview. J. Interferon Cytokine Res. 2009;29:313–326. doi: 10.1089/jir.2008.0027.
    1. Khan K.N., Kitajima M., Hiraki K., Fujishita A., Sekine I., Ishimaru T., Masuzaki H. Changes in tissue inflammation, angiogenesis and apoptosis in endometriosis, adenomyosis and uterine myoma after GnRH agonist therapy. Hum. Reprod. 2010;25:642–653. doi: 10.1093/humrep/dep437.
    1. Sozen I., Senturk L.M., Arici A. Effect of gonadotropin-releasing hormone agonists on monocyte chemotactic protein-1 production and macrophage infiltration in leiomyomatous uterus. Fertil. Steril. 2001;76:792–796. doi: 10.1016/S0015-0282(01)02378-0.
    1. Aleem F.A., Predanic M. The hemodynamic effect of GnRH agonist therapy on uterine leiomyoma vascularity: A prospective study using transvaginal color Doppler sonography. Gynecol. Endocrinol. 1995;9:253–258. doi: 10.3109/09513599509160454.
    1. Matta W.H., Stabile I., Shaw R.W., Campbell S. Doppler assessment of uterine blood flow changes in patients with fibroids receiving the gonadotropin-releasing hormone agonist Buserelin. Fertil. Steril. 1988;49:1083–1085. doi: 10.1016/S0015-0282(16)59966-X.
    1. Kitaya K., Yasuo T. Leukocyte density and composition in human cycling endometrium with uterine fibroids. Hum. Immunol. 2010;71:158–163. doi: 10.1016/j.humimm.2009.11.014.
    1. Rasko J.E., Ben H. Granulocyte-macrophage colony stimulating factor. In: Thomson A., editor. The Cytokine Handbook. Academic Press; London, UK: 1994. pp. 343–369.
    1. Andreutti D., Gabbiani G., Neuville P. Early granulocyte-macrophage colony-stimulating factor expression by alveolar inflammatory cells during bleomycin-induced rat lung fibrosis. Lab. Investig. 1998;78:1493–1502.
    1. Rubbia-Brandt L., Sappino A.P., Gabbiani G. Locally applied GM-CSF induces the accumulation of alpha-smooth muscle actin containing myofibroblasts. Virchows Arch. B Cell Pathol. Incl. Mol. Pathol. 1991;60:73–82. doi: 10.1007/BF02899530.
    1. Xing Z., Gauldie J., Tremblay G.M., Hewlett B.R., Addison C. Intradermal transgenic expression of granulocyte-macrophage colony-stimulating factor induces neutrophilia, epidermal hyperplasia, Langerhans’ cell/macrophage accumulation, and dermal fibrosis. Lab. Investig. A J. Tech. Methods Pathol. 1997;77:615.
    1. Xing Z., Tremblay G.M., Sime P.J., Gauldie J. Overexpression of granulocyte-macrophage colony-stimulating factor induces pulmonary granulation tissue formation and fibrosis by induction of transforming growth factor-beta 1 and myofibroblast accumulation. Am. J. Pathol. 1997;150:59–66.
    1. Xing Z., Ohkawara Y., Jordana M., Graham F., Gauldie J. Transfer of granulocyte-macrophage colony-stimulating factor gene to rat lung induces eosinophilia, monocytosis, and fibrotic reactions. J. Clin. Investig. 1996;97:1102–1110. doi: 10.1172/JCI118503.
    1. Border W.A., Noble N.A. Transforming growth factor beta in tissue fibrosis. N. Engl. J. Med. 1994;331:1286–1292. doi: 10.1056/NEJM199411103311907.
    1. Roberts A.B. Transforming growth factor-beta: Activity and efficacy in animal models of wound healing. Wound Repair Regen. 1995;3:408–418. doi: 10.1046/j.1524-475X.1995.30405.x.
    1. Vyalov S., Desmouliere A., Gabbiani G. GM-CSF-induced granulation tissue formation: Relationships between macrophage and myofibroblast accumulation. Virchows Arch. B Cell Pathol. Incl. Mol. Pathol. 1993;63:231–239. doi: 10.1007/BF02899267.
    1. Ciebiera M., Wlodarczyk M., Wrzosek M., Meczekalski B., Nowicka G., Lukaszuk K., Ciebiera M., Slabuszewska-Jozwiak A., Jakiel G. Role of Transforming Growth Factor beta in Uterine Fibroid Biology. Int. J. Mol. Sci. 2017;18:2435. doi: 10.3390/ijms18112435.
    1. Fallowfield J.A., Mizuno M., Kendall T.J., Constandinou C.M., Benyon R.C., Duffield J.S., Iredale J.P. Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J. Immunol. 2007;178:5288–5295. doi: 10.4049/jimmunol.178.8.5288.
    1. Sierra-Filardi E., Puig-Kroger A., Blanco F.J., Nieto C., Bragado R., Palomero M.I., Bernabeu C., Vega M.A., Corbi A.L. Activin A skews macrophage polarization by promoting a proinflammatory phenotype and inhibiting the acquisition of anti-inflammatory macrophage markers. Blood. 2011;117:5092–5101. doi: 10.1182/blood-2010-09-306993.
    1. Islam M.S., Catherino W.H., Protic O., Janjusevic M., Gray P.C., Giannubilo S.R., Ciavattini A., Lamanna P., Tranquilli A.L., Petraglia F., et al. Role of activin-A and myostatin and their signaling pathway in human myometrial and leiomyoma cell function. J. Clin. Endocrinol. Metab. 2014;99:E775–E785. doi: 10.1210/jc.2013-2623.
    1. Hubner G., Werner S. Serum growth factors and proinflammatory cytokines are potent inducers of activin expression in cultured fibroblasts and keratinocytes. Exp. Cell Res. 1996;228:106–113. doi: 10.1006/excr.1996.0305.
    1. Shao L., Frigon N.L., Jr., Sehy D.W., Yu A.L., Lofgren J., Schwall R., Yu J. Regulation of production of activin A in human marrow stromal cells and monocytes. Exp. Hematol. 1992;20:1235–1242.
    1. Shao L.E., Frigon N.L., Jr., Yu A., Palyash J., Yu J. Contrasting effects of inflammatory cytokines and glucocorticoids on the production of activin A in human marrow stromal cells and their implications. Cytokine. 1998;10:227–235. doi: 10.1006/cyto.1997.0282.
    1. Takahashi S., Uchimaru K., Harigaya K., Asano S., Yamashita T. Tumor necrosis factor and interleukin-1 induce activin A gene expression in a human bone marrow stromal cell line. Biochem. Biophys. Res. Commun. 1992;188:310–317. doi: 10.1016/0006-291X(92)92386-C.
    1. Mantovani A., Sica A., Sozzani S., Allavena P., Vecchi A., Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25:677–686. doi: 10.1016/j.it.2004.09.015.

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