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Departments of 1 Internal Medicine and 2 Pathology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; 3 University of North Carolina and Center for Gastrointestinal Biology and Disease, Chapel Hill, North Carolina 27599; 4 Molecular Oncology Laboratory, Queensland Cancer Fund Experimental Oncology Program, Queensland Institute of Medical Research, Brisbane, Queensland 4029, Australia; and 5 Center for Molecular and Structural Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29425
The pathogenesis of diarrhea in intestinal
inflammatory states is a multifactorial process involving the effects
of inflammatory mediators on epithelial transport function. The effect
of colonic inflammation on the gene expression of DRA (downregulated in
adenoma), a chloride-sulfate anion transporter that is mutated in
patients with congenital chloridorrhea, was examined in vivo as well as in an intestinal epithelial cell line. DRA mRNA expression was diminished five- to sevenfold in the HLA-B27/
2m transgenic rat compared with control. In situ hybridization showed that DRA, which is
normally expressed in the upper crypt and surface epithelium of the
colon, was dramatically reduced in the surface epithelium of the
HLA-B27/2m transgenic rat, the interleukin-10 (IL-10) knockout mouse
with spontaneous colitis, and in patients with ulcerative colitis.
Immunohistochemistry demonstrated that mRNA expression of DRA reflected
that of protein expression in vivo. IL-1 reduced DRA mRNA expression
in vitro by inhibiting gene transcription. The loss of transport
function in the surface epithelium of the colon by attenuation of
transporter gene expression, perhaps inhibited at the level of gene
transcription by proinflammatory cytokines, may play a role in the
pathogenesis of diarrhea in colitis.
electrolyte; Caco-2; colitis; transcription
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