51. Suppression of p21Rac signaling and increased innate immunity mediate remission in Crohn's disease.
- Author
-
Parikh K, Zhou L, Somasundaram R, Fuhler GM, Deuring JJ, Blokzijl T, Regeling A, Kuipers EJ, Weersma RK, Nuij VJ, Alves M, Vogelaar L, Visser L, de Haar C, Krishnadath KK, van der Woude CJ, Dijkstra G, Faber KN, and Peppelenbosch MP
- Subjects
- Animals, Biopsy, Crohn Disease pathology, Cyclin-Dependent Kinase Inhibitor p21 antagonists & inhibitors, Down-Regulation, Enzyme Inhibitors pharmacology, GTPase-Activating Proteins metabolism, Guanine Nucleotide Exchange Factors metabolism, Guanosine Diphosphate metabolism, Guanosine Triphosphate metabolism, Humans, Hydrolysis, Inflammation pathology, Intestinal Mucosa pathology, Protein Kinases metabolism, Remission Induction, Thioguanine pharmacology, rac1 GTP-Binding Protein antagonists & inhibitors, Crohn Disease immunology, Crohn Disease metabolism, Cyclin-Dependent Kinase Inhibitor p21 metabolism, Immunity, Innate, Signal Transduction, rac1 GTP-Binding Protein metabolism
- Abstract
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.
- Published
- 2014
- Full Text
- View/download PDF