Li Jiao1,2, Johannes Inhoffen2, Hongying Gan-Schreier2, Sabine Tuma-Kellner2, Wolfgang Stremmel2, Zhiwei Sun3, Walee Chamulitrat4. 1. Department of Toxicology, School of Public Health, Jilin University, Changchun, China. 2. Department of Internal Medicine IV, University of Heidelberg Hospital, Heidelberg, Germany. 3. Department of Toxicology, School of Public Health, Jilin University, Changchun, China. zwsun@hotmail.com. 4. Department of Internal Medicine IV, University of Heidelberg Hospital, Heidelberg, Germany. Walee.Chamulitrat@med.uni-heidelberg.de.
Abstract
BACKGROUND: Inflammatory bowel disease results from a combination of dysfunction of intestinal epithelial barrier and dysregulation of mucosal immune system. iPLA2β has multiple homeostatic functions and shown to play a role in membrane remodeling, cell proliferation, monocyte chemotaxis, and apoptosis. The latter may render chronic inflammation and susceptibility for acute injury. AIMS: We aim to evaluate whether an inactivation of iPLA2β would enhance the pathogenesis of experimental colitis induced by dextran sodium sulfate. METHODS: iPLA2β-null male mice were administered dextran sodium sulfate in drinking water for 7 days followed by normal water for 3 days. At day 10, mice were killed, and harvested colon and ileum were subjected for evaluation by histology, immunohistochemistry, and quantitative RT-PCR. RESULTS: Dextran sodium sulfate administration caused a significant increase in histological scores and cleaved caspase 3 (+) apoptosis concomitant with a decrease in colon length and crypt cell Ki67 (+) proliferation in iPLA2β-null mice in a greater extent than in control littermates. This sensitization by iPLA2β deficiency was associated with an increase in accumulation of F4/80 (+) macrophages, and expression of proinflammatory cytokines and chemokines, while the number of mucin-containing goblet cells and mucus layer thickness was decreased. Some of these abnormalities were also observed in the ileum. CONCLUSIONS: An inactivation of iPLA2β exacerbated pathogenesis of experimental colitis by promoting intestinal epithelial cell apoptosis, inhibiting crypt cell regeneration, and causing damage to mucus barrier allowing an activation of innate immune response. Thus, iPLA2β may represent a susceptible gene for the development of inflammatory bowel disease.
BACKGROUND:Inflammatory bowel disease results from a combination of dysfunction of intestinal epithelial barrier and dysregulation of mucosal immune system. iPLA2β has multiple homeostatic functions and shown to play a role in membrane remodeling, cell proliferation, monocyte chemotaxis, and apoptosis. The latter may render chronic inflammation and susceptibility for acute injury. AIMS: We aim to evaluate whether an inactivation of iPLA2β would enhance the pathogenesis of experimental colitis induced by dextran sodium sulfate. METHODS: iPLA2β-null male mice were administered dextran sodium sulfate in drinking water for 7 days followed by normal water for 3 days. At day 10, mice were killed, and harvested colon and ileum were subjected for evaluation by histology, immunohistochemistry, and quantitative RT-PCR. RESULTS:Dextran sodium sulfate administration caused a significant increase in histological scores and cleaved caspase 3 (+) apoptosis concomitant with a decrease in colon length and crypt cell Ki67 (+) proliferation in iPLA2β-null mice in a greater extent than in control littermates. This sensitization by iPLA2β deficiency was associated with an increase in accumulation of F4/80 (+) macrophages, and expression of proinflammatory cytokines and chemokines, while the number of mucin-containing goblet cells and mucus layer thickness was decreased. Some of these abnormalities were also observed in the ileum. CONCLUSIONS: An inactivation of iPLA2β exacerbated pathogenesis of experimental colitis by promoting intestinal epithelial cell apoptosis, inhibiting crypt cell regeneration, and causing damage to mucus barrier allowing an activation of innate immune response. Thus, iPLA2β may represent a susceptible gene for the development of inflammatory bowel disease.
Authors: L A Dieleman; M J Palmen; H Akol; E Bloemena; A S Peña; S G Meuwissen; E P Van Rees Journal: Clin Exp Immunol Date: 1998-12 Impact factor: 4.330