BACKGROUND & AIMS:
Inflammatory bowel disease (IBD) is a multifactorial disease thought to be caused by alterations in
epithelial function, innate and
adaptive immunity, and luminal microbiota. The specific role of
epithelial barrier function remains undefined, although increased activity of
intestinal epithelial myosin light chain kinase (
MLCK), which is the primary mechanism of
tumor necrosis factor-induced barrier dysfunction, occurs in human IBD. Our aim was to determine whether, in an intact
epithelium, primary
dysregulation of the
intestinal epithelial barrier by pathophysiologically relevant mechanisms can contribute to development of
colitis. METHODS: We developed
transgenic (Tg)
mice that express constitutively active
MLCK (CA-MLCK) specifically within
intestinal epithelia. Their physiology,
immune status, and susceptibility to disease were assessed and compared with non-Tg littermate controls. RESULTS: CA-MLCK Tg
mice demonstrated significant barrier loss but grew and gained weight normally and did not develop spontaneous disease. CA-MLCK Tg
mice did, however, develop
mucosal immune activation demonstrated by increased numbers of
lamina propria CD4(+)
lymphocytes, redistribution of
CD11c+cells, increased production of
interferon-gamma and
tumor necrosis factor, as well as increased expression of
epithelial major histocompatibility complex class I. When challenged with
CD4+
CD45+Rb(hi)
lymphocytes, Tg
mice developed an accelerated and more severe form of
colitis and had shorter survival times than non-Tg littermates. CONCLUSIONS: Primary pathophysiologically relevant
intestinal epithelial barrier dysfunction is insufficient to cause experimental
intestinal disease but can broadly activate
mucosal immune responses and accelerate the onset and severity of
immune-mediated colitis.
