epidermal-growth-factor and Crohn-Disease

The inflammatory bowel diseases known as Crohn's disease (CD) and ulcerative colitis (UC) are related autoimmune conditions with a complex etiology composed of genetic and environmental factors. Genetic studies have revealed 200 susceptibility loci for inflammatory bowel diseases, but these only account for a small fraction of the genetic heritability of the disease. We employed pathway-based approaches to identify genes that cooperatively make contributions to the genetic etiology of CD.. We exploited the largest CD dataset (20,000 cases + 28,000 controls) and UC dataset (17,000 cases + 33,500 controls) to date. We conducted a meta-analysis of 5 CD cohorts of European ancestry using 3 pathway-based approaches and further performed replication studies in an independent cohort genotyped on the Immunochip and in another pediatric cohort of European ancestry. Similar meta-analysis was performed for UC cohorts.. In addition to the multiple immune-related pathways that have been implicated in the genetic etiology of inflammatory bowel diseases before, we found significant associations involving genes in growth factor signaling for CD. This result was replicated in 2 independent cohorts of European ancestry. This association with growth factor activity is not unique to CD. We found a similar significant association with UC cohorts.. Our findings suggest that genes involved in pathways of growth factor signaling may make joint contributions to the etiology of CD and UC, providing novel insight into the genetic mechanisms of these diseases.

Topics: Autoimmune Diseases; Colitis, Ulcerative; Crohn Disease; Cytokines; Databases, Genetic; Epidermal Growth Factor; Gene Ontology; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Intercellular Signaling Peptides and Proteins; Protein Interaction Domains and Motifs; Protein Interaction Mapping; Quantitative Trait Loci; Receptors, Cytokine; Signal Transduction; STAT Transcription Factors; White People

Epidermal growth factor (EGF) is a multipotent peptide which contributes to epithelial development, inhibition of gastric acid secretion, acceleration of wound healing, and promotion of angiogenesis. The aim of this study is to evaluate serum EGF concentrations in inflammatory bowel disease (IBD) patients, with regard to disease and patients' characteristics.. EGF determination was performed by a commercially available enzyme-linked immunosorbent assay. Fifty-two patients with ulcerative colitis (UC), 59 with Crohn's disease (CD), and 55 healthy controls (HC) were included in the study.. Mean ( ± SEM) serum EGF levels were 217.2 ( ± 30.40) pg/mL in UC patients, 324.6 ( ± 37.29) pg/mL in CD patients, and 453.1 ( ± 39.44) pg/mL in HC. Serum EGF levels were significantly lower in UC and CD patients compared to HC (P < 0.0001 and P = 0.0199, respectively). Lower serum EGF levels were observed in UC compared to CD patients (P = 0.0277). Extent of the disease was found to affect serum EGF levels in UC, demonstrating significant reduction in patients with left-sided colitis and pancolitis in comparison with those with proctitis (P = 0.0190 and P = 0.0024, respectively). EGF concentration was not influenced by other characteristics of patients and disease.. Significantly, lower levels of serum EGF are observed in IBD patients compared to HC, while disease extent plays a key role in regulation of serum EGF in UC. Downregulation of serum EGF may be correlated with different patterns of bowel inflammation, epithelial development, and wound healing in IBD.

Topics: Adolescent; Adult; Aged; Biomarkers; Colitis, Ulcerative; Crohn Disease; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Female; Gastrointestinal Tract; Greece; Humans; Intestinal Mucosa; Male; Middle Aged

Ulceration anywhere in the gastrointestinal tract induces a novel cell lineage, which grows from the bases of existing crypts, ramifies to form a new gland, and ultimately emerges onto the mucosal surface. The lineage produces neutral mucin, shows a unique lectin-binding profile and immunophenotype, and secretes abundant immunoreactive epidermal growth factor/urogastrone (EGF/URO). All gastrointestinal stem cells can produce this cell lineage following mucosal ulceration, secreting EGF/URO to stimulate cell proliferation, regeneration and ulcer healing. This cell lineage is very commonly associated with gastrointestinal ulceration, and we propose that a major in vivo role for EGF/URO is to stimulate ulcer healing throughout the gut via induction of this cell lineage in the adjacent mucosa. EGF/URO should therefore be assessed in the conservative management of inflammatory bowel disease.

Topics: Crohn Disease; Epidermal Growth Factor; Gastric Mucosa; Humans; Immunoenzyme Techniques; Intestinal Mucosa; Peptic Ulcer; Stem Cells; Wound Healing

The pS2 gene encodes for a small cysteine-rich protein, and was originally found by differential screening of a cDNA library from the human breast carcinoma cell line, MCF-7. The presence of pS2 is closely correlated with oestrogen dependence in breast carcinomas. While the function of pS2 is unknown, pS2 protein has been shown to be homologous with the gastrointestinal peptide hormone pancreatic spasmolytic polypeptide (PSP) and its human counterpart hSP, in which a 5-cysteine domain is tandemly repeated. The 5' flanking region of the pS2 gene contains an enhancer region responsive to oestrogens and to epidermal growth factor (EGF/URO). We now report that pS2 and hSP expression occurs in a wide range of endodermally-derived tissues, including the duodenum, the pancreas, and in a recently defined cell lineage associated with chronic gastrointestinal ulceration. In each case, this expression was associated with secretion of immunoreactive EGF/URO. We further show that the co-expression of pS2 and hSP in gastric surface epithelial cells is also associated with the secretion of EGF/URO in the subjacent mucous neck cells. Our results indicate that local EGF/URO secretion induces pS2 and hSP in adjacent cells, and that these molecules are then available to participate in pathophysiological responses. The finding of similar patterns of EGF/URO, hSP and pS2 expression in association with chronic damage suggests that this is a fundamental response in the healing of these tissues.

Topics: Cell Line; Crohn Disease; Epidermal Growth Factor; Estrogens; Gastric Mucosa; Gene Expression Regulation; Humans; Intercellular Signaling Peptides and Proteins; Intestinal Mucosa; Intestine, Small; Mucins; Muscle Proteins; Neoplasm Proteins; Neuropeptides; Pancreatic Ducts; Pancreatitis; Peptic Ulcer; Peptide Biosynthesis; Peptides; Proteins; RNA, Messenger; Trefoil Factor-1; Trefoil Factor-2; Trefoil Factor-3; Tumor Suppressor Proteins

Epidermal growth factor, and its human homologue urogastrone (EGF/URO), are secreted by the gut-associated salivary and Brunner's glands. Recombinant EGF/URO is a powerful stimulator of cell proliferation and differentiation in the rodent and neonatal human intestine. But EGF/URO is not absorbed from the adult gut and has no action when given through the gut lumen; thus the role of secreted EGF/URO is unknown. We now report that ulceration of the epithelium anywhere in the human gastrointestinal tract induces the development of a novel cell lineage from gastrointestinal stem cells. This lineage initially appears as a bud from the base of intestinal crypts, adjacent to the ulcer, and grows locally as a tubule, ramifying to form a new small gland, and ultimately emerges onto the mucosal surface. The lineage produces neutral mucin, shows a unique lectin-binding profile and immunophenotype, is nonproliferative, and contains and secretes abundant immunoreactive EGF/URO. We propose that all gastrointestinal stem cells can produce this cell lineage after mucosal ulceration, secreting EGF/URO to stimulate cell proliferation, regeneration and ulcer healing. This cell lineage is very commonly associated with gastrointestinal mucosal ulceration, and we conclude that a principal in vivo role for EGF/URO is to stimulate ulcer healing throughout the gut through induction of this cell lineage in the adjacent mucosa.

Topics: Crohn Disease; Epidermal Growth Factor; Histocytochemistry; Humans; Intestinal Mucosa; Metaplasia; Mucins; Peptic Ulcer