Functional Effects of TGF-β3: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Conner Chen and Version 1 by Nina Frederike Jeppesen Edin.

Transforming growth factor-beta 3 (TGF-β3) is a ubiquitously expressed multifunctional cytokine involved in a range of physiological and pathological conditions, including embryogenesis, cell cycle regulation, immunoregulation, and fibrogenesis. 

  • cell cycle regulation
  • chemotherapy
  • fibrosis

1. Immunoregulation and Inflammation

TGF-βs (Trare ensforming growth factor-beta) are expressed by immune cells and are thought to play an important immunoregulatory role. TGF-β1 is the most extensively described isoform in regard to immunity, mainly because TGF-β1 null mice develop a fatal systemic autoimmune disease [5][1]. While the role of TGF-β2 is currently considered to be insignificant in the regulation of the immune system because of its negligible expression in immune cells, TGF-β3 is emerging as a potentially important immunoregulator with functions that differ from those of TGF-β1 in many contexts [55][2].
Several cells of the immune system have been reported to produce TGF-β3 either at the mRNA or protein level, and the role of TGF-β3 has been reported to be both pro- and anti-inflammatory. Interleukin-17-producing helper T cells (Th17 cells) are generated from naïve CD4+ T cells via several cytokines, including TGF-β. Lee et al. found that while generation with TGF-β1 produced a type of Th17 cell that did not readily induce autoimmune disease, TGF-β3 generated a functionally distinct type of Th17 cell that was highly pathogenic [56][3]. In B cells, TGF-β3 is thought to enhance antibody production under certain circumstances and can possess bifunctional effects depending on concentration [57][4].
The anti-inflammatory role of TGF-β3 has been highlighted through its ability to inhibit differentiation of forkhead box P3-expressing CD4+ T cells [58][5], its potential to inhibit B cell proliferation and antibody production [59][6], and its role in lymphocyte-activation gene 3+ regulatory T cells (Treg) mediated immune suppression [60][7]. TGF-β3 was also observed to suppress the development of germinal center B cells and thereby inhibiting the T cell-dependent immune response, a function which was not associated with TGF-β1 [57][4].

2. Fibrosis and Wound Healing

Radiation fibrosis is a late complication of radiotherapy, with potentially debilitating effects. While it is widely accepted that the action of TGF-β1 is pro-fibrotic, and TGF-β2 is generally believed to aid in this action, conflicting reports exist regarding TGF-β3 [61,62,63,64][8][9][10][11]. Several studies have reported pro-fibrotic effects of TGF-β3: Sun et al. registered upregulation of TGF-β2 and TGF-β3, but not TGF-β1, in human idiopathic pulmonary fibrosis and non-alcoholic fatty liver disease. In addition, they demonstrated pro-fibrotic effects of TGF-β3 in mouse models of these fibrotic diseases [41][12]. Guo et al. proposed that TGF-β3 promoted liver fibrosis by downregulation of MMP13 [65][13]. Reggio et al. reported an increased expression of extracellular matrix and inflammatory genes after treating cultured adipocytes and endothelial cells with TGF-β3 [66][14].
Others, however, have argued the regulatory or anti-fibrotic roles of TGF-β3 [67,68,69,70][15][16][17][18]. Although they detected the increased expression of TGF-β3 in tissue samples from human myocardial infarction patients, Xue et al. found that TGF-β3 suppressed cardiac fibroblasts and decreased fibrotic markers in an in vitro model [71][19]. Wu et al. concluded that transplanted mesenchymal stem cells reduced skin fibrosis through the action of TGF-β3 [72][20]. Escansany et al. observed renal fibrosis in TGF-β3 deficient mice, in addition to impaired lipid metabolism [73][21].
Wound healing and scar formation are closely tied to the fibrotic response. Early studies indicated that scarless healing observed in mammalian embryos was due to elevated levels of TGF-β3 in fetal tissue [74,75][22][23]. Furthermore, Shah et al. demonstrated that cutaneous scarring in rats was reduced by the addition of exogenous TGF-β3 or by the inhibition of TGF-β1 or -β2 [76][24]. Indeed, recombinant human TGF-β3 under the trade name Avotermin was developed as an anti-scarring agent, showing potential to provide an accelerated and permanent improvement in scarring in several phase I/II trials [77[25][26][27],78,79], but failed the phase III trial [80][28]. Despite the clinical failure of Avotermin, several more recent studies have supported TGF-β3′s anti-scarring effects [72,81,82,83,84][20][29][30][31][32].

3. Growth Regulation and Carcinogenesis

Shortly after its discovery, TGF-β1 was identified as a growth stimulator in fibroblasts, but a potent growth inhibitor in other cell types, including epithelial, lymphoid, and endothelial cells [85][33]. Early studies indicated identical functions for TGF-β2 and TGF-β3, but later research has elucidated isoform-specific variations in the growth-regulatory effects of TGF-βs. The addition of exogenous TGF-β3, but not TGF-β1, increased chondrocyte proliferation in neonatal murine cartilage in vitro [86][34]. Similarly, TGF-β3 increased chondrocyte proliferation in murine cranial suture-derived mesenchymal cells in vitro, while TGF-β1 had the opposite effect [87][35]. In contrast, mesenchymal stem cells were found to inhibit keloid fibroblast proliferation in vitro through a TGF-β3-dependent mechanism [72][20], and the addition of exogenous TGF-β3 reduced the proliferation of cultured taste bud epithelial cells [88][36]. Treatment with TGF-β3 also inhibited the proliferation of smooth muscle cells in vitro [89,90][37][38].
When considering the role of TGF-β3 in radiation cancer therapy, it is also of interest to consider its role in the disease itself. Research regarding the role of TGF-β3 in carcinogenesis and cancer progression is in many cases obscured by an assumption that the three TGF-β isoforms have identical functions and are interchangeable. This assumption is not necessarily true and can often be misleading. Furthermore, the majority of data referenced regarding the tumorigenic role of TGF-β3 originates from protein or mRNA analyses of tumor biopsies and are thus correlative [46][39]. Considerable caution should be applied before interpreting the data as causative.
In an animal model of cutaneous melanoma, TGF-β3, unlike TGF-β1 and TGF-β2, was induced in cells adjacent to tumor tissue by factors released by the malignant cells, suggesting a responsive rather than a causative role of TGF-β3 [91][40]. Another study observed decreased TGF-β3 expression in the skin overlying malignant melanoma and suggested that melanoma cells either suppressed TGF-β3 expression or that the lack of TGF-β3 expression itself promoted melanocyte proliferation [92][41].
In several studies identifying genes associated with prognosis in breast cancer patients, increased TGF-β3 mRNA expression was correlated with a longer interval to distal metastases [93,94,95][42][43][44]. However, increased TGF-β3 protein levels have been observed to correlate with the incidence of lymph node metastases [96][45], a decrease in survival time [97][46], and overall survival [98][47] in breast cancer patients. One study found that the increased expression of TGF-β3 mRNA could lead to ovarian carcinogenesis and tumor progression [99][48], while another concluded that the increased TGF-β3 expression induced by progestin treatment was associated with a lower risk of developing ovarian cancer in macaques [100][49]. An analysis of osteosarcoma biopsies revealed a correlation between TGF-β3 protein content and lung metastasis incidence [101][50]. Leiomyoma samples have been shown to have a higher expression of TGF-β3 mRNA and protein than normal myometrium, and the addition of TGF-β3 increased the proliferation of cultured leiomyoma cells [90,102,103][38][51][52].

References

  1. Kulkarni, A.B.; Huh, C.G.; Becker, D.; Geiser, A.; Lyght, M.; Flanders, K.C.; Roberts, A.B.; Sporn, M.B.; Ward, J.M.; Karlsson, S. Transforming Growth Factor Β1 Null Mutation in Mice Causes Excessive Inflammatory Response and Early Death. Proc. Natl. Acad. Sci. USA 1993, 90, 770–774.
  2. Komai, T.; Okamura, T.; Inoue, M.; Yamamoto, K.; Fujio, K. Reevaluation of Pluripotent Cytokine TGF-Β3 in Immunity. Int. J. Mol. Sci. 2018, 19, 2261.
  3. Lee, Y.; Awasthi, A.; Yosef, N.; Quintana, F.J.; Xiao, S.; Peters, A.; Wu, C.; Kleinewietfeld, M.; Kunder, S.; Hafler, D.A.; et al. Induction and Molecular Signature of Pathogenic T H 17 Cells. Nat. Immunol. 2012, 13, 991–999.
  4. Komai, T.; Inoue, M.; Okamura, T.; Morita, K.; Iwasaki, Y.; Sumitomo, S.; Shoda, H.; Yamamoto, K.; Fujio, K. Transforming Growth Factor-β and Interleukin-10 Synergistically Regulate Humoral Immunity via Modulating Metabolic Signals. Front. Immunol. 2018, 9, 1364.
  5. Shah, S.; Qiao, L. Resting B Cells Expand a CD4+CD25+Foxp3+ Treg Population via TGF-Β3. Eur. J. Immunol. 2008, 38, 2488–2498.
  6. Tsuchida, Y.; Sumitomo, S.; Ishigaki, K.; Suzuki, A.; Kochi, Y.; Tsuchiya, H.; Ota, M.; Komai, T.; Inoue, M.; Morita, K.; et al. TGF-Β3 Inhibits Antibody Production by Human B Cells. PLoS ONE 2017, 12, e0169646.
  7. Okamura, T.; Sumitomo, S.; Morita, K.; Iwasaki, Y.; Inoue, M.; Nakachi, S.; Komai, T.; Shoda, H.; Miyazaki, J.I.; Fujio, K.; et al. TGF-Β3-Expressing CD4+CD25-LAG3+ Regulatory T Cells Control Humoral Immune Responses. Nat. Commun. 2015, 6, 6329.
  8. Martin, M.; Lefaix, J.-L.; Sylvie, D. TGF-Beta1 and radiation fibrosis: A master switch and a specific therapeutic target? Int. J. Radiat. Oncol. 2000, 47, 277–290.
  9. Durani, P.; Occleston, N.; O’Kane, S.; Ferguson, M.W.J. Avotermin: A Novel Antiscarring Agent. Int. J. Low. Extrem. Wounds 2008, 7, 160–168.
  10. Kim, K.K.; Sheppard, D.; Chapman, H.A. TGF-β1 signaling and tissue fibrosis. Cold Spring Harb. Perspect. Biol. 2018, 10, a022293.
  11. Frangogiannis, N.G. Transforming Growth Factor–ß in Tissue Fibrosis. J. Exp. Med. 2020, 217, e20190103.
  12. Sun, T.; Huang, Z.; Liang, W.C.; Yin, J.; Lin, W.Y.; Wu, J.; Vernes, J.M.; Lutman, J.; Caplazi, P.; Jeet, S.; et al. TGFβ2 and TGFβ3 Isoforms Drive Fibrotic Disease Pathogenesis. Sci. Transl. Med. 2021, 13, eabe0407.
  13. Guo, J.; Liu, W.; Zeng, Z.; Lin, J.; Zhang, X.; Chen, L. Tgfb3 and Mmp13 Regulated the Initiation of Liver Fibrosis Progression as Dynamic Network Biomarkers. J. Cell. Mol. Med. 2021, 25, 867–879.
  14. Reggio, S.; Rouault, C.; Poitou, C.; Bichet, J.-C.; Prifti, E.; Bouillot, J.-L.; Rizkalla, S.; Lacasa, D.; Tordjman, J.; Clément, K. Increased Basement Membrane Components in Adipose Tissue During Obesity: Links With TGFβ and Metabolic Phenotypes. J. Clin. Endocrinol. Metab. 2016, 101, 2578–2587.
  15. Serini, G.; Gabbiani, G. Modulation of alpha-smooth muscle actin expression in fibroblasts by transforming growth factor-beta isoforms: An in vivo and in vitro study. Wound Repair Regen. 1996, 3, 278–287.
  16. Loewen, M.S.; Walner, D.L.; Caldarelli, D.D. Improved Airway Healing Using Transforming Growth Factor Beta-3 In a Rabbit Model. Wound Repair Regen. 2001, 9, 44–49.
  17. Ask, K.; Bonniaud, P.; Maass, K.; Eickelberg, O.; Margetts, P.J.; Warburton, D.; Groffen, J.; Gauldie, J.; Kolb, M. Progressive Pulmonary Fibrosis Is Mediated by TGF-β Isoform 1 but Not TGF-Β3. Int. J. Biochem. Cell Biol. 2008, 40, 484–495.
  18. Wilson, S.E. TGF Beta −1, −2 and −3 in the Modulation of Fibrosis in the Cornea and Other Organs. Exp. Eye Res. 2021, 207, 108594.
  19. Xue, K.; Zhang, J.; Li, C.; Li, J.; Wang, C.; Zhang, Q.; Chen, X.; Yu, X.; Sun, L.; Yu, X. The Role and Mechanism of Transforming Growth Factor Beta 3 in Human Myocardial Infarction-Induced Myocardial Fibrosis. J. Cell. Mol. Med. 2019, 23, 4229–4243.
  20. Wu, Y.; Peng, Y.; Gao, D.; Feng, C.; Yuan, X.; Li, H.; Wang, Y.; Yang, L.; Huang, S.; Fu, X. Mesenchymal stem cells suppress fibroblast proliferation and reduce skin fibrosis through a TGF-β3-dependent activation. Int. J. Low. Extrem. Wounds 2015, 14, 50–62.
  21. Escasany, E.; Lanzón, B.; García-Carrasco, A.; Izquierdo-Lahuerta, A.; Torres, L.; Corrales, P.; Rodríguez, A.E.R.; Luis-Lima, S.; Álvarez, C.M.; Ruperez, F.J.; et al. Transforming Growth Factor β 3 Deficiency Promotes Defective Lipid Metabolism and Fibrosis in Murine Kidney. Dis. Model. Mech. 2021, 14, dmm048249.
  22. Whitby, D.J.; Ferguson, M.W.J. The Extracellular Matrix of Lip Wounds in Fetal, Neonatal and Adult Mice. Development 1991, 112, 651–668.
  23. Chen, W.; Fu, X.; Ge, S.; Sun, T.; Zhou, G.; Jiang, D.; Sheng, Z. Ontogeny of Expression of Transforming Growth Factor-β and Its Receptors and Their Possible Relationship with Scarless Healing in Human Fetal Skin. Wound Repair Regen. 2005, 13, 68–75.
  24. Shah, M.; Foreman, D.M.; Ferguson, M.W. Neutralisation of TGF-beta 1 and TGF-beta 2 or exogenous addition of TGF-beta 3 to cutaneous rat wounds reduces scarring. J. Cell Sci. 1995, 108, 985–1002.
  25. Ferguson, M.W.; Duncan, J.; Bond, J.; Bush, J.; Durani, P.; So, K.; Taylor, L.; Chantrey, J.; Mason, T.; James, G.; et al. Prophylactic Administration of Avotermin for Improvement of Skin Scarring: Three Double-Blind, Placebo-Controlled, Phase I/II Studies. Lancet 2009, 373, 1264–1274.
  26. Bush, J.; Duncan, J.A.L.; Bond, J.S.; Durani, P.; So, K.; Mason, T.; O’Kane, S.; Ferguson, M.W.J. Scar-Improving Efficacy of Avotermin Administered into the Wound Margins of Skin Incisions as Evaluated by a Randomized, Double-Blind, Placebo-Controlled, Phase II Clinical Trial. Plast. Reconstr. Surg. 2010, 126, 1604–1615.
  27. So, K.; McGrouther, D.A.; Bush, J.A.; Durani, P.; Taylor, L.; Skotny, G.; Mason, T.; Metcalfe, A.; Okane, S.; Ferguson, M.W.J. Avotermin for Scar Improvement Following Scar Revision Surgery: A Randomized, Double-Blind, within-Patient, Placebo-Controlled, Phase II Clinical Trial. Plast. Reconstr. Surg. 2011, 128, 163–172.
  28. Juvista EU Phase 3 Trial Results. Available online: https://www.fiercebiotech.com/biotech/juvista-eu-phase-3-trial-results (accessed on 13 March 2023).
  29. Chang, Z.; Kishimoto, Y.; Hasan, A.; Welham, N.V. TGF-Β3 Modulates the Inflammatory Environment and Reduces Scar Formation Following Vocal Fold Mucosal Injury in Rats. Dis. Model. Mech. 2014, 7, 83–91.
  30. Gómez-Gil, V.; Pascual, G.; Pérez-Köhler, B.; Cifuentes, A.; Buján, J.; Bellón, J.M. Involvement of Transforming Growth Factor-Β3 and Betaglycan in the Cytoarchitecture of Postoperative Omental Adhesions. J. Surg. Res. 2014, 187, 699–711.
  31. Karamichos, D.; Hutcheon, A.E.K.; Zieske, J.D. Reversal of Fibrosis by TGF-Β3 in a 3D in Vitro Model. Exp. Eye Res. 2014, 124, 31–36.
  32. Honardoust, D.; Varkey, M.; Marcoux, Y.; Shankowsky, H.A.; Tredget, E.E. Reduced decorin, fibromodulin, and transforming growth factor-β3 in deep dermis leads to hypertrophic scarring. J. Burn. Care Res. 2012, 33, 218–227.
  33. Barnard, J.A.; Lyons, R.M.; Moses, H.L. The Cell Biology of Transforming Growth Factor β. Biochimica et Biophysica Acta (BBA)-Rev. Cancer 1990, 1032, 79–87.
  34. Martinez-Alvernia, E.A.; Rudnick, J.A.; Mankarious, L.A. Transforming growth factor β3 increases chondrocyte proliferation and decreases apoptosis in murine cricoid cartilage in vitro. Otolaryngol. Head Neck Surg. 2008, 138, 435–440.
  35. James, A.W.; Xu, Y.; Lee, J.K.; Wang, R.; Longaker, M.T. Differential Effects of TGF-Β1 and TGF-Β3 on Chondrogenesis in Posterofrontal Cranial Suture-Derived Mesenchymal Cells in vitro. Plast. Reconstr. Surg. 2009, 123, 31–43.
  36. Nakamura, S.I.; Kawai, T.; Kamakura, T.; Ookura, T. TGF-Β3 Is Expressed in Taste Buds and Inhibits Proliferation of Primary Cultured Taste Epithelial Cells. Vitr. Cell. Dev. Biol.-Anim. 2010, 46, 36–44.
  37. Zeng, L.; Li, Y.; Yang, J.; Wang, G.; Margariti, A.; Xiao, Q.; Zampetaki, A.; Yin, X.; Mayr, M.; Mori, K.; et al. XBP 1-Deficiency Abrogates Neointimal Lesion of Injured Vessels via Cross Talk with the PDGF Signaling. Arter. Thromb. Vasc. Biol. 2015, 35, 2134–2144.
  38. Miyashita-Ishiwata, M.; El Sabeh, M.; Reschke, L.D.; Afrin, S.; Borahay, M.A. Hypoxia Induces Proliferation via NOX4-Mediated Oxidative Stress and TGF-Β3 Signaling in Uterine Leiomyoma Cells. Free. Radic. Res. 2022, 56, 163–172.
  39. Laverty, H.G.; Wakefield, L.M.; Occleston, N.L.; O’Kane, S.; Ferguson, M.W.J. TGF-Β3 and Cancer: A Review. Cytokine Growth Factor Rev. 2009, 20, 305–317.
  40. Gold, L.I.; Jussila, T.; Fusenig, N.E.; Stenba, F. TGF-β isoforms are differentially expressed in increasing malignant grades of HaCaT keratinocytes, suggesting separate roles in skin carcinogenesis. J. Pathol. A J. Pathol. Soc. Great Br. Irel. 2000, 190, 579–588.
  41. Rodeck, U.; Bossler, A.; Graeven, U.; Fox, F.E.; Nowell, P.C.; Knabbe, C.; Kari, C. Transforming growth factor beta production and responsiveness in normal human melanocytes and melanoma cells. Cancer Res. 1994, 54, 575–581.
  42. van de Vijver, M.J.; He, Y.D.; van ’T Veer, L.; Dai, H.; Hart, A.A.M.; Voskuil, D.W.; Schreiber, G.J.; Peterse, J.L.; Robert, C.; Marton, M.J.; et al. A gene-expression signature as a predictor of survival in breast cancer. N. Engl. J. Med. 2002, 347, 1999–2009.
  43. van t’ Veer, L.; Dai, H.; van de Vijver, M.J.; He, Y.D.; Hart, A.A.M.; Mao, M.; Peterse, H.L.; van der Koey, K.; Marton, M.J.; Witteveen, A.T.; et al. Gene Expression Profiling Predicts Clinical Outcome of Breast Cancer. Nature 2002, 415, 530–536.
  44. Bueno-de-Mesquita, J.M.; Linn, S.C.; Keijzer, R.; Wesseling, J.; Nuyten, D.S.A.; van Krimpen, C.; Meijers, C.; de Graaf, P.W.; Bos, M.M.E.M.; Hart, A.A.M.; et al. Validation of 70-Gene Prognosis Signature in Node-Negative Breast Cancer. Breast Cancer Res. Treat. 2009, 117, 483–495.
  45. Li, C.; Wang, J.; Wilson, P.B.; Kumar, P.; Levine, E.; Hunter, R.D.; Kumar, S. Role of transforming growth factor β3 in lymphatic metastasis in breast cancer. Int. J. Cancer 1998, 79, 455–459.
  46. Amatschek, S.; Koenig, U.; Auer, H.; Steinlein, P.; Pacher, M.; Gruenfelder, A.; Dekan, G.; Vogl, S.; Kubista, E.; Heider, K.; et al. Tissue-Wide Expression Profiling Using CDNA Subtraction and Microarrays to Identify Tumor-Specific Genes. Cancer Res. 2004, 64, 844–856.
  47. Ghellal, A.; Li, C.; Hayes, M.; Byrne, G.; Bundred, N.; Kumar, S. Prognostic Significance of TGF Beta 1 and TGF Beta 3 in Human Breast Carcinoma. Anticancer Res. 2000, 20, 4413–4418.
  48. Bristow, R.E.; Baldwin, R.L.; Yamada, D.S.; Korc, M.; Karlan, B.Y. Altered Expression of Transforming Growth Factor-Beta Ligands and Receptors in Primary and Recurrent Ovarian Carcinoma. Cancer 1999, 85, 658–668.
  49. Rodriguez, G.C.; Nagarsheth, N.P.; Lee, K.L.; Bentley, R.C.; Walmer, D.K.; Cline, M.; Whitaker, R.S.; Isner, P.; Berchuck, A.; Dodge, R.K.; et al. Progestin-induced apoptosis in the macaque ovarian epithelium: Differential regulation of transforming growth factor-β. J. Natl. Cancer Inst. 2002, 94, 50–60.
  50. Kloen, P.; Gebhardt, M.C.; Perez-atayde, A.; Rosenberg, A.E.; Springfield, D.S.; Gold, L.I.; Ph, D.; Mankin, H.J. Expression of transforming growth factor-β (TGF-β) isoforms in osteosarcomas: TGF-β3 is related to disease progression. Cancer 2000, 80, 2230–2239.
  51. Arici, A.; Sozen, I. Transforming Growth Factor-Β3 Is Expressed at High Levels in Leiomyoma Where It Stimulates Fibronectin Expression and Cell Proliferation. Fertil. Steril. 2000, 73, 1006–1011.
  52. Lee, B.; Nowak, R.A. Human leiomyoma smooth muscle cells show increased expression of transforming growth factor-β3 (TGFβ3) and altered responses to the antiproliferative effects of TGFβ. J. Clin. Endocrinol. Metab. 2001, 86, 913–920.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Video Production Service
Feedback