Transforming growth factor-β in GI neoplasia, wound healing and immune response

5

Transforming growth factor-p in GI neoplasia, wound healing and immune response

MASSIMO PIGNATELLI CHRISTOPHER J. GILLIGAN

The gastrointestinal (GI) tract represents the most common location of cancers in humans. The stomach, colon/rectum, mouth/pharynx and oesophagus constitute, respectively, the first, fourth, sixth and seventh most common cancer sites. In developed countries, cancers of the colon/rectum are the second most common type of cancer (after lung tumours), with 389 200 cases occurring per year (Tomatis, 1990). In addition to neoplasms, diseases and injuries of the gastrointestinal tract are important causes of morbidity and mortality worldwide. Thus, the search for knowledge concerning the control of malignant cell transformation and tumour growth and metastasis as well as that of immune response and wound repair in the GI tract has long been a focus of considerable scientific and clinical interest.

Much research concerning the GI tract has focused on the differentiation, proliferation and wound repair of the cells of the mucosal layer. The recog- nition in the past two decades of a large and ever growing group of growth factors that play a major role in regulating these processes represents a major advance in our understanding of GI biology and pathobiology. The most important known growth factors that regulate the differentiation, growth and healing of the GI tract are: the epidermal growth factor (EGF) family (which includes transforming growth factor (TGF) a, amphiregulin, heparin-binding EGF, pox virus growth factors, cripto and heregulin), the newly recognized trefoil peptides (which include pS2 intestinal trefoil factor and human spasmolytic polypeptide (hSP)), enteroglucagon, the fibroblast growth factor (FGF) family and the transforming growth factor-b (TGF-P) superfamily (Alison and Sarraf, 1994).

The diverse cell types that comprise the gut play a variety of roles that include absorptive, immune, endocrine and barrier functions. In order to perform these tasks, the gut epithelium undergoes continuous turnover. Thus, the regulation of GI cell differentiation and proliferation represents a complex process that includes the influences of luminal contents, autocrine, paracrine and endocrine hormones, and cell-cell and cell-matrix interactions (Olson et al, 1991; Hague et al, 1993b; Alison and Sarraf, 1994). A full description of these processes will, of necessity, include a delineation Beilli2re’s Clinical Gastroenterology- 65 Vol. 10, No. 1, March 1996 Copyright 0 1996, by Baillikre Tindall ISBN 0-7020-2002-S All rights of reproduction in any form reserved 0950-3528/96/010065 + 17 $12.00/00

66 M. PIGNATELLI AND C. J. GILLIGAN

of the complex interactions of many such factors in addition to investi- gations of single growth factors in isolation. Nevertheless, increasing knowledge of the actions of specific factors will be required in order to lay the foundation for such a comprehensive understanding of the biological behaviour of each cellular component of the GI tract. We propose to review the current knowledge of one family of growth factors, to wit the TGF-P family, with a focus on its activities in the GI tract.

THE TGF-P SUPERFAMILY

Transforming growth factor-@ represent a ubiquitous group of cytokines that exert a multiplicity of widely differing influences in a wide array of tissue and cell types. The name, transforming growth factor, derives from the observation that normal fibroblasts treated with TGF-a display anchorage independent growth in soft agar as if they had been virally transformed (Suemori et al, 1991; Border and Noble, 1994). Members of the TGF-P family take part in the regulation of growth and differentiation in species ranging from Drosophila to humans (Hursh et al, 1993). TGF-fll, the first member of the family that bears its name, was isolated from human platelets and placenta and bovine kidneys 12 years ago (Sporn and Roberts, 1992). In the intervening years, at least 25 members of the TGF-P superfamily have been identified (see Figure 1) (Kingsley, 1994).

Members of the superfamily are characterized by a variable pro-domain and a more highly conserved 1 lo-140 amino acid residue mature segment containing seven cysteine residues. Six of these cysteine residues interact to form a ‘cysteine knot’. The active molecule is composed of hetero- or homodimers of the mature segment that are held together by hydrophobic contacts and, in most members of the family, by a disulphide bond. The

TGF-0 superfamily

Figure 1. Members of the transforming growth factor-j3 superfamily. Subfamilies are shown outlined with a black box, family members are outlined with an open box.

TGF-P IN GI NEOPLASIA 67

majority of the members of the TGF-P superfamily may be divided into four subfamilies on the basis of amino acid sequence similarities: the 60A, the decapentaplegic (dpp), the activin and the TGF-P subfamilies (Figure 1). Most of the remaining superfamily members may be grouped with the dpp and 60A subfamilies to form the DVR group (Kingsley, 1994). The 60A subfamily is named for the chromosomal location of a Drosophila gene of unknown normal function. This gene has four mammalian homologues, namely bone morphogenetic proteins (BMPs) 5, 6, 7 and 8, which induce bone and cartilage formation. The dpp family is also named for a Drosophila gene, which is known to play an essential role in that species in organizing the development of the dorsoventral axis, the gut and imaginal discs (Hursh et al, 1993; Masucci and Hoffmann, 1993). As in the case of the 60A gene, mammalian homologues of dpp, namely BMP-2 and -3, influence bone and cartilage formation, Members of the activin subfamily are homo- or heterodimers of two subunits, A and B. These factors, also known as inhibin p A and inhibin p B, exert variable influences in different tissue types. Finally, the TGF-0 subfamily contains five isoforms: TGF-j31, -p2, -p3, -p4 and -p5 (McCartney-Francis and Wahl, 1994). TGF-P4 appears to be the chick homologue of TGF-/31. The first three TGF-Ps are expressed in mammals, and the influence that these factors exert on cellular, physiological and immune processes in the GI tract will be the focus of this chapter, For the purpose of this work, TGF-P will refer to the three isoforms expressed in mammals; a particular isoform will be specified where data or experiments focusing on its properties are available.

TGF-Pl, $2 AND $3

In first trimester human embryos, TGF-PI is expressed in haematopoetic, endothelial and osteogenic tissue, whereas TGF-P2 and -p3 are expressed in various mesenchymal tissues including chondrogenic regions (Kingsley, 1994; McCartney-Francis and Wahl, 1994). TGF-P2 is also found in several epithelial cell types and in the ventral nervous system (Gatherer et al, 1990). These three isoforms share 70-80% sequence homology and are largely indistinguishable at the functional level (Derynck et al, 1988; Kim et al, 1994). Expression of TGF-Pl is governed largely by three AP-1 (activated protein-l) binding sites located in two promoter regions of the TGF-Pl gene. Retinoic acid receptor-a and -p, and retinoid X receptor-a strongly inhibit induction of these promoters (Salbert et al, 1993). TGF-Pl is synthesized as a 391 amino acid residue precursor that is proteolytically cleaved to a 112 amino acid residue subunit and protein fragments which form a latency-associated peptide. It is secreted in a latent form as a high molecular mass complex non-covalently bound to the latency-associated peptide. Conversion of latent TGF-pl to the active form occurs at the cell surface and in the extracellular matrix (ECM) by unknown mechanisms, which may involve acidification or proteolysis (Harpel et al, 1992; Border and Noble, 1994). Although the TGF-fil gene promoter is the most well studied to date, the promoter regions from TGF-P2 and -p3 have also now


been cloned and characterized (Kim et al, 1994). Overall, expression of TGF-Ps is regulated by both pre- and post-trancriptional mechanisms, which include oncogenes, tumour suppressor genes, viral transactivators, retinoids, growth factors and tumour promoters (Glick et al, 1991).

Five TGF-P receptors have been identified to date (O’Grady et al, 1992). The high-affinity TGF-P receptors type I and II represent the most widely distributed receptor types and play the most significant roles in receptor- mediated signal transduction (Lopez-Casillas et al, 1991; Massague et al, 1992). Wrana and colleagues have recently reported that TGF-/3 binds directly to the type II receptor, which is a constitutively active kinase (Wrana et al, 1994). The type I receptor recognizes bound TGF-P and is recruited into the complex, whereupon it is phosphorylated by the type II receptor. The phosphorylated type I receptor then propagates the signal to substrates further downstream (Lin et al, 1992; Inagaki et al, 1993). When a mutant hepatoma cell line was derived that lacked the TGF-j3 type II receptor, it displayed resistance to TGF-P growth inhibition. Subsequent transfection of the type II receptor into this cell line restored TGF-P responsiveness, thus directly demonstrating a role for the type II receptor in growth inhibition (Inagaki et al, 1993). Data from experiments in which recombinant type III receptor, also known as betaglycan, was transfected into myoblasts that lacked it suggest that the type III receptor may regulate the ligand binding ability or surface expression of the type II receptor (Lopez-Casillas et al, 1991; Wang et al, 1991). In addition, type III receptors bind TGF-/3 and present it to type II receptors (Lopez-Casillas et al, 1994).

TGF-PS IN THE GI TRACT

TGF-/%s inhibit proliferation in normal epithelial cell populations, but promote it in many mesenchymal tissues (Lamprecht et al, 1989; Baldwin and Whitehead, 1994). Regions of the GI tract where TGF-P inhibition of epithelial cell growth has been demonstrated include gastric, jejunal and colonic epithelia (Barnard et al, 1993; Nakajima and Kuwayama, 1993). In the normal GI tract, TGF-P expression appears to occur predominantly in the differentiated, non-proliferating cells of the villus tips, although some investigators have reported high levels of expression in the crypt cells (Koyama and Podolsky, 1989; Avery et al, 1993; Barnard et al, 1993; Hague et al, 1993a). Factors that stimulate TGF-P expression in the intestine include TGF-P itself, TGF-a and components of the extracellular matrix (Ciacci et al, 1993; Dignass and Podolsky, 1993).

In an enterocytic-differentiated human colon carcinoma cell line and in a rat intestinal crypt line, TGF-Pl has been shown to block cell cycle progression in the middle Gl phase (Hafez et al, 1992; Ko et al, 1994). In addition, in the latter case, it suppressed induction of the proliferation- associated gene cdc2. TGF-Pl prevents phosphorylation of the retinoblastoma susceptibility gene product, Rb, in late Gl phase of the cell cycle. Underphosphorylation is believed to maintain Rb in its growth inhibitory

TGF-0 IN GI NEOPLASIA 69

state (Kim et al, 1991). Furthermore, simian virus 40 T antigen, which binds underphosphorylated Rb, blocks TGF-PI-mediated cell cycle arrest, presumably by preventing Rb from exerting its growth suppressive effects (Laiho et al, 1991). In TGF-P-sensitive intestinal epithelial cells, the signal transduction mechanism of the TGF-P receptors in response to stimulation appears to be mediated by the ras-encoded 21 kDa GTP binding protein, p21 ras (Mulder and Morris, 1992).

Neoplasia

Much research interest surrounding TGF-Ps in the GI tract has focused on the mechanisms by which neoplastic epithelial cell populations escape the growth inhibitory influences of TGF-Ps and even adapt to derive a growth promoting effect from them (Figure 2) (Roberts and Sporn, 1990; Kim et al, 1994). Whereas normal colonic epithelia, adenomas and even some well-differentiated carcinomas are growth inhibited by TGF-Ps, poorly- differentiated carcinomas frequently display resistance to its growth inhibitory effects (Manning et al, 1991; Gregoire et al, 1992; Olive et al, 1993). TGF-PI has been demonstrated to exert a growth inhibitory effect on enterocytic-differentiated colon carcinoma cell lines, a growth stimulatory effect on poorly-differentiated colon carcinoma lines and no effect on cell lines showing goblet cell differentiation (Yan et al, 1992). In these experiments, goblet cells were observed to lack TGF-P type I and II receptors, thus explaining their resistance to TGF-l3. In addition, the enterocytic cell response to TGF-P was mediated by decreased Rb expression at the mRNA and protein levels and pRb levels in addition to under-

Normal GI epithelia

Adenoma Well- Poorly- differentiated differentiated

carcinoma carcinoma

Figure 2. Transforming growth factor-P suppresses the growth of normal gastrointestinal epithelium, adenomas and well-differentiated carcinomas, but appears to promote the growth of some poorly- differentiated carcinomas.


phosphorylation of Rb protein. Whereas some human colorectal carcinoma cell lines display equal sensitivity to TGF-Pl and -p2, others respond only to TGF-P 1 (Suardet et al, 1992). Exposure of a colon carcinoma cell line to the differentiation agent hexamethylene bisacetamide for 7 days produced both a 4-5-fold increase in TGF-fil mRNA levels and decreased tumourigenicity in vivo (Hafez et al, 1990). Transfection of an antisense cDNA encoding for TGF-P produced markedly increased tumourigenicity in a human colon carcinoma cell line (Wu et al, 1992; Hague et al, 1993a). Furthermore, as a given colon adenoma cell line progresses to tumourigenicity it becomes resistant to TGF-P mediated growth inhibition (Markowitz et al, 1994). In mice with colonic adenocarcinomas, serum TGF-P concentration correlates with increased tumour size (Tanaka et al, 1993). Conversely, evaluation of the tumourigenicity of 12 clones derived from a single rat colon adenocarcinoma revealed no correlation with secretion of active or latent TGF-P (Zennadi et al, 1992). In human pancreatic adenocarcinomas, TGF-P isoform expression is increased 7-l l- fold in comparison with normal pancreas and the presence of TGF-P correlates with decreased post-operative survival (Friess et al, 1993).

One explanation for the mechanism by which tumour cells become resistant to the growth inhibitory influence of TGF-fls may lie in the observation that TGF-PI upregulates TGF-a mRNA and protein expression in colon carcinoma cell lines but not in untransformed cells (Lynch et al, 1993; Zipfel et al, 1993). Another possibility is suggested by the observation that while resistant clones cannot be distinguished on the basis of decreased TGF-P binding affinity or decreased total receptor expression, TGF-j31 resistant clones have been reported to express an elevated ratio of type II receptors to type I receptors in comparison to TGF-P sensitive clones (Mulder et al, 1993). In gastric carcinomas, a predominance of type I receptors has been observed in TGF-P sensitive clones in addition to a reduction in type I receptor expression in resistant cell lines (Ito et al, 1990, 1992). However, some investigators have observed a shift to predominantly type I receptors in resistant cell lines (Filmus et al, 1992). It is noteworthy that TGF-P2 resistance does not appear to be receptor related, suggesting that resistance to TGF-Pl and -p2 may develop through different mechanisms (Mulder et al, 1993).

In rat intestinal epithelial cells, resistance to TGF-Pl correlates with the degree of H-ras over-expression. Furthermore, inducible expression of activated H-rus allowed direct demonstration of the link between H-ras and TGF-P resistance (Filmus et al, 1992). In a well-differentiated colon carcinoma cell line, TGF-P blocks the growth stimulatory effects as well as c-myc and TGF-a upregulation consequent upon combined treatment with EGF, insulin and transferrin. Addition of TGF-P after growth factor mediated c-myc upregulation has taken place, however, has no effect, suggesting that c-myc plays a role in mediating the action of TGF-P (Mulder et al, 1990a, b). Furthermore, TGF-j3 did not alter either c-myc or TGF-a n-RNA expression in a poorly-differentiated, TGF-P-resistant colon carcinoma cell line.

Alternatively, in hepatocytes, TGF-PI has been shown to suppress


expression of several anti-oxidative enzymes: manganese-superoxide dismutase, copper, zinc-superoxide dismutase and catalase (Kayanoki et al, 1994). On the basis of this data, it has been proposed that TGF-Ps may also induce cellular injury by reducing production of protective anti-oxidative enzymes. In human colon carcinoma cell lines that are growth inhibited by TGF-P, addition of basic fibroblast growth factor (bFGF) abolished the effects of TGF-p (New and Yeoman, 1992). When a human colon carcinoma cell line (designated RCA), which is neither stimulated nor inhibited by TGF-PI was simultaneously treated with TGF-P and sodium butyrate (NaB), the growth rate did not change. However, exposure of RCA cells grown in the presence of NaB to TGF-Pl stimulated growth, suggesting that NaB may affect the expression of proteins that mediate the proliferative stimulus of TGF-PI (Lewis and Levine, 1992).

Certain mechanisms, however, appear not to play a role. In vitro and in nude mice, expression of a mutant p53 protein did not affect the sensitivity of a non-tumourigenic adenoma cell line to TGF-P (Williams et al, 1994). Furthermore, when a TGF-0 sensitive human colon adenoma cell line, VACO-235, was observed to progress to a tumourigenic, TGF-p-resistant state, it continued to express only wild-type ~53, indicating that cell lines may progress to TGF-P independence and malignancy by mechanisms that do not involve ~53 (Markowitz et al, 1994). In colonic adenoma and carcinoma cell lines, TGF-Pl does not induce apoptosis, thus escape from TGF-P responsiveness does not appear to be linked to escape from pro- grammed cell death (Hague et al, 1993a, b). To summarize, cancer cell resistance to TGF-P appears to be a late and progressive event in tumour progression and it may involve multiple mechanisms that include receptor alterations, cell-signalling defects and modifications of cell-cell and cell-ECM interactions (Filmus et al, 1992; Fynan and Reiss, 1993; Newman, 1993).

With regard to tumour cell adhesion to the ECM, TGF-/31 exerts a potent, albeit highly variable, effect on human colon carcinoma cells (Chakrabarty, 1992). TGF-P1 regulates the adhesion response of TGF-P-sensitive well- differentiated colon carcinoma cells as well as resistant and poorly- differentiated cell lines. Binding to bovine serum albumin, plastic wells, fibronectin, collagen and laminin was evaluated. Adhesion is variably increased or decreased contingent upon the cell line, the type of ECM and the growth factor treatment protocol. Upmodulation of adhesion to fibronectin, collagen and laminin was mediated through Arg-Gly- Asp(RGD)-related integrin receptors. In well-differentiated human colon carcinoma cells, TGF-PI upregulated both the expression of fibronectin and laminin and the expression of their receptors (Huang and Chakrabarty, 1994). In an enterocytic-differentiated TGF-P sensitive colon carcinoma cell line, TGF-Pl increased cell adhesion to collagen I films and upregulated expression of the collagen I-binding protein a2-integrin and of the accessory collagen-binding protein carcinoembryonic antigen (Hafez et al, 1992). TGF-/3 enhances collagen binding of a human colorectal carcinoma cell line, and this enhanced binding is accompanied by increased crypt-like glandular differentiation and decreased proliferation (Pignatelli and


Bodmer, 1989). This finding suggests that regulation of cell-ECM interactions may represent one of the mechanisms by which TGF-P influences the proliferation and differentiation of intestinal epithelial cells. In addition to promoting the growth of poorly-differentiated carcinomas, TGF-P may directly increase the metastatic potential of cancer cells by means of autocrine stimulation of cell locomotion and invasion consequent upon increased synthesis of hyaluronan and RHAMM (receptor for hyaluronan mediated motility), a hyaluronan cell surface receptor (Wright et al, 1993).

In addition to its role in the evolution of carcinomas, TGF-P has been implicated in the desmoplastic reaction that accompanies many GI tumors (Yasui et al, 1991). Cell lines from scirrhous gastric carcinomas produce a more active TGF-Pl form than non-scirrhous gastric carcinoma cell lines (Mahara et al, 1994). In an in vitro model for gastric cancer, gastric carcinoma cells of the scirrhous type, but not those of the non-scirrhous type, caused fibroblasts to contract collagen gels. In addition, the scirrhous type cells produce the active TGF-P form, whereas the non-scirrhous type cells produced the latent form (Ura et al, 1991). TGF-P has also been proposed to play a role in the scirrhous growth of penetrating type early gastric cancer (Hirayama et al, 1992). On the basis of this observation, it has been proposed that immunostaining of biopsy specimens for TGF-/3 may assist in the diagnosis of this form of gastric cancer and of the initial lesion of linitis plastica. Immunoelectron microscopy of human gastric carcinomas has localized pro-TGF-pl to the cytosol of cancer cells rather than the rough endoplasmic reticulum and perinuclear cisternae, suggesting disarranged or blocked intracellular transport of TGF-P in neoplastic cells (Mizoi et al, 1993). On the basis of this observation, it has been proposed that stromal cells produce the TGF-Pl that stimulates the fibrosis that accompanies many such tumours. Neuroendocrine GI tumours often display marked stromal proliferation and the majority of midgut carcinoids, pancreatic carcinoids and endocrine pancreatic tumours express all three TGF-P isoforms (Beauchamp et al, 199 1; Chaudhry et al, 1993). In cultured human colon carcinoma cells, TGF-P increases heparan sulphate proteoglycan expression primarily through an increase in mRNA levels encoding the protein core (Dodge et al, 1990). In guinea pig liver cells, TGF-PI stimulates synthesis and release of plasminogen activator inhibitor type 1 (Rieder et al, 1993). This finding suggests that TGF-Pl may inhibit ECM degradation by downregulating plasmin activity. Overall, TGF-/3 displays three distinct effects on ECM: increased synthesis, decreased degradation and altered receptor expression (Noble et al, 1992).

Wound healing

In addition to its role in the regulation and evolution of neoplasms, TGF-/3 has attracted considerable interest with regard to its role in wound healing. From one perspective, TGF-P holds promise as an agent to promote and accelerate wound healing. In this regard, it has proven clinically useful in promoting healing of cornea1 wounds in humans (Schultz et al, 1992). From another, inhibition of TGF-/3s actions may be the key to preventing fibrosis


as a result of exaggerated healing responses. Dermal wounds have long served as a model for wound healing in general. The response to dermal wounds is a sequential, multi-step process characterized by several key events: platelet-induced haemostasis, migration of inflammatory cells and fibroblasts to the wound site, deposition of ECM, angiogenesis and cell proliferation. TGF-01 plays an active role in promoting each of these processes through release from platelets and activation of latent tissue- bound TGF-PI at the time of injury; stimulation of neutrophil, T cell, monocyte and fibroblast chemotaxis; activation of these cells with subsequent release of other growth factors and ECM synthesis; and autoinduction of further TGF-01 expression (Hosgood, 1993; Border and Noble, 1994; McCartney-Francis and Wahl, 1994). TGF-P exerts its effects on wound healing when administered either topically or systemically (Cromack et al, 1990; Zioncheck et al, 1994). In addition to increasing both the speed of wound repair and the breaking strength of healed wounds, TGF-P reverses glucocorticoid-induced inhibition of wound healing (Amento and Beck, 1991).

In the intestine, TGF-j3 appears to perform a similar array of functions. In an in vitro model of intestinal wound healing, TGF-PI stimulated migration over laminin but inhibited migration over collagen. This result suggested that TGF-/3 may selectively target specific phases of mucosal healing (Basson et al, 1992). In another model for wound healing, TGF-P inhibited proliferation of intestinal epithelial cells after wounding, but paradoxically promoted wound repair by stimulating cell migration into the defect (Ciacci et al, 1993). In addition, epithelial cells in this model both produced and activated TGF-P, the latter process occurring possibly through the action of a plasmin-like protease. Furthermore, TGF-P inhibition with anti-TGF-P antibodies blocked the initial response to injury. Acidic and basic FGFs, TGF-a, EGF, IL-lp and interferon-y (IFN-y) have been proposed to promote epithelial restitution by augmenting production of bioactive TGF-Pl in epithelial cells (Dignass and Podolsky, 1993; Dignass et al, 1994). In pigs with pharmacologically induced steroid- impaired wound healing, local application of TGF-P significantly increased breaking load of ileal wounds (Slavin et al, 1992).

On the basis of its central role in the regulation of both ECM metabolism and the immune system, TGF-P has been proposed as a major factor in the pathogenesis of fibrosis. In diseases such as glomerulonephritis, pulmonary fibrosis, systemic sclerosis and chronic liver disease, TGF-P appears to exert the dominant stimulus for the evolution of fibrosis in both animals and humans (Smith and LeRoy, 1990; Border et al, 1991; Faust0 et al, 1991; Khalil and Greenberg, 1991; Anscher et al, 1993). Furthermore, inhibition of TGF-Pi’s actions by anti-TGF-pl antibodies has successfully blocked the development of fibrosis (Border et al, 1991). TGF-P-mediated fibrosis affects the GI tract both directly and indirectly. In addition to the mentioned putative involvement of TGF-P in desmosplastic reactions accompanying tumours and in systemic sclerosis, all three isoforms of TGF-P have been implicated in the formation and maintenance of surgically induced pelvic adhesions in the rat (Chegini et al, 1994). In normal wound healing, TGF-P


increases transiently and eventually returns to normal through unknown mechanisms. With repeated injury, TGF-P remains elevated through a vicious circle of autoinduction without appropriate downregulation, result- ing in progressive deposition of ECM with eventual accompanying fibrosis (Border and Noble, 1994).

Immune response

Through processes that are strongly implicated in its role in wound healing, TGF-/3 also regulates the immune response in a significant, and in many instances seemingly contradictory, fashion (Ruscetti et al, 1993). For the sake of simplicity, TGF-P may be understood to exert two opposing effects depending on the level at which it acts (Figure 3). It suppresses the immune system at the systemic level, whereas it stimulates the immune and inflammatory responses at the local level (McCartney-Francis and Wahl, 1994). Clearly, this view represents an over-simplification, albeit a useful one, of a complex process that depends on the interaction of factors such as the nature of the stimulus, the differentiation and metabolic state of the target cells, the site of action, the concentration of numerous cytokines and the timing of the entire event (Bogdan and Nathan, 1993). At the site of inflammation, TGF-/3 attracts neutrophils, monocytes and lymphocytes through

Local immune response

Systemic immune response

Figure 3. At the systemic level transforming growth factor-p acts as an immunosuppressant, but at the local level it stimulates the immune response.


chemotaxis, facilitates leukocyte adhesion to the vessel wall and ECM, and stimulates monocytes to secrete proinflammatory cytokines (Wahl et al, 1993). In both monocytes and lymphocytes, TGF-P activates immature cells to mount an inflammatory response and switches off activated mature cells. Evidence for the immunosuppressive effects of systemic TGF-P derives in part from experiments in mice that were rendered TGF-Pl- deficient by targeted disruption of the TGF-Pl gene. In these animals, death occurred at 3-5 weeks consequent upon massive leukocyte infiltration of numerous organs accompanied by increased expression of tumour necrosis factor a (TNF-a), IFN-y, and macrophage inflammatory protein-l (MIP- la) (Shull et al, 1992; Kulkami and Karlsson, 1993). TGF-P has been proposed to play a role in both autoimmune and immunosuppressive processes in humans as well (Kehrl, 1991; Del and Crow, 1993).

In the GI tract, TGF-P exerts a variety of influences on the immune response. Proinflammatory actions of TGF-P include enhancing IL-6 secretion by intestinal epithelial cells (McGee et al, 1993). IL-lb displays a similar effect and acts in a synergistic fashion with TGF-P. On the basis of these observations, it has been proposed that intestinal epithelial cells may represent an important source of IL-6 in the inflammatory response and that TGF-P may play a central role in regulating its secretion. In a human hepatoma cell line, TGF-P did not affect the acute-phase protein response to IL-6 but it inhibited the response to IL-l (Raynes and Bevan, 1993). Steady-state mRNA expression of both IL-1 and TGF-P is elevated in samples of intestinal mucosa from patients with inflammatory bowel disease as compared with control specimens (McCabe et al, 1993). Intestinal epithelial cells bear IL-2 receptors, and treatment with IL-2 enhances their expression of TGF-fi 4-50-fold (Ciacci et al, 1993).

While TGF-P suppresses B-cell immunoglobulin secretion, it stimulates them to shift to IgA isotype production (McGee et al, 1992; McCartney- Francis and Wahl, 1994). In addition, TGF-fil-deficient mice displayed decreased serum IgA levels. In an intestinal epithelial cell line, TGF-Pl upregulated expression of surface secretory component, a protein respon- sible for mediating transport of polymeric IgA into the intestinal lumen (McGee et al, 1991). In these same cells, TGF-Pl also increased the expression of major histocompatibility complex class I antigens. Intestinal intraepithelial lymphocytes (iIELs) express the integrin aEp7, which mediates binding to mucosal epithelial cells. TGF-P induces aEp7 integrin expression on cultured iIELs (Parker et al, 1992; Cepek et al, 1993, 1994). Thus, TGF-P may play a central role in the regulation of lymphocyte binding to intestinal epithelial cells (Kilshaw and Murant, 1991).

SUMMARY

The last decade has been marked by tremendous advances in the bio- chemical and functional characterization of TGF-Ps and their receptors in normal and transformed cells. TGF-Ps have been shown to modulate


proliferation, differentiation and motility of different cell types in a number of in vitro model systems and in some cases with some intriguing results. It is obvious that there is no simple pattern that explains the TGF-0s biological activity in vitro and their effects on cell behaviour need to be assessed in the context of an appropriate physiological cellular environ- ment. Cell-cell and cell-matrix interactions, the differentiating status of the cell together with the functional activity of other soluble growth factors can influence how TGF-Ps modulate cell behaviour. However, the overwhelm- ing interest in this field shown by clinicians and basic scientists is rapidly increasing our understanding of how growth factors such as TGF-/3s regulate the homeostasis of the GI mucosa and their role in gastrointestinal carcinogenesis.

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Transforming growth factor-β in GI neoplasia, wound healing and immune response

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