The Complexities of Transforming Growth Factor Beta-1 (TGF-B1)

Transforming growth factor beta (TGF-B) is a cytokine expressed by almost all cells in the body, especially muscle, kidney, liver, heart, brain, and salivary gland cells. It regulates cell metabolism, growth, proliferation, differentiation, adhesion, migration, and survival. It is vital to immune balance, wound healing, tissue homeostasis, and embryonic development. Disruptions in TGF-B signaling contribute to cell and tissue dysfunction (Deng 2024).

TGF-B participates in inflammatory and suppressive immune responses and alters immunity under various conditions. It helps maintain immune tolerance against “self” as well as against innocuous antigens, including food and commensal bacteria. It also facilitates the immune response to pathogens (Sanjabi 2017).

The three isoforms of TGF-B are TGF-B1, TGF-B2, and TGF-B3.

Immune cells primarily produce TGF-B1, a form commonly measured in plasma. TGF-B1 is anti-inflammatory and immunosuppressive, but is linked to increased inflammation and autoimmunity when combined with certain T cell and cytokine activity. TGF-B1 expression is dysfunctional in systemic lupus erythematosus (Gómez-Bernal 2022).

TGFB-1’s tightly controlled regulation of the healing and repair process can become dysregulated with severe trauma, chronic injury, or infection. The repair process becomes pathological, leading to fibrosis and scar formation, which can disrupt organ function (Lodyga 2020).

Defective TGF-B1 production and/or signaling in the gastrointestinal tract can lead to immune-inflammatory pathologies, fibrosis, and malignancy. Associated pathways are complex and TGFB-1 signaling can have opposing fibrinogenic and carcinogenic effects depending on the GI tract location and stage of disease. Mutations in TGF-B receptor genes are seen in almost half of observed colorectal cancers and elevated TGF-B1 levels in plasma and tumor tissue correlate with metastases and poor prognosis (Stolfi 2020).

TGF-B1 has potent anti-inflammatory effects that benefit neuropathic conditions. Therapeutic administration of TGF-B1 may reduce neuropathic pain caused by injury or pathology, and shows promise as a neuroprotective agent (Echeverry 2009).

Elevated TGF-B1 is associated with:

• Chronic liver disease with certain TGF-B1 polymorphisms (Cai 2022)
• Colorectal cancer, liver metastases, poor prognosis (Stolfi 2020)
• COVID-19, higher severity (Laloglu 2022)
• Liver cancer, metastatic disease (Devan 2024, Lin 2015)
• Liver fibrosis caused by viruses or alcohol exposure (Devan 2024)
• Lymphedema and fibrosis (Baik 2022)
• Lupus ocular and cardiovascular manifestations (Gómez-Bernal 2022)
• Pre-eclampsia risk increases with certain TGF-B1 polymorphisms (Zheng 2022)
• Pulmonary fibrosis (Laloglu 2022)

Lower TGF-B1 is associated with:

• Disrupted spinal cord remyelination following toxin-induced demyelination (Hamaguchi 2019)
• Lupus gastrointestinal and musculoskeletal manifestations (Gómez-Bernal 2022)

Optimal Takeaways

• Transforming growth factor beta (TGF-B) metabolism is complex and depends on genetic immune, and signaling factors that determine its effects on inflammation, fibrosis, and organ function.
• TGF-B1 is the form most commonly evaluated and altered levels must be interpreted alongside clinical and diagnostic data.
• Elevations in TGF-B1 may be associated with malignancy, fibrosis, excess repair mechanisms, or increased disease severity
• Low TGF-B1 levels may increase risk of inflammation, neurological, and gastrointestinal complications

References

Baik, Jung Eun et al. “TGF-β1 mediates pathologic changes of secondary lymphedema by promoting fibrosis and inflammation.” Clinical and translational medicine vol. 12,6 (2022): e758. doi:10.1002/ctm2.758

Cai, Xuanyan et al. “Genetic dominance of transforming growth factor-β1 polymorphisms in chronic liver disease.” Frontiers in immunology vol. 13 1058532. 16 Nov. 2022, doi:10.3389/fimmu.2022.1058532

Deng, Ziqin et al. “TGF-β signaling in health, disease, and therapeutics.” Signal transduction and targeted therapy vol. 9,1 61. 22 Mar. 2024, doi:10.1038/s41392-024-01764-w

Devan, Aswathy R et al. “Deciphering the role of transforming growth factor-beta 1 as a diagnostic-prognostic-therapeutic candidate against hepatocellular carcinoma.” World journal of gastroenterology vol. 28,36 (2022): 5250-5264. doi:10.3748/wjg.v28.i36.5250

Echeverry, Stefania et al. “Transforming growth factor-beta1 impairs neuropathic pain through pleiotropic effects.” Molecular pain vol. 5 16. 27 Mar. 2009, doi:10.1186/1744-8069-5-16

Gómez-Bernal, Fuensanta et al. “Serum Levels of Transforming Growth Factor Beta 1 in Systemic Lupus Erythematosus Patients.” Biomolecules vol. 13,1 73. 29 Dec. 2022, doi:10.3390/biom13010073

Gough, Nancy R et al. “TGF-β Signaling in Liver, Pancreas, and Gastrointestinal Diseases and Cancer.” Gastroenterology vol. 161,2 (2021): 434-452.e15. doi:10.1053/j.gastro.2021.04.064

Hamaguchi, Machika et al. “Circulating transforming growth factor-β1 facilitates remyelination in the adult central nervous system.” eLife vol. 8 e41869. 9 May. 2019, doi:10.7554/eLife.41869  

Sanjabi, Shomyseh et al. “Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection.” Cold Spring Harbor perspectives in biology vol. 9,6 a022236. 1 Jun. 2017, doi:10.1101/cshperspect.a022236

Laloglu, Esra, and Handan Alay. “Role of transforming growth factor-beta 1 and connective tissue growth factor levels in coronavirus disease-2019-related lung Injury: a prospective, observational, cohort study.” Revista da Sociedade Brasileira de Medicina Tropical vol. 55 e06152021. 25 Jul. 2022, doi:10.1590/0037-8682-0615-2021

Lin, Tzu-Hsuan et al. “High Serum Transforming Growth Factor-β1 Levels Predict Outcome in Hepatocellular Carcinoma Patients Treated with Sorafenib.” Clinical cancer research : an official journal of the American Association for Cancer Research vol. 21,16 (2015): 3678-84. doi:10.1158/1078-0432.CCR-14-1954

Lodyga, Monika, and Boris Hinz. “TGF-β1 - A truly transforming growth factor in fibrosis and immunity.” Seminars in cell & developmental biology vol. 101 (2020): 123-139. doi:10.1016/j.semcdb.2019.12.010

Stolfi, Carmine et al. “Role of TGF-Beta and Smad7 in Gut Inflammation, Fibrosis and Cancer.” Biomolecules vol. 11,1 17. 27 Dec. 2020, doi:10.3390/biom11010017

Zheng, Nengneng et al. “Association between transforming growth factor-beta 1 polymorphisms and risk of pre-eclampsia: a meta-analysis.” The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians vol. 35,25 (2022): 9470-9480. doi:10.1080/14767058.2022.2044470