Colonic epithelial functional phenotype varies with type and phase of experimental colitis

Background & Aims: 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 CECs 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-IIIgamma was detectable in the CECs 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 CECs during chronic colitis. CEC functions are likely to be differentially regulated in the context of the stage and mechanism of colitis.