transforming-growth-factor-beta and Gastroenteritis

Inflammation is a primary defense process against various extracellular stimuli, such as viruses, pathogens, foods, and environmental pollutants. When cells respond to stimuli for short periods of time, it results in acute or physiological inflammation. However, if the stimulation is sustained for longer time or a pathological state occurs, it is known as chronic or pathological inflammation. Several studies have shown that tumorigenesis in the gastrointestinal (GI) tract is closely associated with chronic inflammation, for which abnormal cellular alterations that accompany chronic inflammation such as oxidative stresses, gene mutations, epigenetic changes, and inflammatory cytokines, are shared with carcinogenic processes, which forms a critical cross-link between chronic inflammation and carcinogenesis. Transforming growth factor (TGF)-beta is a multi-potent cytokine that plays an important role in regulation of cell growth, apoptosis and differentiation. Most importantly, TGF-beta is a strong anti-inflammatory cytokine that regulates the development of effector cells. TGF-beta has a suppressive effect on carcinogenesis under normal conditions by inhibiting abnormal cell growth, but on the other hand, many GI cancers originate from uncontrolled cell growth and differentiation by genetic loss of TGF-beta signaling molecules or perturbation of TGF-beta adaptors. Once a tumor has developed, TGF-beta exerts a promoting effect on the tumor itself and stromal cells to enhance cell growth, alter the responsiveness of tumor cells to stimulate invasion and metastasis, and inhibited immune surveillance. Therefore, novel development of therapeutic agents to inhibit TGF-beta-induced progression of tumor and to retain its growth inhibitory activities, in addition to anti-inflammatory actions, could be useful in oncology. In this review, we discuss the role of TGF-beta in inflammation and carcinogenesis of the GI tract related to abnormal TGF-beta signaling.

Topics: Animals; Colorectal Neoplasms; Esophageal Neoplasms; Esophagitis, Peptic; Gastritis, Atrophic; Gastroenteritis; Gastrointestinal Neoplasms; Homeostasis; Humans; Inflammation Mediators; Inflammatory Bowel Diseases; Ligands; Pancreatic Neoplasms; Pancreatitis, Chronic; Signal Transduction; Stomach Neoplasms; Transforming Growth Factor beta

Immaturity of gut-associated immunity may contribute to pediatric mortality associated with enteric infections. A murine model to parallel infantile enteric disease was used to determine the effects of probiotic, Lactobacillus acidophilus (La), prebiotic, inulin, or both (synbiotic, syn) on pathogen-induced inflammatory responses, NF-κB, and Smad 7 signaling. Newborn mice were inoculated bi-weekly for 4 weeks with La, inulin, or syn and challenged with Citrobacter rodentium (Cr) at 5 weeks. Mouse intestinal epithelial cells (CMT93) were exposed to Cr to determine temporal alterations in NF-Kappa B and Smad 7 levels. Mice with pretreatment of La, inulin, and syn show reduced intestinal inflammation following Cr infection compared with controls, which is associated with significantly reduced bacterial colonization in La, inulin, and syn animals. Our results further show that host defense against Cr infection correlated with enhanced colonic IL-10 and transforming growth factor-β expression and inhibition of NF-κB in syn-treated mice, whereas mice pretreated with syn, La, or inulin had attenuation of Cr-induced Smad 7 expression. There was a temporal Smad 7 and NF-κB intracellular accumulation post-Cr infection and post-tumor necrosis factor stimulation in CMT93 cells. These results, therefore, suggest that probiotic, La, prebiotic inulin, or synbiotic may promote host-protective immunity and attenuate Cr-induced intestinal inflammation through mechanisms affecting NF-κB and Smad 7 signaling.

Topics: Animals; Animals, Newborn; Cell Line; Citrobacter rodentium; Enterobacteriaceae Infections; Epithelial Cells; Gastroenteritis; Gene Expression Regulation; Interleukin-10; Intestines; Inulin; Lactobacillus acidophilus; Mice; NF-kappa B; Prebiotics; Probiotics; Signal Transduction; Smad7 Protein; Transforming Growth Factor beta

Children with acute RV-gastroenteritis (GE) had low or undetectable levels of circulating IFN-gamma(+), IL-13(+), IL-2(+), IL-10(+) or IL-17(+) RV-T cells. IFN-gamma(+) T cells and low frequencies of IL-10(+) and IL-2(+) CD4(+) T cells were found in adults with RV-GE during acute and convalescence phases, respectively. Circulating single IFN-gamma(+)>double IFN-gamma(+)/IL-2(+)>single IL-2(+)RV-CD4(+)T cells were observed in healthy adults. In this group, frequencies of IFN-gamma(+) RV-T cells increased after removing CD25(+)cells, blocking TGF-beta with its natural inhibitor, LAP, or inhibiting TGF-betaRI signalling pathway with ALK5i. The frequencies of IFN-gamma(+) RV-T cells were also incremented in PBMC depleted of CD25(+)cells and treated with ALK5i, suggesting that TGFbeta inhibition may be independent of Treg cells. The ALK5i effect was observed in adults but not in children with RV-GE, who had normal numbers of TGF-beta+ Treg cells. Thus, a TGF-beta-mediated regulatory mechanism that modulates RV-T cells in adults is not evident in children.

Topics: Adult; Age Factors; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Female; Gastroenteritis; Humans; Immunity, Cellular; Infant; Interferon-gamma; Interleukin-2; Lymphocyte Count; Male; Rotavirus; Rotavirus Infections; T-Lymphocytes; Transforming Growth Factor beta

Mouse models of intestinal inflammation resemble aspects of inflammatory bowel disease in humans. These models have provided important insights into mechanisms that control intestinal homeostasis and regulation of intestinal inflammation. This viewpoint discusses themes that have emerged from mouse models of intestinal inflammation including bacterial recognition, autophagy, the IL-23/Th-17 axis of inflammation as well as the role of negative regulators. Many of the pathways highlighted by model systems have been identified in recent genome-wide association studies in human validating the relevance of mouse models to human inflammatory bowel disease. Understanding of the complex biological mechanisms that lead to intestinal inflammation in mouse models may help to define targets for treatment of human diseases.

Topics: Animals; Bacteria; Disease Models, Animal; Gastroenteritis; Host-Pathogen Interactions; Humans; Inflammatory Bowel Diseases; Interleukin-10; Intestines; Mice; Models, Biological; Signal Transduction; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Acute gastroenteritis is a strong risk factor for the development of irritable bowel syndrome (IBS). We have developed an animal model in which transient acute infection leads to persistent muscle hypercontractility. Here, we investigate the mechanisms underlying the maintenance of this hypercontractility in the postinfective (PI) state.. Muscle contraction and messenger RNA (mRNA) or protein expression of cytokines were examined from jejunal longitudinal muscle cells of NIH Swiss mice infected with Trichinella spiralis or incubated with or without cytokines.. During acute infection, interleukin (IL)-4 or IL-13, transforming growth factor (TGF)-beta1, and cyclooxygenase (COX)-2 were increased in the muscle layer ( P < .05). In the PI phase of the model, T helper (Th)2 cytokines returned to normal, but TGF-beta1 remained in the muscle ( P < .05). Exposure of muscle cells to IL-4 or IL-13 increased TGF-beta1 ( P < .01), COX-2 protein, and prostaglandin (PG)E 2 . Exposure of muscle cells to TGF-beta1 increased PGE 2 ( P < .05) and COX-2 protein. Incubation of tissue with IL-4, IL-13, TGF-beta1, or PGE 2 enhanced carbachol-induced muscle cell contractility ( P < .05). COX-2 inhibitor attenuated TGF-beta1-induced muscle hypercontractility ( P < .05).. These results support the hypothesis that Th2 cytokines induce muscle hypercontractility during infection by a direct action on smooth muscle. The maintenance of hypercontractility results from Th2 cytokine-induced expression of TGF-beta1 and the subsequent up-regulation of COX-2 and PGE 2 at the level of the smooth muscle cell. We propose that PI gut dysfunction reflects mediator production in the neuromuscular tissues and that this may occur in PI-IBS.

Topics: Acute Disease; Animals; Carbachol; Cells, Cultured; Cholinergic Agonists; Chronic Disease; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Gastroenteritis; Gastrointestinal Motility; Interleukin-13; Interleukin-4; Irritable Bowel Syndrome; Male; Mice; Muscle Contraction; Muscle, Smooth; Polymerase Chain Reaction; Prostaglandin-Endoperoxide Synthases; Proteoglycans; Receptors, Interleukin-4; Receptors, Transforming Growth Factor beta; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1; Trichinella spiralis; Trichinellosis