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

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.

• Authors: Aida Habtezion, Diana M Toivola, Eugene C Butcher, M Bishr Omary
• Journal: Journal of cell science (J Cell Sci) Vol. 118 Issue Pt 9 Pg. 1971-80 (May 01 2005) ISSN: 0021-9533 [Print] England
• PMID: 15840656 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anti-Bacterial Agents
• Antigens, Surface
• CD4 Antigens
• CD8 Antigens
• Cell Adhesion Molecules
• Cytokines
• Immunoglobulins
• Integrins
• Interleukin-13
• Interleukin-5
• Ions
• L-selectin counter-receptors
• Madcam1 protein, mouse
• Membrane Proteins
• Mucoproteins
• Receptors, Antigen, T-Cell
• integrin alpha4beta7
• Interleukin-4
• Keratins

Topics

• Animals
• Anti-Bacterial Agents (pharmacology)
• Antigens, Surface (biosynthesis, metabolism)
• CD4 Antigens (biosynthesis)
• CD4-Positive T-Lymphocytes (cytology)
• CD8 Antigens (biosynthesis)
• Cell Adhesion Molecules
• Cell Membrane (metabolism)
• Colitis (genetics, immunology)
• Colon (immunology, pathology)
• Cytokines (metabolism)
• Disease Progression
• Endothelium, Vascular (metabolism, pathology)
• Epithelial Cells (pathology)
• Flow Cytometry
• Immunoglobulins (biosynthesis)
• Immunohistochemistry
• Inflammation
• Integrins (biosynthesis)
• Interleukin-13 (metabolism)
• Interleukin-4 (metabolism)
• Interleukin-5 (metabolism)
• Ions
• Keratins (chemistry, genetics, physiology)
• Lymphocytes (cytology, metabolism)
• Membrane Proteins (biosynthesis, metabolism)
• Mice
• Mice, Transgenic
• Microscopy, Fluorescence
• Models, Biological
• Mucoproteins (biosynthesis)
• Phenotype
• Protein Structure, Tertiary
• Receptors, Antigen, T-Cell (biosynthesis)
• Th2 Cells (immunology)
• Time Factors