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Trefoil factors: initiators of mucosal healing

An Erratum to this article was published on 01 October 2003

Key Points

  • Restitution is the initial repair process of mucosa whereby epithelial cells spread and migrate across the basement membrane to re-establish surface-cell continuity. Trefoil proteins (TFFs) are essential for restitution to occur.

  • The TFFs are 7–12-kDa protease-resistant proteins that are secreted by mucus-secreting cells of the stomach (TFF1 and TFF2) and intestine (TFF3). All three TFFs are encoded together as a contig on human chromosome 21.

  • The trefoil domain is a motif of 38 or 39 amino acids containing six cysteine residues forming three disulphide-linked loops. In vivo, TFFs form two trefoil domains through interchain disulphide bonds (TFF1 and TFF3) or genomic duplication (TFF2). Dimer formation seems to be essential for some TFF functions but not for cell migration.

  • Tff1-null mice show gastric hyperproliferation and adenoma formation. Tff2-null mice seem normal, but show increased acid secretion and are susceptible to injury by non-steroidal anti-inflammatory drugs. Tff3-null mice also seem normal but are fatally susceptible to colonic damage.

  • Ulcer-associated mucosal epithelia show a substantial and coordinated increase in expression of the TFF family with the spread of expression into adjacent, non-metaplastic glands. New enhancer elements within TFF1 and TFF2 promoters have been reported, including elements that confer co-ordinated expression. TFF3 goblet-cell-specific transcription is conferred through a goblet-cell response element (GCRE) and an upstream silencer inhibitor. The GCRE is also found in the promoter of the mucin MUC2, which is consistent with the co-regulation of mucins and TFFs.

  • TFFs cause mucosal healing through unique mechanisms. Unlike other motogens, TFFs are not mitogenic and no receptor has yet been demonstrated. However, TFF2 and TFF3 activate signal-transduction events, including the induction of epidermal growth factor (EGF) receptor and β-catenin phosphorylation, activation of extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and prevention of apoptotic signalling.

  • TFF1 mRNA and protein expression is frequently reduced in gastric cancer, often associated with somatic mutations in TFF1. Present data do not indicate that TFF2 or TFF3 have tumour-suppressor roles.

  • TFFs show many properties that are necessary for therapeutic efficacy. TFFs are compact, stable molecules and exert a protective effect when given orally. Possible therapeutic targets include prevention of the mucositis that follows radiotherapy and chemotherapy, which results in substantial morbidity in cancer patients.

Abstract

Maintaining the integrity of the gastrointestinal tract, despite the continual presence of microbial flora and injurious agents, is essential. Epithelial continuity depends on a family of small, yet abundant, secreted proteins — the trefoil factors (TFFs). TFFs protect mucous epithelia from a range of insults and contribute to mucosal repair, although the signalling events that mediate these responses are only partially understood.

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Figure 1: A schematic representation of restitution.
Figure 2: Trefoil peptide structure.
Figure 3: Model of Tff3 transcription in the mouse.
Figure 4: Established and putative trefoil protein functions.
Figure 5: Established and putative signalling by trefoil peptides.

Notes

  1. 1.

    ‡ Please note that this entry has been corrected and differs from the print version, in which HER2 has been omitted.

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Acknowledgements

Studies in the authors laboratory are supported by the National Institutes of Health.

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Correspondence to Daniel K. Podolsky.

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DATABASES

InterPro

β integrin

Forkhead

leucine-zipper

Locuslink

DAF

Ductin

MAPK

Met

NF-κB

SHP2

TBRI

TBRII

TGF-β

Swiss-Prot

STAT1

STAT3

EGF

FAK

GATA4

GATA6

gp130

HGF

IL-6

IL-11

MUC2

NOD2

TFF1

TFF2

TFF3

TGF-α

USF

FURTHER INFORMATION

Trefoil structure

Glossary

RESTITUTION

The process that promotes epithelial-cell migration to reseal superficial wounds after injury. This involves the rapid disassembly of cell–cell and cell–substratum adhesion, de-differentiation and spreading of surface cells.

REGENERATION

The process of epithelial repair, whereby the normal epithelia is recapitulated. It involves proliferation and differentiation of epithelial cells and restoration of specialized elements.

BASEMENT MEMBRANE

A dense, sheet-like, laminated extracellular matrix that separates epithelia, muscle or other tissues that form connective tissue.

CONTIG

Usually refers to an overlapping set of DNA fragments. Here, we use contig in the context of clusters of DNA in which contiguous series of genes can be found.

METAPLASIA

The conversion of one cell or tissue type into another. Includes transdifferentiation and also conversion between undifferentiated stem cells of different tissues.

PIT CELLS

Columnar mucous cells that line surface invaginations of the gastric mucosa, which are known as gastric pits.

THECA

The apical storage compartment of the goblet cell. It is typically filled with granules of secreted mucins.

GOBLET CELLS

Specialized secretory cells of the mucosa, which are named for their apparent flask-like shape (which is an artefact of tissue fixation). Goblet cells are highly polarized with a basal nucleus, mitochondria, endoplasmic reticulum and Golgi. The body and apex of the cell (theca) is filled with mucin-filled membrane-bound secretory granules.

BASIC-HELIX–LOOP–HELIX

A transcription factor with a basic domain that binds to a hexanucleotide known as the E-box, and a hydrophobic domain (the helix–loop–helix) that allows the formation of homo- and heterodimers. They can also have leucine repeats known as a leucine-zipper motif.

ULCERATIVE COLITIS

An inflammatory disorder of the large intestine that is characterized by loss of surface absorptive cells, often with ulceration and bleeding. This disorder is typically chronic and idiopathic.

ENTEROCYTES

The columnar surface epithelial cells of the intestine. These cells mediate transport and barrier functions.

PARACRINE

Describing, or relating to, a regulatory cell that secretes an agonist into intercellular spaces from which it diffuses to a target cell other than the one that produces it.

AUTOCRINE

Induction of cellular effects by factors that are produced by the same cell in which the effect occurs.

MOTOGENS

Compounds that induce cell motility.

BASOLATERAL POLE

The area of an epithelial cell below the tight junction that seals the apical surface.

TRANSACTIVATION

Cross-communication between signalling pathways, typically involving receptor tyrosine kinases. This is sometimes known as 'signal transactivation', to differentiate it from 'transcriptional transactivation', which results from binding of a transcriptional activator or repressor to a target gene.

STRESS FIBRES

Axial bundles of F-actin that underlie the cell bodies, which are typically induced by the activity of the GTPase RhoA.

LAMELLIPODIA

Flattened, sheet-like structures, which are composed of a crosslinked F-actin meshwork, that project from the surface of a cell. They are often associated with cell migration.

ANOIKIS

Induction of programmed cell death by detachment of cells from the extracellular matrix.

ADHERENS JUNCTION

A cell–cell adhesion complex that is composed of cadherins and catenins that are attached to cytoplasmic actin filaments.

RHO-FAMILY GTPASES

Ras-related GTPases that are involved in controlling the polymerization of actin.

DOMINANT-NEGATIVE PROTEIN

A defective protein that retains interaction abilities and so distorts or competes with normal proteins.

COMMENSAL

Either of two species that live in close association with benefit to one partner but with little or no effect on the other partner.

MONOCYTES

Large leukocytes with horseshoe-shaped nuclei. They derive from pluripotent stem cells and become phagocytic macrophages when they enter the tissues.

COMPLEMENT

A family of plasma proteins that is essential for antimicrobial defence. They function either as enzymes or as binding proteins, and are activated by a cascade of cleavage events after binding of antibody to a foreign particle (classical pathway) or directly by invading micro-organisms (alternative pathway).

INTEGRINS

A large family of heterodimeric transmembrane proteins that act as receptors for cell-adhesion molecules.

ALLOGRAFT

A tissue or organ graft between individuals of the same species who are genetically dissimilar. Such grafts are invariably rejected unless the recipient is immunosuppressed, or the graft is to an immune-privileged site.

MUCOSITIS

Injury and inflammation of gastrointestinal-tract mucosal surfaces that results from chemotherapy or radiotherapy.

METHOTREXATE

A commonly used chemotherapy drug that acts through inhibition of DNA synthesis.

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Taupin, D., Podolsky, D. Trefoil factors: initiators of mucosal healing. Nat Rev Mol Cell Biol 4, 721–732 (2003). https://doi.org/10.1038/nrm1203

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