Intestinal inflammation reduces expression of DRA, a transporter responsible for congenital chloride diarrhea.
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/beta2m 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/beta2m 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-1beta 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.
Yang
H
H
Department of Internal Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Jiang
W
W
Furth
E E
EE
Wen
X
X
Katz
J P
JP
Sellon
R K
RK
Silberg
D G
DG
Antalis
T M
TM
Schweinfest
C W
CW
Wu
G D
GD
D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics; D017920:Antiporters; D018938:Caco-2 Cells / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D027963:Chloride-Bicarbonate Antiporters; D002712:Chlorides / Q000378:metabolism; D003092:Colitis / Q000235:genetics* / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000378:metabolism; D003967:Diarrhea / Q000151:congenital / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D015796:HLA-B27 Antigen / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D000076988:Sulfate Transporters; D001613:beta 2-Microglobulin / Q000235:genetics
D017920:Antiporters; D002352:Carrier Proteins; D027963:Chloride-Bicarbonate Antiporters; D002712:Chlorides; D015796:HLA-B27 Antigen; D008565:Membrane Proteins; D012333:RNA, Messenger; C081011:SLC26A3 protein, human; C489860:Slc26a3 protein, mouse; C489861:Slc26a3 protein, rat; D000076988:Sulfate Transporters; D001613:beta 2-Microglobulin