TGF beta 1 explained

Transforming growth factor beta 1 or TGF-β1 is a polypeptide member of the transforming growth factor beta superfamily of cytokines. It is a secreted protein that performs many cellular functions, including the control of cell growth, cell proliferation, cell differentiation, and apoptosis. In humans, TGF-β1 is encoded by the gene.^{[1] [2]}

Function

See also: TGF beta signaling pathway. TGF-β is a multifunctional set of peptides that controls proliferation, differentiation, and other functions in many cell types. TGF-β acts synergistically with transforming growth factor-alpha (TGF-α) in inducing transformation. It also acts as a negative autocrine growth factor. Dysregulation of TGF-β activation and signaling may result in apoptosis. Many cells synthesize TGF-β and almost all of them have specific receptors for this peptide. TGF-β1, TGF-β2, and TGF-β3 all function through the same receptor signaling systems.^[3]

TGF-β1 was first identified in human platelets as a protein with a molecular mass of 25 kilodaltons with a potential role in wound healing.^{[4] [5]} It was later characterized as a large protein precursor (containing 390 amino acids) that was proteolytically processed to produce a mature peptide of 112 amino acids.^[6]

TGF-β1 plays an important role in controlling the immune system, and shows different activities on different types of cell, or cells at different developmental stages. Most immune cells (or leukocytes) secrete TGF-β1.^[7]

T cells

Some T cells (e.g. regulatory T cells) release TGF-β1 to inhibit the actions of other T cells. Specifically, TGF-β1 prevents the interleukin(IL)-1- & interleukin-2-dependent proliferation in activated T cells,^{[8] [9]} as well as the activation of quiescent helper T cells and cytotoxic T cells.^{[10] [11]} Similarly, TGF-β1 can inhibit the secretion and activity of many other cytokines including interferon-γ, tumor necrosis factor-alpha (TNF-α), and various interleukins. It can also decrease the expression levels of cytokine receptors, such as the IL-2 receptor to down-regulate the activity of immune cells. However, TGF-β1 can also increase the expression of certain cytokines in T cells and promote their proliferation,^[12] particularly if the cells are immature.

B cells

TGF-β1 has similar effects on B cells that also vary according to the differentiation state of the cell. It inhibits proliferation, stimulates apoptosis of B cells,^[13] and controls the expression of antibody, transferrin and MHC class II proteins on immature and mature B cells.^{[7] [13]}

Myeloid cells

The effects of TGF-β1 on macrophages and monocytes are predominantly suppressive; this cytokine can inhibit the proliferation of these cells and prevent their production of reactive oxygen (e.g. superoxide (O₂^-)) and nitrogen (e.g. nitric oxide (NO)) intermediates. However, as with other cell types, TGF-β1 can also have the opposite effect on cells of myeloid origin. For example, TGF-β1 acts as a chemoattractant, directing an immune response to certain pathogens. Likewise, macrophages and monocytes respond to low levels of TGF-β1 in a chemotactic manner. Furthermore, the expression of monocytic cytokines (such as interleukin(IL)-1α, IL-1β, and TNF-α),^[11] and macrophage's phagocytic can be increased by the action of TGF-β1.^[7]

TGF-β1 reduces the efficacy of the MHC II in astrocytes and dendritic cells, which in turn decreases the activation of appropriate helper T cell populations.^{[14] [15]}

Interactions

TGF beta 1 has been shown to interact with:

• Decorin,^{[16] [17] [18]}
• EIF3I^[19]
• LTBP1,^[20]
• TGF beta receptor 1,^{[21] [22]} and
• YWHAE.^[23]

Further reading

• Border WA, Noble NA . Transforming growth factor beta in tissue fibrosis . N. Engl. J. Med. . 331 . 19 . 1286–92 . 1994 . 7935686 . 10.1056/NEJM199411103311907 .
• Munger JS, Harpel JG, Gleizes PE, Mazzieri R, Nunes I, Rifkin DB . Latent transforming growth factor-beta: structural features and mechanisms of activation . Kidney Int. . 51 . 5 . 1376–82 . 1997 . 9150447 . 10.1038/ki.1997.188 . free .
• Iozzo RV . The biology of the small leucine-rich proteoglycans. Functional network of interactive proteins . J. Biol. Chem. . 274 . 27 . 18843–6 . 1999 . 10383378 . 10.1074/jbc.274.27.18843 . free.
• Reinhold D, Wrenger S, Kähne T, Ansorge S . HIV-1 Tat: immunosuppression via TGF-beta1 induction . Immunol. Today . 20 . 8 . 384–5 . 1999 . 10431160 . 10.1016/S0167-5699(99)01497-8 .
• Yamada Y . Association of polymorphisms of the transforming growth factor-beta1 gene with genetic susceptibility to osteoporosis . Pharmacogenetics . 11 . 9 . 765–71 . 2001 . 11740340 . 10.1097/00008571-200112000-00004 .
• Book: Chen W, Wahl SM . TGF-beta: receptors, signaling pathways and autoimmunity . TGF-β: Receptors, Signaling Pathways and Autoimmunity . Curr. Dir. Autoimmun. . 5 . 62–91 . 2002 . 11826761 . 10.1159/000060548 . 978-3-8055-7308-5 . Current Directions in Autoimmunity .
• Marone M, Bonanno G, Rutella S, Leone G, Scambia G, Pierelli L . Survival and cell cycle control in early hematopoiesis: role of bcl-2, and the cyclin dependent kinase inhibitors P27 and P21 . Leuk. Lymphoma . 43 . 1 . 51–7 . 2002 . 11908736 . 10.1080/10428190210195 . 28490341 .
• Schnaper HW, Hayashida T, Hubchak SC, Poncelet AC . TGF-beta signal transduction and mesangial cell fibrogenesis . Am. J. Physiol. Renal Physiol. . 284 . 2 . F243–52 . 2003 . 12529270 . 10.1152/ajprenal.00300.2002 . 17046094 .
• Kalluri R, Neilson EG . Epithelial-mesenchymal transition and its implications for fibrosis . J. Clin. Invest. . 112 . 12 . 1776–84 . 2003 . 14679171 . 297008 . 10.1172/JCI20530 .
• Grainger DJ . Transforming growth factor beta and atherosclerosis: so far, so good for the protective cytokine hypothesis . Arterioscler. Thromb. Vasc. Biol. . 24 . 3 . 399–404 . 2004 . 14699019 . 10.1161/01.ATV.0000114567.76772.33 .
• Attisano L, Labbé E . TGFbeta and Wnt pathway cross-talk . Cancer Metastasis Rev. . 23 . 1–2 . 53–61 . 2004 . 15000149 . 10.1023/A:1025811012690 . 41685620 .
• McGowan TA, Zhu Y, Sharma K . Transforming growth factor-beta: a clinical target for the treatment of diabetic nephropathy . Curr. Diab. Rep. . 4 . 6 . 447–54 . 2004 . 15539010 . 10.1007/s11892-004-0055-z . 45122439 .
• Sheppard D . Integrin-mediated activation of latent transforming growth factor beta . Cancer Metastasis Rev. . 24 . 3 . 395–402 . 2005 . 16258727 . 10.1007/s10555-005-5131-6 . 1929903 .
• Gressner AM, Weiskirchen R . Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-beta as major players and therapeutic targets . J. Cell. Mol. Med. . 10 . 1 . 76–99 . 2006 . 16563223 . 3933103 . 10.1111/j.1582-4934.2006.tb00292.x .
• Seoane J . Escaping from the TGFbeta anti-proliferative control . Carcinogenesis . 27 . 11 . 2148–56 . 2006 . 16698802 . 10.1093/carcin/bgl068 . free .
• Lee CG, Kang HR, Homer RJ, Chupp G, Elias JA . Transgenic modeling of transforming growth factor-beta(1): role of apoptosis in fibrosis and alveolar remodeling . Proc Am Thorac Soc . 3 . 5 . 418–23 . 2006 . 16799085 . 2658706 . 10.1513/pats.200602-017AW .
• Wahl SM . Transforming growth factor-beta: innately bipolar . Curr. Opin. Immunol. . 19 . 1 . 55–62 . 2007 . 17137775 . 10.1016/j.coi.2006.11.008 .
• Redondo S, Santos-Gallego CG, Tejerina T . TGF-beta1: a novel target for cardiovascular pharmacology . Cytokine Growth Factor Rev. . 18 . 3–4 . 279–86 . 2007 . 17485238 . 10.1016/j.cytogfr.2007.04.005 .
• Ren H, Han R, Chen X, Liu X, Wan J, Wang L, Yang X, Wang J . Potential therapeutic targets for intracerebral hemorrhage-associated inflammation: An update . J Cereb Blood Flow Metab . May 2020 . 40 . 9 . 1752–1768 . 32423330 . 10.1177/0271678X20923551. 7446569 . 218689863 .

Notes and References

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2. Vaughn SP, Broussard S, Hall CR, Scott A, Blanton SH, Milunsky JM, Hecht JT . Confirmation of the mapping of the Camurati-Englemann locus to 19q13. 2 and refinement to a 3.2-cM region . Genomics . 66 . 1 . 119–21 . May 2000 . 10843814 . 10.1006/geno.2000.6192 .
3. Web site: Entrez Gene: TGFB1 transforming growth factor, beta 1.
4. Assoian RK, Komoriya A, Meyers CA, Miller DM, Sporn MB . Transforming growth factor-beta in human platelets. Identification of a major storage site, purification, and characterization . J. Biol. Chem. . 258 . 11 . 7155–60 . 1983 . 10.1016/S0021-9258(18)32345-7 . 6602130 . free .
5. Custo . S . Baron . B . Felice . A . Seria . E . A comparative profile of total protein and six angiogenically-active growth factors in three platelet products . GMS Interdisciplinary Plastic and Reconstructive Surgery DGPW . 5 July 2022 . 11 . Doc06 . Doc06 . 10.3205/iprs000167 . 35909816 . 9284722.
6. Derynck R, Jarrett JA, Chen EY, Eaton DH, Bell JR, Assoian RK, Roberts AB, Sporn MB, Goeddel DV . Human transforming growth factor-beta complementary DNA sequence and expression in normal and transformed cells . Nature . 316 . 6030 . 701–5 . 1985 . 3861940 . 10.1038/316701a0 . 1985Natur.316..701D . 4245501 .
7. Letterio JJ, Roberts AB . Regulation of immune responses by TGF-beta . Annu. Rev. Immunol. . 16 . 137–61 . 1998 . 9597127 . 10.1146/annurev.immunol.16.1.137 .
8. Wahl SM, Hunt DA, Wong HL, Dougherty S, McCartney-Francis N, Wahl LM, Ellingsworth L, Schmidt JA, Hall G, Roberts AB . Transforming growth factor-beta is a potent immunosuppressive agent that inhibits IL-1-dependent lymphocyte proliferation . J. Immunol. . 140 . 9 . 3026–32 . 1988 . 10.4049/jimmunol.140.9.3026 . 3129508 . 35425214 . free .
9. Tiemessen MM, Kunzmann S, Schmidt-Weber CB, Garssen J, Bruijnzeel-Koomen CA, Knol EF, van Hoffen E . Transforming growth factor-beta inhibits human antigen-specific CD4+ T cell proliferation without modulating the cytokine response . Int. Immunol. . 15 . 12 . 1495–504 . 2003 . 14645158 . 10.1093/intimm/dxg147 . free .
10. Gilbert KM, Thoman M, Bauche K, Pham T, Weigle WO . Transforming growth factor-beta 1 induces antigen-specific unresponsiveness in naive T cells . Immunol. Invest. . 26 . 4 . 459–72 . 1997 . 9246566 . 10.3109/08820139709022702 .
11. Wahl SM, Wen J, Moutsopoulos N . TGF-beta: a mobile purveyor of immune privilege . Immunol. Rev. . 213 . 213–27 . 2006 . 16972906 . 10.1111/j.1600-065X.2006.00437.x . 84309271 .
12. Zhu H, Wang Z, Yu J, Yang X, He F, Liu Z, Che F, Chen X, Ren H, Hong M, Wang J . Role and mechanisms of cytokines in the secondary brain injury after intracerebral hemorrhage . Prog. Neurobiol. . 178 . 101610 . March 2019 . 30923023 . 10.1016/j.pneurobio.2019.03.003. 85495400 .
13. Lebman DA, Edmiston JS . The role of TGF-beta in growth, differentiation, and maturation of B lymphocytes . Microbes Infect. . 1 . 15 . 1297–304 . 1999 . 10611758 . 10.1016/S1286-4579(99)00254-3 . free .
14. Rodríguez LS, Narváez CF, Rojas OL, Franco MA, Ángel J . Human myeloid dendritic cells treated with supernatants of rotavirus infected Caco-2 cells induce a poor Th1 response . Cellular Immunology . 272 . 2 . 154–61 . 2012-01-01 . 22082567 . 10.1016/j.cellimm.2011.10.017 .
15. Dong Y, Tang L, Letterio JJ, Benveniste EN . The Smad3 protein is involved in TGF-beta inhibition of class II transactivator and class II MHC expression . Journal of Immunology . 167 . 1 . 311–9 . July 2001 . 11418665 . 10.4049/jimmunol.167.1.311 . free .
16. Hildebrand A, Romarís M, Rasmussen LM, Heinegård D, Twardzik DR, Border WA, Ruoslahti E . Interaction of the small interstitial proteoglycans biglycan, decorin and fibromodulin with transforming growth factor beta . Biochem. J. . 302 . 2. 527–34 . September 1994 . 8093006 . 1137259 . 10.1042/bj3020527.
17. Schönherr E, Broszat M, Brandan E, Bruckner P, Kresse H . Decorin core protein fragment Leu155-Val260 interacts with TGF-beta but does not compete for decorin binding to type I collagen . Arch. Biochem. Biophys. . 355 . 2 . 241–8 . July 1998 . 9675033 . 10.1006/abbi.1998.0720 .
18. Takeuchi Y, Kodama Y, Matsumoto T . Bone matrix decorin binds transforming growth factor-beta and enhances its bioactivity . J. Biol. Chem. . 269 . 51 . 32634–8 . Dec 1994 . 10.1016/S0021-9258(18)31681-8 . 7798269 . free .
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20. Saharinen J, Keski-Oja J . Specific sequence motif of 8-Cys repeats of TGF-beta binding proteins, LTBPs, creates a hydrophobic interaction surface for binding of small latent TGF-beta . Mol. Biol. Cell . 11 . 8 . 2691–704 . August 2000 . 10930463 . 14949 . 10.1091/mbc.11.8.2691.
21. Ebner R, Chen RH, Lawler S, Zioncheck T, Derynck R . Determination of type I receptor specificity by the type II receptors for TGF-beta or activin . Science . 262 . 5135 . 900–2 . November 1993 . 8235612 . 10.1126/science.8235612. 1993Sci...262..900E .
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