Expression of the regenerating gene family in inflammatory bowel disease mucosa: Reg Iα upregulation, processing, and antiapoptotic activity

Background: The pathophysiology of inflammatory bowel disease (IBD) reflects a balance between mucosal injury related to an ongoing inflammatory process and mucosal reparative mechanisms. Proreparative mucosal factors may offer new therapeutic paradigms. Transcriptional profiling can be applied to identify candidate gene products involved in colonic mucosal regeneration. Methods: Resection specimens from patients who underwent colonic resection for IBD or non-IBD indications were analyzed by performing Affymetrix GeneChip hybridization (Affymetrix, Inc., Santa Clara, Calif) and histopathologic scoring. Expression and physiologic processing of Reg Iα, the most highly expressed member of the regenerating (Reg) gene family, was further studied by performing specific immunohistochemistry, protein sequencing, and mass spectroscopy. Results: Foregut-derived tissues normally express human Reg proteins with minimal expression in the colon. In the setting of tissue injury associated with IBD, Reg Iα, Reg Iβ, and Reg III mRNA were highly expressed in colonic mucosa. Paired histopathologic scoring demonstrated that Reg expression was not related to the presence or the degree of mucosal inflammation. Studies of the Reg Iα protein revealed evidence of proteolytic cleavage at the N-terminus. In IBD, intact Reg Iα protein was expressed by the metaplastic Paneth granular cell population. Whereas Reg Iα cleaved at the N-terminus, it was also deposited throughout the lamina propria. Reg Iα treatment was shown to reduce epithelial apoptosis that occurred in response to treatment with hydrogen peroxide. Conclusion: Ectopic expression, physiologic processing, and directed tissue deposition of Reg Iα are components of the colonic mucosal regenerative response in IBD. Reg Iα may serve to reduce epithelial apoptosis in inflammation.