Keratin-8-deficient mice develop chronic spontaneous Th2 colitis amenable to antibiotic treatment

A1 Journal article (refereed)


Internal Authors/Editors


Publication Details

List of Authors: Habtezion A, Toivola DM, Butcher EC, Omary MB
Publisher: COMPANY BIOLOGISTS LTD
Publication year: 2005
Journal: Journal of Cell Science
Journal acronym: J CELL SCI
Volume number: 118
Start page: 1971
End page: 1980
Number of pages: 10
ISSN: 0021-9533


Abstract

Keratin 8 (K8) is the major intermediate filament protein present in intestinal epithelia. Depending on the mouse genetic background, absence of K8 causes embryonic lethality or colonic hyperplasia and colitis. We studied disease progression, the inflammatory responses, and role of luminal bacteria in K8-null mice in order to characterize the intestinal pathology of K8-associated colitis. Colon lymphocytes were isolated for analysis of their phenotype and cytokine production, and vascular and lymphocyte adhesion molecule expression in K8-/- mice of varying ages. K8-/- mice had a marked increase in TCR beta-positive/CD4-positive T cells infiltrating the colon lamina propria, in association with enhanced Th2 cytokine (IL-4, IL-5 and IL-13) production. K8-/- mice show early signs of inflammation even prior to weaning, that increases with age, and their epithelial cells overexpress MHC class II antigens. The chronic colitis is related to increased CD4-positive infiltrating T cells displaying memory and naive phenotypes, and an altered vascular endothelium with aberrant expression of peripheral node addressin. Analysis of normal gut-specific homing molecules, reveals an increased number Of alpha(4)beta(7)-positive cells and vascular mucosal addressin cell adhesion molecule-1 in K8-null colons. Antibiotic treatment markedly decreased colon inflammation and ion transporter AE1/2 mistargeting, indicating that luminal bacteria play an important role in the observed phenotype. Therefore, K8-null mice develop chronic spontaneous Th2-type colitis due to a primary epithelial rather than immune cell defect, which is amenable to antibiotic therapy. These mice provide a model to investigate epithelial-leukocyte and epithelial-microbial cross-talk.


Keywords

colitis, inflammatory bowel disease, intermediate filaments, Th2 cytokine

Last updated on 2019-19-06 at 05:37