Peptide growth factors are usually characterized by a relatively low molecular weight of less than 25 kDa. Generally, they exert their effects through binding to specific high-affinity cell-surface receptors present on their respective target cells [1–3]. In contrast to classical peptide hormones, peptide growth factors tend to act locally on adjacent cells (paracrine or juxtacrine action), or on the same cell that has expressed the peptide factor (autocrine action) [2,4,5]. The terminology of regulatory peptides is often confusing and arbitrary. The term ‘cytokine’ is increasingly used to describe various regulatory peptides that can be identified as regulatory peptides, peptide growth factors, interleukins, interferons and colony-stimulating or haematopoietic stem cell factors .
Although the full variety of peptide factors that play a role in the control of the intestinal epithelium and non-epithelial compartment of the intestine has not been defined, there is increasing appreciation of the diversity of these factors and the importance of several specific peptides produced within the intestine. An increasing number of peptide growth factor genes have been identified, and some have been fully sequenced, cloned and synthesized. Several distinct peptide families are now recognized to modulate different cell functions of intestinal cell populations, including cell proliferation and differentiation. The identification and characterization of numerous peptide growth factors has led to the recognition of a network of interrelated factors within the intestine. The constituents of this network generally possess multiple functional properties and exhibit pleiotropism in their cellular sources and targets (Table 1). As a result, this network is highly redundant in several dimensions [6,7]. First, each cell type appears to produce more than one peptide growth factor. Second, each peptide growth factor may be produced by multiple different cell populations within the intestinal tract. Third, most or perhaps all cell populations seem to express receptors specific for more than one growth factor. Fourth, receptors for a single growth factor may be present on multiple different cell types, thus a single growth factor can exert a spectrum of different functional effects within a circumscribed region of the intestinal tract. Fifth, functional effects of a certain growth factor may be modulated by the co-presence of other growth factors. Sixth, multiple structurally related members of a peptide growth factor family may interact with a single receptor (e.g. epidermal growth factor (EGF) family peptides). Seventh, growth factors may modulate their own expression and also that of other growth factors and their receptors on various cellular targets.
Peptide growth factors can be reasonably classified on the basis of structural homology and disparities into several discrete families (Table 2). They include the EGF family, the transforming growth factor beta (TGF-β) family, the insulin-like growth factor (IGF) family, the fibroblast growth factor (FGF) family, the colony-stimulating factor (CSF) or haematopoietic stem cell factor family, and the trefoil factor (TFF) family. In addition to the structural similarities between peptides within a family, members of a peptide family share a single receptor or a family of receptors, so that functionally they are partially or wholly interchangeable. In addition to these families, a small number of peptide growth factors, seemingly without structural similarities to other growth factors, have been identified within the gastrointestinal tract, including hepatocyte growth factor (HGF) or scatter factor, vascular endothelial cell growth factor (VEGF), and platelet-derived growth factor (PDGF).
Various members of these regulatory peptide families play an important role in the modulation of cell proliferation, cell differentiation, angiogenesis, inflammation, gastrointestinal defence mechanisms, and intestinal wound repair both in vitro and in vivo. Furthermore, they serve as important messengers between the intestinal mucosa and the enteric nervous and immune systems (Fig. 1). This review is designed to describe general properties of prototypic peptide growth factors that are likely to be important in the intestine, rather than to discuss all relevant growth factors in extensive detail. For a more detailed description of peptide growth factors, interested readers are referred to handbooks and reviews and the references therein [5,7–16].
Epidermal growth factor/transforming growth factor alpha family
This family consists of at least eight different peptides, including EGF, transforming growth factor alpha (TGF-α), amphiregulin, heparin-binding epidermal growth factor (HB-EGF), betacellulin, pox virus growth factors (found in vaccinia, shope and myxoma viruses), cripto and heregulin. Members of the EGF family are defined by three properties: the ability to bind to the EGF receptor, the capacity to mimic the biological activities of EGF, and amino acid sequence similarity to EGF. The overall identity of sequences within all members of the EGF family is approximately 20% .
Members of the EGF family act via the stimulation of specific cell-surface receptors . The EGF receptor (EGFR) is well characterized and possibly the most biologically important receptor for EGF family members. Nevertheless, additional receptors similar in structure have been identified and seem to bind some or all of the EGF family growth factors. They include the human EGF receptors 2 (HER-2) and 3 (HER-3). Although mRNA encoding HER-2 and HER-3 has been detected in normal and fetal gastrointestinal tissues, as well as in colon cancers, the relative physiological importance remains unclear. Most members of the EGF family can bind to the EGFR to effect cellular responses. In view of the ability of the EGFR to bind various peptide members of the EGF family, the physiological ligand acting on the EGFR at a given site cannot be predicted a priori. Thus, activities observed in a given experimental system following addition of one member of this peptide family (e.g. EGF) might reflect a physiological response actually induced by another family member in vivo (e.g. TGF-α). This is especially relevant in the gastrointestinal tract, where EGFRs are detected widely but EGF itself is expressed in only highly circumscribed distribution in contrast to the broad expression of TGF-α and perhaps other related peptides. Binding sites in the gastrointestinal tract appear equivalent in distribution when either EGF or TGF-α have been used as the ligand in a manner consistent with the assumption that they share a common receptor [18–23].
EGF and TGF-α are the prototype members of the EGF family. Within the gastrointestinal tract, EGF is produced in submaxillary glands and Brunner's glands in the duodenum . Small amounts appear to be produced within the exocrine pancreas. EGF is also present in gastric juice and within the intestinal lumen as a result of secretion from salivary glands, the pancreas and Brunner's glands. It is presumed to exert trophic and biological properties within the gastrointestinal tract through interaction at the mucosal surface [23,25,26]. This assumption is supported by the demonstration of apparent EGF binding sites on the apical (brush border) surface of enterocytes [21,27]. However, other workers have reported the presence of EGFRs on basolateral surfaces .
EGF is a potent stimulator of cell proliferation in epithelial and non-epithelial cell types present throughout the gastrointestinal tract [17,29,30]. The widespread distribution of EGFRs, including many cells committed to terminal differentiation, suggests that EGF (or another member of the EGF family) has a range of actions beyond its mitogenic activity. EGF has been demonstrated to modulate the expression of enzymes involved in the production of polyamines, to up-regulate intestinal electrolyte and nutrient transport in the enterocyte, to stimulate expression of brush border enzymes, to attenuate intestinal damage, and to promote intestinal healing [31–34].
TGF-α has been identified as a product of many cell types, including most epithelial cells . TGF-α mRNA and bioactive protein have been demonstrated directly in human and rodent stomach, small intestinal and colonic epithelium [21,35,36]. TGF-α appears to act through the same receptor as EGF. Important functional activities of TGF-α and EGF are summarized in Table 3. Because of its proliferative effects, it has been proposed that TGF-α may play an important role in the development of intestinal malignancies [37,38].
Amphiregulin presumably acts through the same mechanisms as the other members of the EGF family. Amphiregulin expression has been found in normal and neoplastic colonic mucosa, and growth stimulation through an autocrine mechanism by amphiregulin has been demonstrated in a colon carcinoma-derived cell line [39–41].
Heregulin seems to be expressed in several isoforms in stomach, liver, pancreas and small intestine . Cripto has been found in a small proportion of normal colonic mucosal cells, but in a high percentage of primary and metastatic human colorectal cancers .
Transforming growth factor beta family
The prototypic member of the TGF-β family is TGF-β1 [5,43,44]. Despite intracellular cleavage, the TGF-β1 dimer remains in a biological inactive complex with the two propeptide segments through non-covalent association, the so-called latent form. The physiological processes regulating the bioactivation of TGF-β from its latent state have not been finally characterized .
TGF-β1 has been found to bind to several specific cell-surface TGF-β receptors. The type-1 and type-2 receptors work in a cooperative fashion: ligand binding to the type-1 receptor facilitates activation of the associated type-2 receptor, which then activates the intracellular signalling machine via SMAD proteins [44,46–51].
The TGF-βs have a diverse range of biological effects, summarized in Table 4. In adults, three isoforms of TGF-β (TGF-β1−−3) may be detected in all gastrointestinal tract tissues and accessory organs . Within the small intestine, TGF-β expression has been demonstrated in both lamina propria cells and the epithelium . It is generally accepted that almost all expression of TGF-β is observed in epithelial cells of the intestine and only minor amounts within constituents of the mucosal immune system.
Many observations indicate a role for TGF-β in both inflammation and tissue repair [10,54,55]. This is also supported by targeted disruption of the TGF-β1 gene by ‘gene knock-out’ technology, which results in multifocal, mixed inflammatory cell infiltration, often with necrosis. Animals homozygous for the mutated TGF-β allele show no gross developmental abnormalities at birth and develop a severe, multifocal inflammatory disease that affects several organs including diffuse inflammation in the stomach and intestine. TGF-β deficiency resulted in severe pathology leading to death at about 20 days of age associated with dysfunction of the immune and inflammatory system, indicating its essential role as a potent regulator of the immune and inflammatory system. Increased expression of TGF-β was also demonstrated following acute epithelial injury in vivo, and in patients with active inflammatory bowel diseases, suggesting that TGF-β may play a role during periods of active inflammation regulating the activation and inactivation of immune and other cell populations present within the intestinal mucosa [38,53].
Other TGF-β family peptides, such as activin A, and their respective receptors, Act I and Act II, have recently been demonstrated to be expressed within the intestine and to modulate intestinal epithelial cell function [56–58].
Insulin-like growth factor family
IGF I and IGF II are expressed in diverse sites, including the gastrointestinal tract, with intrinsic biological activities in these tissues. The IGFs mediate their biological activities through interactions with at least three cell surface receptors. Both type-I and type-II IGF receptors and IGF I and IGF II are expressed in the gastrointestinal epithelium. IGF bioactivity is modulated by several IGF binding proteins. IGF peptides have been demonstrated to stimulate proliferation of epithelial and non-epithelial cells, to promote intestinal wound healing, to exert trophic effects within the intestine, and to promote tumour growth through autocrine mechanisms [29,59–64]. There is evidence that IGF I may be important in the development of fibrosis in Crohn's disease .
Fibroblast growth factor family
The FGFs are a family of related 16–18-kDa proteins controlling normal growth and differentiation of mesenchymal, epithelial and neuroectodermal cell types . FGF-1, or acidic FGF (aFGF), and FGF-2, or basic FGF (bFGF), are the best-characterized members of the FGF family. Although only limited data are available on the expression and biological activities of FGFs and their receptors in the gastrointestinal tract, several reports have described the presence of FGF family peptides and FGF receptors in the intestine [67–72]. Recent evidence supports the assumption that FGFs might serve as autocrine growth factors and stimulate intestinal epithelial cell proliferation [69,73–75]. In addition, aFGF and bFGF promoted intestinal epithelial restitution through a TGF-β-dependent pathway in vitro [73,76]. FGF-18, a novel member of the FGF family, stimulates proliferation in a number of tissues, most notably the liver and small intestine .
Trefoil factor family
The TFF peptides are a family of proteins expressed in a region-selective pattern throughout the gastrointestinal tract. TFF peptides are characterized by a highly conserved motif designated a ‘P’ or trefoil domain that consists of six cysteine residues that are believed to result in the formation of three intrachain loops [78–81]. Members of the TFF family include TFF1 (formerly pS2), TFF2 (formerly spasmolytic polypeptide, SP), and TFF3 (previously intestinal trefoil factor, ITF). TFF1 was first identified in human breast carcinoma cell lines and is usually expressed in the stomach, Brunner's glands, and large-intestinal goblet cells near the surface. TFF2 is expressed in the fundus and antrum of the stomach, and the Brunner's gland acini and distal ducts of the small intestine. TFF3 is absent in the stomach, but is expressed in goblet cells in the small and large intestine and in Brunner's gland acini and ducts in the small intestine. TFF1 is expressed in a wide variety of human carcinomas, and TFF1 knock-out mice exhibit severe hyperplasia and dysplasia of antrum cells, indicating that TFF1 may be a specific tumour suppressor gene for the stomach . TFF2 mRNA levels increase within 30 min after mucosal injury induced in the rat stomach, and administration of exogenous TFF2 protects against ethanol-induced gastric injury . TFF peptides play an important role in the repair and healing of the gastrointestinal tract [84–86]. Mashimo et al.  showed that TFF3 knock-out mice have impaired mucosal healing properties. Interestingly, TFF peptides stimulate epithelial repair through TGF-β-independent pathways. Recent studies suggest that modulation of repair mechanisms by TFF peptides may be mediated by modulation of E-cadherin/catenin complex function [87,88]. In addition to the important effects on intestinal wound-healing mechanisms, TFF3 may also function as an inhibitory factor for the growth of colonic neoplasms .
Although the receptors for TFF peptides have not been identified definitely, it is assumed that TFF peptides that are secreted onto the luminal surface of the gastrointestinal epithelium may act at the luminal site of the epithelium through mechanisms distinct from those that act at the basolateral site of the epithelium.
The CSFs comprise a family of acidic glycoproteins characterized by their ability to induce the formation of distinct haematopoietic cell lineages that play an important role in haematopoiesis. Key members of this family are the stem cell growth factors interleukin 3 (IL-3, multi-CSF), GM-CSF, M-CSF (CSF-1) and G-CSF. Although the sites of action of these peptides seem to be predominantly the blood-forming tissues, they may be produced at a variety of different sites, including the intestine. Constituents of the lamina propria, predominantly macrophages/monocytes, have been found to produce each of these critical stem cell factors. There is some evidence that intraepithelial lymphocytes might proliferate in response to IL-3, but in general the presumptive targets of these peptides produced in the intestine are in the bone marrow . Enhanced expression of GM-CSF, and to a lesser extent M-CSF, has been documented in lamina propria in association with inflammatory bowel disease . It is speculated that CSFs serve to integrate the recruitment of inflammatory cells from the bone marrow with their utilization in inflammatory processes of the intestine.
Hepatocyte growth factor
HGF, also identified as scatter factor, has been recognized to be the natural ligand of the Met-protooncogene . Recent studies have demonstrated the expression of both Met/HGF receptor mRNA and protein in a broad range of tissues, including stomach, small intestine and colon . Few data are available on the biological activities of HGF in the small and large intestine, but it is likely that HGF may play a role in the growth and morphogenesis of the gastrointestinal tract and in its remodelling following injury [94–99].
Part of the work that was performed in the authors’ laboratories was supported by grants from the Deutsche Forschungsgemeinschaft (Di 477/3-1 and Di 477/3-4) and research support from the University of Essen and Charité Medical School to AD.
• Of special interest
•• Of outstanding interest
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