Cytokines & Cells Online Pathfinder Encyclopaedia
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[transforming growth factor-beta] also abbr.: TGFB or B-TGF.
ALTERNATIVE NAMES
Aqueous humor lymphocyte inhibitory activity;
CIF-A (cartilage inducing factor A = TGF-beta-1);
CIF-B (cartilage inducing factor B = TGF-beta-2);
Corneal epithelial inhibitor of stromal cell collagenase synthesis (TGF-beta-2);
DIF (differentiation-inhibiting factor);
DSF (decidual suppressor factor = TGF-beta-2);
EGI [epithelial cell-specific growth inhibitor; epithelial growth inhibitor]
EIF (Epstein-Barr virus inducing factor);
Epithelial cell growth inhibiting factor;
G-TsF (glioma-derived T-cell suppressor factor);
ISF (immunosuppressive factor = TGF-beta-1)
MDGF (milk-derived growth factor);
MGF (milk growth factor);
MGF-a (milk growth factor = TGF-beta-2);
MGF-b (milk growth factor = TGF-beta-1);
PDGI (platelet-derived endothelial cell growth inhibitor = TGF-beta-1);
Polyergin;
Simian BSC-1 cell growth inhibitor;
SP factor;
TCGF (transformed cell growth factor);
TGI (tissue-derived growth inhibitor);
TIF-1 (tumor inducing factor-1).
See also: individual entries for further information.
SOURCES
Platelets yield milligram amounts of TGF-beta/ kilogram. The factor and its isoforms (see below) can be isolated also from other tissues (microgram TGF/kg) and is found predominantly in spleen and bone tissues. Human milk also contains this factor (see: MGF, milk growth factor). It is synthesized also for example by macrophages (TGF-beta-1), lymphocytes (TGF-beta-1), endothelial cells (TGF-beta-1), keratinocytes (TGF-beta-2), granulosa cells (TGF-beta-2), chondrocytes (TGF-beta-1), glioblastoma cells (TGF-beta-2), leukemia cells (TGF-beta-1).
Depending upon cell type or conditions, the secretion of TGF-beta can be induced by a number of different stimuli including steroids, retinoids, EGF, NGF, activators of lymphocytes (see also: cell activation), vitamin D3, and IL1. The synthesis of TGF-beta can be inhibited by EGF, FGF, dexamethasone, calcium (see also: Calcium ionophore), retinoids and follicle stimulating hormone. TGF-beta also influences the expression of its own gene and this may be important in wound healing.
TGF-beta can exist associated with the extracellular matrix as a complex with betaglycan and decorin. This allows the factor to be stored in a biologically inactive form. The exact molecular mechanisms underlying its release from these reservoirs is unknown.
PROTEIN CHARACTERISTICS
TGF-beta exists in at least five isoforms, known as TGF-beta-1, TGF-beta-2, TGF-beta-3, TGF-beta-4, TGF-beta-5, that are not related to TGF-alpha. Their amino acid sequences display homologies on the order of 70-80 %. TGF-beta-1 is the prevalent form and is found almost ubiquitously while the other isoforms are expressed in a more limited spectrum of cells and tissues. TGF-beta-2, NGF, and PDGF-BB (see: PDGF) share a similar overall topology (see also: Cystine knot growth factor family).
The biologically active forms of all isoforms are disulfide-linked homodimers. Disulfide-linked heterodimers of TGF isoforms have been reported also. The heat- and acid-stable monomeric subunits have a length of 112 amino acids. TGF-beta-4 contains two additional amino acids in the vicinity of the aminoterminal end.
The isoforms of TGF-beta arise by proteolytic cleavage of longer precursors (TGF-beta-1: 390 amino acids, TGF-beta-2: 412 amino acids, TGF-beta-3: 412 amino acids, TGF-beta-4: 304 amino acids (see also: EBAF), TGF-beta-5: 382 amino acids). The isoforms are derived from the carboxyterminal ends of these precursors.
Isoforms isolated from different species are evolutionarily closely conserved and have sequence identities on the order of 98 %. Mature human, porcine, simian and bovine TGF-beta-1 are identical and differ from murine TGF-beta-1 in a single amino acid position. Human and chicken TGF-beta-1 are also identical.
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| Biosynthesis and processing of mature TGF-beta TGF-beta (dark blue) is synthesized initially as a long precursor molecule containing a signal sequence. When this is removed the remaining part of the molecule forms a disulfide-bonded dimer. Proteolytic cleavage (red arrow heads) yields a complex in which the mature TGF-beta protein remains associated with the rest of the precursor molecule (green). The complex is held together by means of a binding protein. TGF-beta in this complex is said to be in a latent form. Acid activation releases mature biologically active TGF-beta from this non-covalent complex. |
Almost all forms of TGF-beta are released as biologically inactive forms that are known also as L-TGF (latent TGF). Latent forms are complexes of TGF-beta, an aminoterminal portion of the TGF-beta precursor, designated TGF-LAP (TGF-latency associated peptide), and a specific binding protein (205 kDa; 125-160 kDa in platelets), known as LTBP (latent TGF binding protein, 1394 amino acids). See also: LTBP2, LTBP3.
L-TGF has been shown to be localized at the cell surface by binding to the mannose-6-phosphate/IGF-2 receptor (see: MPR) through mannose-6-phosphate-containing carbohydrates of TGF-LAP and through interaction with the L-TGF binding protein. LTBP may be processed in a cell-type specific manner. Biologically active TGF-beta results after dissociation from the LAP complex. The nature of the activation mechanism of L-TGF in vivo is unclear. It may involve direct cell-to-cell contacts, proteases, specifically plasmin, and has recently also been shown to be mediated by transglutaminases (EC2.3.2.13). Another potent physiologic regulator of TGF-beta activation is Thrombospondin. TGF-beta-2 is unique among various isoforms in that it lacks an RGD integrin-binding sequence in its precursor.
The mechanisms of TGF-beta activation are not known in detail. The main fraction of the factor in the serum is covalently attached to one of the acute phase proteins, Alpha-2-Macroglobulin (Alpha2M) the synthesis of which is known to be induced several hundred-fold by IL6. Alpha2M/TGF-beta complexes are believed to represent TGF-beta molecules released by platelets after tissue injuries and destined to degradation (see also: inflammation, wound healing).
Mutant forms of TGF-beta have been created. They form wild-type/mutant heterodimers deficient in assembly or processing. Such mutants behave as dominant negative mutants and are useful in investigation of the role of TGF-beta in normal and pathological conditions.
GENE STRUCTURE
The different isoforms of TGF-beta are encoded by different genes. All genes have a length of more than 100 kb and contain seven exons. The genes map to different chromosomes. The TGF-beta-1 gene maps to human chromosome 19q13; the TGF-beta-2 gene maps to human chromosome 1q41; the TGF-beta-3 gene maps to human chromosome 14q24. These genes are expressed differentially. The TGF-beta-3 gene is expressed strongly in embryonic heart and lung tissues but only marginally in liver, spleen, and kidney tissues. TGF-beta-1 is expressed strongly in spleen tissues.
RELATED FACTORS
TGF-beta is the prototype of a protein family known as the TGF-beta superfamily. This family includes Inhibins, Activin A, MIS (Müllerian inhibiting substance), BMP (bone morphogenetic proteins), dpp (decapentaplegic) and Vg-1. MNSF (monoclonal nonspecific suppressor factor) shows 60 % sequence identity with TGF-beta-2.
RECEPTORS
An entire family of glycoprotein receptors for TGF-beta has emerged. Some of these proteins do not bind TGF-beta-related factors belonging to the TGF-beta family. Some receptors bind TGF-beta and the related factors Activin A and Inhibins. A type 5 receptor (proteoglycan, 400 kDa) has also been described.
Type 1 receptors and type 2 receptors have a molecular mass of 53 and 75 kDa, respectively. Signaling through the receptor requires heterodimeric complexes between both types of receptors. The type 2 receptor has been shown to bind the ligand, but it is incapable of mediating TGF-beta responses in the absence of the type 1 receptor. The type 1 receptor is expressed predominantly in hematopoietic progenitor cells. The type 2 receptor encodes a protein with an intracellular domain that functions as a serine/threonine kinase.
Individual TGF-b isotypes bind to the receptors with varying affinities. For example, TGF-beta-1 binds approximately tenfold better than TGF-beta-2. In several cell types the expression of the TGF-beta receptors is decreased by EGF (see also: Receptor transmodulation). In endothelial cells the expression of the TGF-beta receptor is decreased by bFGF.
Almost all types of cells express a 560 kDa high-affinity receptor for TGF-beta, called type 3 receptor. This receptor is betaglycan. The receptor density can vary between 600 and 80000 per cell. This receptor type is not expressed in primary epithelial, endothelial, and lymphoid cells.
The type 3 receptor is a proteoglycan (Betaglycan; see also: extracellular matrix) with a length of 853 amino acids. This receptor contains a transmembrane domain and a short cytoplasmic domain of 41 amino acids. The type 3 receptor binds TGF-beta-1 and TGF-beta-2 equally well. Membrane betaglycan appears to be a regulator of TGF-beta access to the signaling receptors; it increases binding of TGF-beta to the signaling receptor, enhances cell responsiveness to TGF-beta, and eliminates some of the marked biological differences between different TGF-beta isoforms.
The major TGF-beta-1 binding protein co-existing with TGF-beta receptors I and II on human umbilical vein endothelial cells appears to be Endoglin, a dimeric integral membrane glycoprotein of 95 kDa that shares regions of sequence identity with betaglycan and that is expressed at high levels on human vascular endothelial cells.
Two human receptors, designated TSR-I and AcrR-I, have been cloned and found to encode transmembrane serine/threonine kinases distantly related to known mammalian TGF-beta and Activin A receptors. These new receptor types form heterodimeric complexes with type 2 TGF-beta receptors, which possess signaling capacities differing from those of the other receptor types.
Retinoblastoma cells, undifferentiated embryonic stem cells and several leukemic cell types do not express TGF receptors. In endothelial cells the expression of TGF receptors is downregulated by FGF.
TGF receptor-associated signal transduction mechanisms are largely unknown. None of the receptors appears to encode a tyrosine-specific protein kinase found in the intracellular domain of many other cytokine receptors. Signal transduction may involve a G-protein. Intracellular signaling following engagement of has been shown recently to involve the action of SMAD proteins.
BIOLOGICAL ACTIVITIES
The biological activities of TGF-beta are not species-specific. The various TGF-beta isotypes share many biological activities and their actions on cells are qualitatively similar in most cases although there are a few examples of distinct activities. In some systems TGF-beta-3 appears to be more active than the other isotypes. TGF-beta-2 is the only variant that does not inhibit the growth of endothelial cells. TGF-beta-2 and TGF-beta-3, but not TGF-beta-1, inhibit the survival of cultured embryonic chick ciliary ganglionic neurons. The most pronounced differences in the TGF-beta isoforms is their spatially and temporally distinct expression of both the mRNAs and proteins in developing tissues, regenerating tissues, and in pathologic responses.
TGF-beta is the most potent known growth inhibitor for normal and transformed epithelial cells, endothelial cells, fibroblasts, neuronal cells, lymphoid cells and other hematopoietic cell types (see also: CFU-S), hepatocytes, and keratinocytes.
TGF-beta inhibits the proliferation of T-lymphocytes by downregulating predominantly IL2 mediated proliferative signals. It also inhibits the growth of natural killer cells in vivo and deactivates macrophages. TGF-b blocks the antitumor activity mediated in vivo by IL2 and transferred lymphokine-activated or tumor infiltrating lymphocytes (see: LAK cells, TIL). TGF-beta inhibits the synthesis of GM-CSF, IL3, and the expression of the receptor for G-CSF. It also inhibits the growth of immature hematopoietic progenitor cells induced by IL3, GM-CSF, and M-CSF, in particular growth of CFU-GEMM. TGF-beta-1 inhibits CFU-GEMM approximately 100-fold stronger than TGF-beta-2. TGF-beta also inhibits megakaryocytopoiesis (see: CFU-GM). In many cell types TGF-beta antagonizes the biological activities of EGF, PDGF, aFGF and bFGF. TGF-beta-1 and TGF-beta-2 inhibit the proliferation of lymphocytes induced by IL1. The latent form of TGF-beta is a strong inhibitor of erythroleukemia cell lines.
The extent of growth inhibition induced by TGF-beta depends on the cell type, on the concentration of TGF-beta, and on the presence of other factors. Epithelial cells of the lung and keratinocytes are practically arrested in their growth. The growth of some cells is inhibited by TGF-beta although these cells secrete TGF-beta complexes and can growth in the presence of these biologically inactive complexes. The growth-inhibitory activities of TGF-beta can be abolished by HGF (hepatocyte growth factor). Some mutations occurring in the TGF precursor protein have been described that act as dominant negative mutations. These altered proteins can inhibit the secretion of normal TGF isotypes if they are produced simultaneously.
At concentrations of 1-2 fg/cell TGF-beta is a growth inhibitor for smooth muscle cells, fibroblasts, and chondrocytes. At higher concentrations TGF-beta stimulates the growth of these cells. This bimodal activity is mediated in part by PDGF (A-chain homodimer) the synthesis and secretion of which is stimulated by low concentrations of TGF-beta, while higher concentrations lower the expression of the PDGF receptors and hence diminish the biological effects of PDGF.
Although TGF-beta inhibits the growth of endothelial cells it promotes angiogenesis in several bioassays. Under certain circumstances TGF-beta may, however, also inhibit angiogenesis. It has been suggested that overproduction of TGF-beta-1 by tumor cells can contribute to neovascularization and may help promote tumor development in vivo.
TGF-beta is an autocrine growth modulator for malignant gliomas. TGF-beta stimulates the growth of some cell types of mesenchymal origin including fibroblasts and osteoblasts in vivo and in vitro. TGF-beta-1 and TGF-beta-2 promote the proliferation of Schwann cells. TGF-beta induces the synthesis of bone matrix proteins in osteoblasts. The anabolic activity on bone cells is antagonized by glucocorticoids. Factors that promote bone resorption (IL1, 1,25-Dihydroxy-vitamin D3, parathormone) induce the synthesis of TGF-beta in bone cells while calcitonin, an inhibitor of bone resorption, reduces the synthesis of TGF-beta. TGF-beta regulates the expression of the PDGF beta chain (see also: sis oncogene).
TGF-beta appears to be one of the major factors promoting neurogenesis in the olfactory epithelium that gives rise to olfactory neurons. In pituitary cells TGF-beta inhibits the synthesis of TGF-alpha. TGF-beta also suppresses cell activation and proliferation of microglial cells induced by GM-CSF or M-CSF; it suppresses the expression of MHC class 2 antigens induced by IFN-gamma and the production of IL1, IL6, and TNF-alpha by these cells and may thus play an important role in the development of various diseases in the central nervous system by inhibiting the functions of microglial cells in inflammation or in immunoregulation.
TGF-beta stimulates the synthesis of the major extracellular matrix proteins, including collagen, proteoglycans, glycosaminoglycans, fibronectin, integrins, Thrombospondin, osteonectin, osteopontin. It inhibits their degradation mainly by inhibiting the synthesis of neutral metalloproteinases and by increasing the synthesis of proteinase inhibitors (see: TIMP).
TGF-beta also regulates the expression of plasminogen activator and plasminogen activator inhibitor. The gene encoding plasminogen activator I inhibitor contains a specific TGF-beta-1 responsive element in its promoter region which mediates the binding of specific transcription factors (see also: gene expression, Response elements). TGF-beta also inhibits the secretion of proteases (plasminogen activator, cathepsin L, stromelysin, collagenase). These activities of TGF-beta are antagonized by IL1.
TGF-beta-1 modulates the interaction of tumor cells with the cellular matrix. It is therefore probably also involved in metastatic processes together with other protein factors. TGF-beta-3 is involved in the early development of the heart. It is responsible for the transformation of epithelial cells within the membranes into mesenchymal cells.
TGF-beta has mainly suppressive effects on the immune system since it inhibits the IL2 dependent proliferation of T-cells and B-lymphocytes. TGF-beta inhibits the proliferation of B-lymphocytes, and proliferation of thymocytes induced by IL2 and IL1, respectively. It also inhibits the maturation of B-cells. It also suppresses the interferon induced (see also: IFN) cytotoxic activity of natural killer cells, the activity of cytotoxic T-lymphocytes, and the proliferation of the precursors of lymphokine-activated killer cells.
TGF-beta also influences the secretion of immunoglobulins by B-lymphocytes. The synthesis of IgG and IgM by B-lymphocytes is inhibited while the synthesis of IgA is stimulated (see also: Isotype switching).
TGF-beta modulates the synthesis of acute phase proteins by hepatocytes and inhibits the ACTH induced synthesis of cortisol (see also: POMC).
TGF-beta-1 is the most potent known chemoattractant for neutrophils (see also: Chemotaxis). It specifically attracts neutrophils at concentrations of 1 fM and is therefore approximately 150000-fold more potent than fMLP (Formyl-Met-Leu-Phe).
TGF-beta stimulates the expression of IL1, PDGF, bFGF in monocytes and inhibits the synthesis of TNF-alpha, TNF-beta and IFN-gamma in adherent human monocytes and murine macrophages.
TGF-beta stimulates the synthesis of estrogens, mediated by FSH (follicle stimulating hormone), the synthesis of progesterone in ovarian granulosa cells. It inhibits the synthesis of testosterone in Leydig cells.
TRANSGENIC ANIMALS, KNOCK-OUT, AND ANTISENSE STUDIES
The biological consequences of the overexpression of TGF-beta have been studied in transgenic mice overexpressing the factor in the epidermis. These animals are characterized by a marked reduction in the number of replicating cells in the epidermis and hair follicles. They show a compact orthohyperkeratosis and a reduction in the number of hair follicles. The skin is shiny and tautly stretched, and the animals are rigid and appear to be restricted in their ability to move and breathe. These animals usually die within 24 hrs after birth.
Overexpression of TGF-beta has been investigated also in transgenic mice harboring a fusion gene consisting of a porcine TGF-beta-1 cDNA placed under the control of regulatory elements of the pregnancy-responsive mouse whey-acidic protein gene. Females from two of four transgenic lines have been found to be unable to lactate due to inhibition of the formation of lobuloalveolar structures and suppression of production of endogenous milk protein. TGF-beta-1 thus may play an important in vivo role in regulating the development and function of the mammary gland.
The biological consequences of an TGF-beta-1 gene disruption have been studied in mice generated from ES cells carrying a targeted deletion of the gene. The transgenic knock-out animals show no gross developmental abnormalities, but about 20 days after birth they succumb to a wasting syndrome accompanied by a multifocal, mixed inflammatory cell response and tissue necrosis, leading to organ failure and death. Pathological examination reveals an excessive inflammatory response with massive infiltration of lymphocytes and macrophages in many organs, but primarily in heart and lungs. Many lesions resemble those found in autoimmune disorders, graft-versus-host disease, or certain viral diseases. This phenotype suggests a prominent role for TGF-beta-1 in homeostatic re-gulation of immune cell proliferation and extravasation into tissues. It has been shown that mice not expressing TGF-beta-1 express elevated levels of both the class 1 and class 2 major histocompatibility antigens.
Another study by Dickson reports a high incidence of prenatal lethality in TGF-beta-1 negative animals due to defective haematopoiesis and endothelial differentiation.
DETECTION AND ASSAY METHODS
TGF-beta can be detected in bioassays involving the use of cell lines that respond to the factor (see: AKR-2B; CCL-64; NRK; MV-3D9; NRK-49F; TF-1). TGF-beta can be assayed also in sensitive ELISA test or by a radioreceptor assay or with colorimetric methods.
Phillips et al (1995) have described an antibody capture enzyme linked immunoassay which detects 0.2 to 100 ng/mL of human recombinant TGF-beta-1, natural platelet extracted TGF-beta-1, and TGF-beta-1 derived from human monocytes stimulated with phorbol 12-myristate 13-acetate (PMA). Latent TGF-beta-1 can be measured indirectly following acid activation of samples.
Kropf et al (1997) have described the development of a sensitive immunoassay for measuring TGF-beta-1.
Danielpour and Roberts (1995) have described a sandwich enzyme-linked immunosorbent assay (SELISA) for the quantitattion of human TGF-beta-3 in complex biological fluids. The detection limit is 2 pg. 1000-fold molar excesses of TGF-beta-1 or TGF-beta-2 do not interfere with the assay.
An alternative and entirely different detection method is RT-PCR quantitation of cytokines. For further information see also subentry "Assays" in the reference section. For further information on assays for cytokines see also: bioassays, cytokine assays.
CLINICAL USE AND SIGNIFICANCE
Many of the biological activities of TGF-beta point to the fact that it may be a potent regulator of wound healing and of bone fracture healing. Local application of TGF-beta has been shown to accelerate wound repair. In combination with bone morphogenetic protein-2 (see: BMP) TGF-beta plays an important role in the development of ossification of the posterior longitudinal ligament of the cervical spine. The factor may be helpful in the treatment of traumatic tissue injuries (see also: inflammation, wound healing) and in the treatment of osteoporosis. TGF-beta-2 has been used for the treatment of full-thickness macular holes and has been shown to improve visual acuity. In one incisional wound healing rat model systemic administration of TGF-beta has been shown to enhance wound healing and to reverse age- or glucocorticoid-impaired wound healing even if given 24 hours before wounding. Although the exact mechanism of action is unclear it has been suggested that this may be due to the ability of TGF-beta to induce its own synthesis. TGF-beta, therefore, may prime macrophages and fibroblasts throughout the body (see also: cell activation) to respond more effectively to future injury and if this could be verified systemic treatment with one priming dose of TGF-beta would represent a novel approach to endocrine replacement therapy.
Antagonists of TGF-beta may be valuable in the treatment of fibrotic disorders, which are associated often with increases in TGF-beta activities. TGF-beta has been implicated as a mediator of a range of inflammatory disorders such as rheumatoid arthritis and nephritis, myelofibrosis, scleroderma, and pulmonary fibrosis.
Animal experiments demonstrate that TGF-beta has cardioprotective activities following ischemic injuries. This activity is probably due to the inhibition of processes mediated by TNF-alpha. In addition TGF-beta minimizes the loss of the protective factor EDRF (endothelium-derived relaxing factors). EDRF is identical with nitrogen monoxide that mediates acetylcholine- and thrombin induced vasodilatation and that also inhibits platelet aggregation.
Immunohistochemical staining of TGF-beta (and also of EGF) in endoscopic biopsy specimens may be useful for the diagnosis of the penetrating type of early gastric cancer and also for the diagnosis of the initial lesion of linitis plastica-type gastric cancer.
Expression of TGF-beta-1 does not appear to correlate with histological grade, estrogen receptor status, EGF receptor status, and Ki-67 labeling in mammary carcinomas. However, prominent reactivity appears to correlate with node status and metastasizing potential, suggesting that TGF-beta-1 may be a determining factor for invasion and metastasis.
TGF-beta produced by neonatal rat cardiac myocytes stabilizes the beating rate and sustains their spontaneous rhythmic beating in serum-free medium. This effect is inhibited by I IL1-beta (see: IL1), an inflammatory mediator secreted by immune cells during myocardial injury, and TGF-beta can overcome this inhibition. TGF-beta thus may be an important regulator of contractile function of the heart and have significant implications for understanding cardiac physiology in health and disease.
See REFERENCES for entry TGF-beta
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