guanosine-triphosphate and Crohn-Disease

Inflammatory bowel disease (IBD) including Crohn's disease and ulcerative colitis is often precipitated by an abnormal immune response to microbiota due to host genetic aberrancies. Recent studies highlight the importance of the host genome and microflora interactions in the pathogenesis of mucosal inflammation including IBD. Specifically, genome-wide (GWAS) and also next-generation sequencing (NGS)-including whole exome or genome sequencing-have uncovered a large number of susceptibility loci that predispose to autoimmune diseases and/or the two phenotypes of IBD. In addition, the generation of "IBD-prone" animal models using both reverse and forward genetic approaches has not only helped confirm the identification of susceptibility loci but also shed critical insight into the underlying molecular and cellular pathways that drive colitis development. In this review, we summarize recent findings derived from studies involving a novel early-onset model of colitis as it develops in GTPase of immunity-associated protein 5- (Gimap5-) deficient mice. In humans, GIMAP5 has been associated with autoimmune diseases although its function is poorly defined. Here, we discuss how defects in Gimap5 function impair immunological tolerance and lymphocyte survival and ultimately drive the development of CD4(+) T cell-mediated early-onset colitis.

Topics: Animals; Colitis, Ulcerative; Crohn Disease; Genetic Predisposition to Disease; Genome-Wide Association Study; GTP Phosphohydrolases; GTP-Binding Proteins; Guanosine Triphosphate; Homeostasis; Humans; Immunity; Inflammatory Bowel Diseases; Intestines; Mice; Mice, Transgenic; Peripheral Tolerance; Phenotype; Rats; T-Lymphocytes

In inflammatory bowel disease (IBD), large areas of apparently healthy mucosa lie adjacent to ulcerated intestine. Knowledge of the mechanisms that maintain remission in an otherwise inflamed intestine could provide important clues to the pathogenesis of this disease and provide rationale for clinical treatment strategies. We used kinome profiling to generate comprehensive descriptions of signal transduction pathways in inflamed and noninflamed colonic mucosa in a cohort of IBD patients, and compared the results to non-IBD controls. We observed that p21Rac1 guanosine triphosphatase (GTPase) signaling was strongly suppressed in noninflamed colonic mucosa in IBD. This suppression was due to both reduced guanine nucleotide exchange factor activity and increased intrinsic GTPase activity. Pharmacological p21Rac1 inhibition correlated with clinical improvement in IBD, and mechanistically unrelated pharmacological p21Rac1 inhibitors increased innate immune functions such as phagocytosis, bacterial killing, and interleukin-8 production in healthy controls and patients. Thus, suppression of p21Rac activity assists innate immunity in bactericidal activity and may induce remission in IBD.

Topics: Animals; Biopsy; Crohn Disease; Cyclin-Dependent Kinase Inhibitor p21; Down-Regulation; Enzyme Inhibitors; GTPase-Activating Proteins; Guanine Nucleotide Exchange Factors; Guanosine Diphosphate; Guanosine Triphosphate; Humans; Hydrolysis; Immunity, Innate; Inflammation; Intestinal Mucosa; Protein Kinases; rac1 GTP-Binding Protein; Remission Induction; Signal Transduction; Thioguanine

The role of colonic mucosal ornithine decarboxylase (ODC) in inflammatory bowel disease (IBD) remains controversial. This study assessed mucosal ODC activity in IBD patients segment by segment with regard to patient characteristics, disease activity/duration, medication, degree of mucosal inflammation, and presence/absence of epithelial regeneration and guanosine triphosphate (GTP) stimulation. Mucosal ODC activity was determined in biopsy specimens from the terminal ileum, cecum/ascending, transverse, and descending colon, and the sigmoid/rectum of 35 patients with IBD (18 with Crohn's disease, 17 with ulcerative colitis) and 29 controls, using the amount of 14CO2 liberated from (carboxyl-14C)ornithine hydrochloride. GTP-stimulatable activity was expressed as the ratio of ODC activity in the presence and absence of GTP (70 micromol/L). Mucosal inflammation was assessed endoscopically/microscopically with previously described criteria. Presence/absence of mucosal regeneration also was determined by predefined criteria. Mucosal ODC-activity did not significantly differ in IBD patients and controls. There was a 4.4-fold activity gradient from the ileum to the rectum. Mucosal ODC activity was significantly higher in areas with epithelial regeneration compared to those without regeneration, and was stimulated by GTP by a factor of 1.42 in Crohn's disease and 1.19 in ulcerative colitis patients compared to controls (p < 0.004). On the other hand, there was no significant association/relationship of mucosal ODC activity with disease activity/duration and the endoscopic/histologic degree of mucosal inflammation. The observation of unchanged mucosal ODC activity in patients with IBD and the absence of a significant relationship with clinical and endoscopic/histologic disease characteristics speaks against a major role of ODC in IBD as a major disease marker. The role of the ileorectal gradient, the enhanced activity in areas with epithelial regeneration, and the GTP-stimulatable form, however, need further investigation with regard to a possible involvement in carcinogenesis in IBD.

Topics: Adult; Cecum; Colitis, Ulcerative; Colon; Colon, Sigmoid; Crohn Disease; Epithelium; Female; Guanosine Triphosphate; Humans; Ileum; Intestinal Mucosa; Male; Middle Aged; Ornithine Decarboxylase; Rectum; Regeneration