The trefoil factor family (TFF) consists of a group of small peptides highly expressed in tissues containing mucus-producing cells, predominantly in the mucosa lining the gastrointestinal tract. These peptides are crucial for epithelial restitution and may act through mechanisms distinct from conventional restitution factors. Several studies have observed the diverse mechanisms through which TFFs promote restitution. Additionally, these peptides interact with the immune system. Despite extensive study of their therapeutic effects, it remains uncertain which in vitro properties of TFFs directly translate to their in vivo engagement. Studying mice with genetic deletion of TFF peptides can elucidate the peptides' functions, indicated by the absence of the target protein or adaptive regulation of affected proteins downstream of the deleted gene product. This approach can identify functional networks controlled by a TFF isoform and its downstream effectors.
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Fig. 1 The role of TFF peptides in epithelial restitution (Kozina N., Jukić I. 2019).
Biological Properties of TFF
The TFF includes a group of small peptides, the earliest member of which was discovered approximately thirty years ago. TFF1 (formerly known as breast cancer-associated peptide pS2), TFF2 (formerly spasmolytic polypeptide SP), and TFF3 (formerly intestinal trefoil factor) are three mammalian members of the trefoil factor family. These proteins are small, compact peptides with one or two trefoil domains. While TFF1 and TFF3 each contain one trefoil domain, TFF2 contains two trefoil domains. The basic elements of a trefoil domain consist of 42–43 amino acid residues. Six cysteine residues form three disulfide bonds, creating a characteristic three-leafed structure.
TFF's Role in Mucosal Protection and Repair
Due to its compact structure, TFF exhibits high resistance to proteolytic degradation in the stomach and small intestine. TFF primarily exists as secreted molecules within the mucus covering normal epithelium. The main site of TFF synthesis is in mucin-producing cells or goblet cells dispersed within the epithelium. All three TFFs are expressed in the stomach, localized to the surface gastric mucosal cells. While TFFs are found in nearly all tissues containing mucus-secreting cells, their predominant expression occurs in the gastrointestinal tract. The function of TFFs likely involves interaction with mucins, particularly considering their presence in mucosal tissues. However, different TFFs may have distinct roles in epithelial protection, as evidenced by their complementary expression in the GI tract and simultaneous presence with unique mucin types (MUC). For instance, TFF1 co-exists with MUC5AC, TFF2 with MUC6, and TFF3 with MUC2, although TFF3 also co-localizes with MUC5AC in gastric and ocular tissues.
TFF's Impact on Energy Metabolism
The influence of trefoil factor proteins (TFFs) on energy metabolism extends beyond their role in gastrointestinal protection. Studies, particularly focusing on TFF3, have elucidated significant implications in glucose homeostasis and metabolic regulation.
Glucose Metabolism and TFF3
TFF3, prominently expressed in the gastrointestinal tract and other tissues, emerges as a regulator of glucose metabolism. In experimental models using TFF3 gene knockout (TFF3-/-) mice, researchers have observed distinct alterations in metabolic pathways associated with glycolysis and gluconeogenesis. These mice exhibit differential expression profiles of microRNAs involved in these pathways compared to their wild-type counterparts. This suggests a pivotal role for TFF3 in modulating cellular responses to glucose levels and insulin sensitivity.
Hepatic Expression and Metabolic Effects
Further insights from studies on TFF3 reveal its specific impact on hepatic functions. Overexpression of TFF3 in the liver has been shown to enhance glucose tolerance and improve insulin sensitivity in murine models. This effect is crucial in contexts such as type 2 diabetes mellitus, where impaired glucose regulation is a primary concern. By influencing the expression of genes involved in gluconeogenesis and glucose uptake, TFF3 contributes to maintaining metabolic balance and response to dietary changes.
TFF's Role in Defense Against Harmful Agents
Trefoil factor peptides (TFFs) play a crucial role not only in mucosal protection but also in defending the organism against various harmful agents, highlighting their broader implications in physiological defense mechanisms.
Neuroprotective Effects on Ischemic Injury
One significant aspect of TFF's defensive role is observed in ischemic conditions affecting the brain and other tissues. Studies utilizing TFF3-deficient (TFF3-/-) animal models have demonstrated heightened susceptibility to tissue damage following myocardial and cerebral ischemia. In these models, the absence of TFF3 exacerbates neuronal injury, evidenced by increased activity of caspase 3 and higher levels of cell death in ischemic regions. However, administration of recombinant TFF3 intravenously reverses these effects, underscoring TFF3's neuroprotective function in experimental cerebral ischemia/reperfusion injury. This mechanism suggests an endocrine pathway wherein TFF3 synthesized in the liver acts systemically to mitigate ischemic damage, potentially through anti-apoptotic and anti-inflammatory pathways.
Impact on Vascular Reactivity
TFF3 also influences vascular reactivity, particularly in response to environmental stressors like high-salt diets. Transgenic TFF3-deficient mice exhibit altered responses to salt intake, manifesting in modified metabolism of arachidonic acid and diminished flow-induced responses compared to wild-type counterparts. These findings imply that TFF3 may regulate endothelial function and vascular integrity under conditions of dietary challenge, suggesting a role in cardiovascular health beyond mucosal protection.
Wound Healing and Tissue Repair
In addition to its neuroprotective and vascular roles, TFF3 contributes significantly to wound-healing processes in various tissues. Studies have shown delayed re-epithelialization and impaired tissue repair in TFF3-deficient mice following injuries such as corneal abrasions and gastrointestinal mucosal damage. External application of recombinant TFF3 accelerates wound closure in both wild-type and TFF3-deficient mice, underscoring its crucial role in tissue regeneration and repair mechanisms.
TFF's Role in the Respiratory System, Pregnancy, and Tumorigenesis
Trefoil factor peptides (TFFs) have been identified to play diverse roles beyond their well-established functions in gastrointestinal mucosal protection. Emerging research highlights their involvement in respiratory system development, pregnancy, and tumorigenesis, underscoring their versatile physiological roles.
Respiratory System Development
TFF peptides, notably TFF1 and TFF3, exhibit significant roles in the differentiation and homeostasis of the respiratory epithelium. Studies employing murine models have demonstrated that TFF1 is crucial for the trans-differentiation of Clara cells into goblet cells, particularly in conditions like asthma where mucin production is enhanced. Additionally, TFF3 promotes differentiation of ciliated cells in an EGF-receptor-dependent manner, suggesting its involvement in maintaining airway integrity and function. These findings position TFFs as potential targets for therapeutic interventions in respiratory diseases characterized by epithelial dysfunction.
Pregnancy and Developmental Roles
During pregnancy, TFFs are implicated in embryogenesis and organogenesis. Research has identified TFF3 expression in fetal cartilage during endochondral ossification, indicating its role in skeletal development. Moreover, studies in mice lacking TFF3 gene expression have revealed altered histomorphological structures in bones and potential implications for hearing development. These findings underscore TFFs' involvement in morphogenesis and highlight their significance in prenatal development.
Implications in Tumorigenesis
TFF peptides have been implicated in various aspects of tumorigenesis across different tissues. Elevated expression of TFF3 has been observed in gastrointestinal tumors, lung cancer, prostate cancer, and hepatocellular carcinoma, among others. In breast cancer, TFF3 expression serves as a predictive marker and may aid in disease prognosis. Additionally, serum TFF3 levels have shown promise in screening for gastric cancers, complementing existing diagnostic tools such as the pepsinogen test. These findings suggest TFFs' potential as biomarkers for cancer detection and their roles in tumor progression and metastasis.
Conclusion
While much remains unknown about TFF signaling pathways, their straightforward benefits for healthy and damaged tissues have been identified. TFFs play pivotal roles in mucosal protection, epithelial surface repair, and cancer development and progression. Trefoil factors serve as prognostic markers for various carcinomas, although their precise biological effects are still not fully understood. Given the limited research on how TFF peptides influence vascular reactivity, further exploration of their role in this aspect would be beneficial.
Reference
- Kozina N., Jukić I. Trefoil factor family (TFF): peptides with numerous functions. Southeastern European Medical Journal: SEEMEDJ. 2019, 3 (1): 69-77.
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