Colonic epithelial functional phenotype varies with type and phase of experimental colitis.
OBJECTIVE
Colonic crypt elongation occurs during both chronic colitis and in the recovery phase of acute colitis. The impact of these alterations on epithelial cell functions is not fully defined.


METHODS
DNA microarray analysis of freshly isolated colonic epithelial cells (CECs) from acute and chronic colitis was performed, and the results were confirmed by reverse transcription polymerase chain reaction. Localization of the selected molecules was examined by immunohistochemistry using newly generated antibodies. The function of selected molecules detected in this study was examined by administering the specific inhibitors in dextran sodium sulfate (DSS) colitis.


RESULTS
Several detoxification-associated molecules, which contribute to prevent inflammation by regulating physiological balance under normal conditions, were markedly down-regulated, and anti-inflammatory molecules, which are not normally expressed, were up-regulated in the CEC under the chronic colitis. Among the detoxification-associated molecules, carbonic anhydrase IV was specifically down-regulated in CEC of Th2- but not Th1-mediated colitis. Functionally, inhibition of carbonic anhydrase activity led to the enhancement of recovery from DSS-induced acute colitis by directly stimulating CEC proliferation. Increased expression of regeneration-associated molecules such as regenerating gene-III gamma was detectable in the CEC of acute and chronic colitis but not in the recovery phase of colitis. The expression of this molecule was restricted in surface epithelium and upper crypts but not lower crypts.


CONCLUSIONS
These studies suggest that functional alterations, which result in either the exacerbation or the suppression of colitis, coexist in the CEC during chronic colitis. CEC functions are likely to be differentially regulated in the context of the stage and mechanism of colitis.
Mizoguchi
Emiko
E
Center for the Study of Inflammatory Bowel Diseases and Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, USA. emizoguchi@partners.org
Xavier
Ramnik J
RJ
Reinecker
Hans-Christian
HC
Uchino
Hirofumi
H
Bhan
Atul K
AK
Podolsky
Daniel K
DK
Mizoguchi
Atsushi
A
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D002908:Chronic Disease; D003092:Colitis / Q000276:immunology* / Q000503:physiopathology*; D003106:Colon / Q000502:physiology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D015870:Gene Expression / Q000276:immunology; D018398:Homeodomain Proteins / Q000235:genetics; D015212:Inflammatory Bowel Diseases / Q000276:immunology / Q000503:physiopathology; D016753:Interleukin-10 / Q000235:genetics; D007413:Intestinal Mucosa / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics
D018398:Homeodomain Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; C064658:RAG-1 protein; D016753:Interleukin-10