transforming-growth-factor-beta and Pancreatic-Diseases

Genetic alterations affecting transforming growth factor-β (TGF-β) signaling are exceptionally common in diseases and cancers of the gastrointestinal system. As a regulator of tissue renewal, TGF-β signaling and the downstream SMAD-dependent transcriptional events play complex roles in the transition from a noncancerous disease state to cancer in the gastrointestinal tract, liver, and pancreas. Furthermore, this pathway also regulates the stromal cells and the immune system, which may contribute to evasion of the tumors from immune-mediated elimination. Here, we review the involvement of the TGF-β pathway mediated by the transcriptional regulators SMADs in disease progression to cancer in the digestive system. The review integrates human genomic studies with animal models that provide clues toward understanding and managing the complexity of the pathway in disease and cancer.

Topics: Animals; Digestive System Neoplasms; Disease Progression; Gastrointestinal Diseases; Gene Expression Regulation, Neoplastic; Humans; Liver Diseases; Pancreatic Diseases; Receptors, Transforming Growth Factor beta; Signal Transduction; Smad Proteins; Transforming Growth Factor beta; Tumor Microenvironment

Pancreatic diseases, such as acute pancreatitis, chronic pancreatitis, and pancreatic cancer, are common gastrointestinal diseases resulting in the development of local and systemic complications with a high risk of death. Numerous studies have examined pancreatic diseases over the past few decades; however, the pathogenesis remains unclear, and there is a lack of effective treatment options. Recently, emerging evidence has suggested that transforming growth factor beta (TGF-β) exerts controversial functions in apoptosis, inflammatory responses, and carcinogenesis, indicating its complex role in the pathogenesis of pancreas-associated disease. Therefore, a further understanding of relevant TGF-β signalling will provide new ideas and potential therapeutic targets for preventing disease progression. This is the first systematic review of recent data from animal and human clinical studies focusing on TGF-β signalling in pancreas damage and diseases. This information may aid in the development of therapeutic agents for regulating TGF-β in this pathology to prevent or treat pancreatic diseases.

Topics: Animals; Humans; Pancreatic Diseases; Transforming Growth Factor beta

In recent years, numerous studies have provided novel insights into the pathomechanisms of pancreatic fibrogenesis. This includes in particular the identification and characterization of the pancreatic stellate cells (PSCs) and their role in the synthesis of extracellular matrix (ECM) proteins. It has become clear that pancreatic stellate cell activation is regulated by a complex network of growth factors and cytokines and results in increased expression and release of collagens I and II, fibronectin and other components of ECM. Among the cytokines involved in PSC activation and other fundamental mechanisms of pancreatic fibrosis, transforming growth factor beta (TGFbeta) is of particular relevance. TGFbeta stimulates PSC activation and induces transcription of ECM proteins mainly via activation of the Smad proteins which regulate gene expression through functional interaction with co-operating partner proteins such as the zinc finger transcription factor Sp1. Recent progress in understanding of the biochemical and molecular mechanisms of pancreatic fibrosis, is reviewed here.

Topics: DNA-Binding Proteins; Extracellular Matrix Proteins; Fibrosis; Humans; Neoplasm Proteins; Pancreas; Pancreatic Diseases; Pancreatic Neoplasms; Pancreatitis; Repressor Proteins; Smad Proteins; Trans-Activators; Transcription Factors; Transforming Growth Factor beta; Up-Regulation

Topics: Animals; Body Patterning; Cell Communication; Cell Differentiation; Endoderm; Hedgehog Proteins; Humans; Islets of Langerhans; Membrane Proteins; Morphogenesis; Notochord; Pancreas; Pancreatic Diseases; Proteins; Receptors, Notch; Signal Transduction; Trans-Activators; Transcription Factors; Transforming Growth Factor beta

The prevalence of pancreatic adenocarcinoma (PAC) parallels rising rates of obesity and dysmetabolism, a possible link being non-alcoholic fatty pancreas disease (NAFPD). We have recently shown that maternal obesity programmes the development of a dysmetabolic and fatty liver (non-alcoholic fatty liver disease, NAFLD) phenotype in adult offspring. Since the pancreas and liver originate from the same embryonic bud, it is plausible that maternal obesity may similarly programme the development of NAFPD. Our objective was to determine the effect of maternal obesity on development of NAFPD in offspring and ascertain contributions of the intra/extra-uterine periods.. Female C57BL/6J mice were fed either a standard chow (3% fat, 7% sugar) or a hypercalorific diet (16% fat, 33% sugar) for six weeks prior to mating and throughout pregnancy and lactation. Female offspring were cross-fostered for suckling to dams on the same or opposite diet to yield four groups: offspring of lean suckled by lean dams (n=6), offspring of obese suckled by obese dams (n=6), offspring of lean suckled by obese dams (n=5) and offspring of obese suckled by lean dams (n=6). All offspring were weaned onto a standard chow diet at 21 days and sacrificed at 3 months post-partum for tissue collection.. Offspring subjected to an adverse suckling environment showed significant increases in body weight, pancreatic triglyceride content, TGF-beta, collagen gene expression and SBP at rest along with an enhanced restraint stress response, indicating a dysmetabolic and NAFPD phenotype.. Developmental programming is involved in the pathogenesis of NAFPD and appears to be largely dependent on an adverse extra-uterine environment.

Topics: Animals; Animals, Suckling; Blood Pressure; Body Weight; Collagen Type I; Fatty Acids; Female; Mice; Mice, Inbred C57BL; Obesity; Pancreatic Diseases; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Sympathetic Nervous System; Transforming Growth Factor beta

Transforming growth factors betas (TGF-betas) are implicated in pancreatic tissue repair but their role in acute pancreatitis is not known. To determine whether endogenous TGF-betas modulate the course of caerulein induced acute pancreatitis, caerulein was administered to wild-type (FVB-/-) and transgenic mice that are heterozygous (FVB+/-) for expression of a dominant negative type II TGF-beta receptor.. After 7 hourly supramaximal injections of caerulein, the pancreas was evaluated histologically and serum was assayed for amylase and lipase levels. Next, the effects of caerulein on amylase secretion were determined in mouse pancreatic acini, and cholecystokinin (CCK) receptor expression was assessed.. The normal mouse pancreas was devoid of inflammatory cells whereas the pancreas from transgenic mice contained lymphocytic infiltrates. Caerulein injection in wild-type mice resulted in 6- and 36-fold increases in serum amylase and lipase levels, respectively, increased serum trypsinogen activation peptide (TAP) levels, gross oedema and a marked inflammatory response in the pancreas that consisted mainly of neutrophils and macrophages. By contrast, FVB+/- mice exhibited minimal alterations in response to caerulein with attenuated neutrophil-macrophage infiltrates. Moreover, acini from FVB+/- mice did not exhibit restricted stimulation at high caerulein concentrations, even though CCK receptor mRNA levels were not decreased.. Our findings indicate that a functional TGF-beta signalling pathway may be required for caerulein to induce acute pancreatitis and for the CCK receptor to induce acinar cell damage at high ligand concentrations. Our results also support the concept that restricted stimulation at high caerulein concentrations contributes to the ability of caerulein to induce acute pancreatitis.

Topics: Acute Disease; Amylases; Animals; Blotting, Northern; Ceruletide; Edema; Ligands; Lipase; Mice; Mice, Transgenic; Oligopeptides; Pancreatic Diseases; Pancreatitis; Receptors, Cholecystokinin; Severity of Illness Index; Signal Transduction; Transforming Growth Factor beta

Cytokine concentration in pancreatic juice of patients with pancreatic disease is unknown. Secretin stimulation allows endoscopic collection of pancreatic juice secreted into the duodenum. We aimed to evaluate the cytokine concentrations in pancreatic juice of patients with abdominal pain to discriminate presence from absence of pancreatic disease.. From January 2003-December 2004, consecutive patients with abdominal pain compatible with pancreatic origin were enrolled. Patients underwent upper endoscopy. Intravenous secretin (0.2 mug/kg) was given immediately before scope intubation. Pancreatic juice collected from the duodenum was immediately snap-frozen in liquid nitrogen until assays were performed. Pancreatic juice levels of interleukin-8, interleukin-6, intercellular adhesion molecule 1, and transforming growth factor-beta 1 were measured by modified enzyme-linked immunosorbent assays. The final diagnosis was made by the primary gastroenterologist on the basis of medical history; laboratory, endoscopic, and imaging studies; and clinical follow-up. Fisher exact test and Kruskal-Wallis rank sum test were used for statistical analysis.. Of 130 patients screened, 118 met the inclusion criteria. Multivariate analysis revealed that only interleukin-8 was able to discriminate between normal pancreas and chronic pancreatitis (P = .011), pancreatic cancer (P = .044), and the presence of pancreatic diseases (P = .007). Individual cytokine concentrations were not significantly different in chronic pancreatitis compared with pancreatic cancer.. Cytokine levels can be measured in pancreatic juice obtained from the duodenum without direct cannulation of the pancreatic duct. Interleukin-8 concentration in pancreatic juice can be used to discriminate between normal pancreas and patients with pancreatic disease. This is a relatively simple and noninvasive method to aid in the diagnosis of pancreatic diseases.

Topics: Abdominal Pain; Adult; Aged; Aged, 80 and over; Biomarkers; Cytokines; Diagnosis, Differential; Endoscopy, Gastrointestinal; Female; Humans; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Lipase; Male; Middle Aged; Pancreatic Diseases; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis, Chronic; Secretin; Transforming Growth Factor beta

To study the effect of emodin on pancreatic fibrosis and potential mechanism thereof.. Fifty SD rats were randomly divided into 5 equal groups: normal control group, model control group, low-dose emodin-treated group, mediate-dose emodin-treated group, and high-dose emodin-treated group. The rats of the latter 4 groups underwent infusion of trinitrobenzene sulfonic acid (TNBS) into the pancreatic duct so as to establish models of pancreatic fibrosis. The emodin-treated rats were fed with different doses of emodin (20, 40, and 80 mg/kg body weight), while the normal and model control groups received 0.9% sodium chloride solution instead. Twenty-eight days later the rats were killed, blood samples were collected, and their pancreases were taken out. The serum levels of hyaluronic acid (HA) and laminin (LN) were determined by radioimmunoassay. The histopathological alterations were studied by optical microscopy. The expression of collagen was examined by Van Gieson staining. Western blotting was used to detect the protein expression of transforming growth factor-beta(1) (TGF-beta(1)).. (1) The serum level of HA of the low-dose, mediate-dose, and high-dose emodin-treated groups were 87 microg/L +/- 22 microg/L, 78 microg/L +/- 25 microg/L, and 62 microg/L +/- 19 microg/L respectively, all significantly lower than that of the model control group (113 microg/L +/- 27 microg/L, P < 0.05 or < 0.01). The serum levels of laminin in the low-dose, mediate-dose, and high-dose emodin-treated groups were 67 microg/L +/- 14 microg/L, 57 microg/L +/- 12 microg/L, and 44 microg/L +/- 10 microg/L respectively, all significantly lower than that of the model control group (86 microg/L +/- 17 microg/L, P < 0.05 or P < 0.01); (2) The degrees of fibrosis of the emodin-treated groups were obviously ameliorated in comparison with the model control group, the higher the dose of emodin the more improved the pathological changes, especially in the high-dose emodin-treated group (P < 0.05). (3) The percentages of collagen positive cells of the low-dose, mediate-dose, and high-dose emodin-treated groups were 39% +/- 7%, 38% +/- 4%, and 36% +/- 5% respectively, all lower than that of the model control group (42% +/- 6%), with a significant difference between the high-dose emodin-treated group and the model control group (P < 0.05). (4) The protein content of TGF-beta(1) of the low-dose, mediate-dose, and high-dose emodin-treated groups were 44.3% +/- 2.1%, 39.2% +/- 1.8%, and 28.8% +/- 1.6% respectively, all significantly lower than that of the model control group (60.7% +/- 1.7%, all P < 0.05), and the protein content of TGF-beta(1) of the high-dose emodin-treated group was significantly lower than those of the other 2 emodin-treated groups (both P < 0.05).. Emoidn has an anti-fibrosis effect on pancreatic fibrosis, which maybe related to the content of TGF-beta(1) protein.

Topics: Animals; Blotting, Western; Collagen; Disease Models, Animal; Dose-Response Relationship, Drug; Emodin; Fibrosis; Hyaluronic Acid; Laminin; Male; Pancreas; Pancreatic Diseases; Phytotherapy; Radioimmunoassay; Random Allocation; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta; Trinitrobenzenesulfonic Acid

Rosiglitazone (RGTZ) has protective effect against various types of injury. This study was performed to evaluate the effect of RGTZ on pancreatic and renal injury caused by cyclosporine (CsA). CsA (15 mg/kg) and RGTZ (3 mg/kg) were administered alone and together to the rats for 28 days. The effect of RGTZ on CsA-induced pancreatic injury was evaluated by intraperitoneal glucose tolerance test (IPGTT), plasma insulin concentrations and pancreatic beta-cell morphology. The effect of RGTZ on CsA-induced renal injury was evaluated by assessing renal function and pathology; mediators of inflammation and fibrosis such as angiotensin II (AngII), osteopontin (OPN) and transforming growth factor-beta1 (TGF-beta1) and apoptotic cell death. Four weeks of CsA treatment caused diabetes, renal dysfunction, typical pathologic lesions (arteriolopathy, interstitial fibrosis and inflammatory cells infiltration) and apoptotic cell death. RGTZ treatment decreased blood glucose concentration, increased plasma insulin concentration and preserved pancreatic beta islet mass. RGTZ treatment improved renal function and histopathology. Pro-inflammatory and pro-fibrotic molecules such as AngII, OPN and TGF-beta1, and apoptotic cell death also decreased with RGTZ treatment. These data suggest that RGTZ has a protective effect against CsA-induced pancreatic and renal injury.

Topics: Angiotensin II; Animals; Apoptosis; Cyclosporine; Diabetes Mellitus, Experimental; Glucose Tolerance Test; Hypoglycemic Agents; Immunosuppressive Agents; Insulin; Islets of Langerhans; Kidney; Osteopontin; Pancreatic Diseases; Rats; Rats, Sprague-Dawley; Rosiglitazone; Sialoglycoproteins; Thiazolidinediones; Transforming Growth Factor beta; Transforming Growth Factor beta1

The renin-angiotensin system (RAS) plays important roles in various pathophysiological processes. However, the role of the RAS in pancreatic fibrosis has not been established. We investigated the role of angiotensin II (ANG II)-ANG II type 1 (AT(1)) receptor pathway in the development of pancreatic fibrosis with AT(1a) receptor-deficient [AT(1a)(-/-)] mice. To induce pancreatic fibrosis, AT(1a)(-/-) and wild-type (WT) mice were submitted to three episodes of acute pancreatitis induced by six intraperitoneal injections of 50 microg/kg body wt cerulein at hourly intervals, per week, for four consecutive weeks. Pancreatic fibrosis was assessed by histology and hydroxyproline content. Pancreatic stellate cell (PSC) activation and the localization of AT(1) receptors were assessed by Western blot analysis for alpha-smooth muscle actin and immunostaining. Transforming growth factor-beta(1) (TGF-beta(1)) mRNA expression in the pancreas was assessed by RT-PCR. Six intraperitoneal injections of cerulein induced acute pancreatitis in both AT(1a)(-/-) and WT mice. There were no significant differences between two groups with regard to serum amylase and histological changes. Pancreatic fibrosis induced by repeated episodes of acute pancreatitis was significantly attenuated in AT(1a)(-/-) mice compared with that in WT mice. This finding was accompanied by a reduction of activated PSCs. Dual-immunofluorescence staining in WT mice revealed that activated PSCs express AT(1) receptors. The level of TGF-beta(1) mRNA was lower in AT(1a)(-/-) mice than in WT mice. Our results demonstrate that the ANG II-AT(1) receptor pathway is not essential for the local pancreatic injury in acute pancreatitis but plays an important role in the development of pancreatic fibrosis through PSC activation and proliferation.

Topics: Animals; Ceruletide; Fibrosis; Hydroxyproline; Mice; Mice, Inbred C57BL; Mice, Knockout; Pancreas; Pancreatic Diseases; Protein Isoforms; Receptor, Angiotensin, Type 1; Recurrence; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1

Transforming growth factor-beta (TGF-beta) is an important cytokine in the fibrogenesis in many organs, including the pancreas. Using an adenoviral vector expressing the entire extracellular domain of type II human TGF-beta receptor (AdTbeta-ExR), we investigated whether inhibition of TGF-beta action is effective against persistent pancreatic fibrosis, and whether it exerts a beneficial effect on the pancreas in the process of chronic injury. To induce chronic pancreatic injury and pancreatic fibrosis, mice were subjected to three episodes of acute pancreatitis induced by six intraperitoneal injections of 50 microg/kg body weight cerulein at hourly intervals, per week for 3 consecutive weeks. Mice were infected once with AdTbeta-ExR, or with a control adenoviral vector expressing bacterial beta-galactosidase (AdLacZ). Pancreatic fibrosis was evaluated by histology and hydroxyproline content. Activation of pancreatic stellate cells (PSCs) was assessed by immunostaining for alpha-smooth muscle actin. Apoptosis and proliferation of acinar cells were assessed by immunostaining of ssDNA and Ki-67, respectively. Three-week cerulein injection induced pancreatic fibrosis and pancreatic atrophy with proliferation of activated PSCs. In AdTbeta-ExR-injected mice, but not AdLacZ-injected mice, pancreatic fibrosis was significantly attenuated. This finding was accompanied by a reduction of activated PSCs. AdTbeta-ExR, but not AdLacZ, significantly increased pancreas weight after chronic pancreatic injury. AdTbeta-ExR did not change the proportion of proliferating acinar cells, whereas it reduced the number of apoptotic acinar cells. Our results demonstrate that inhibition of TGF-beta action not only decreases pancreatic fibrosis but also protects the pancreas against chronic injury by preventing acinar cell apoptosis.

Topics: Animals; Ceruletide; Chronic Disease; Disease Models, Animal; Fibrosis; Male; Mice; Mice, Inbred BALB C; Mice, Transgenic; Pancreatic Diseases; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta