Up-regulation of pancreatitis-associated protein in a rat model of inflammatory bowel disease

Abstract

Introduction: Pancreatitis-associated protein (PAP) is a Reg gene family protein normally expressed in small intestine with minimal expression in the colon. PAP gene expression has been found to be highly elevated in colonic mucosa in patients with inflammatory bowel disease (IBD). To further dissect the role of PAP in colonic inflammation in vivo, differential gene expression of PAP in inflamed colon was studied using a rat model of chronic IBD. Method: IBD was induced by intraluminal installation of trinitrobenzensulfonic acid (TNBS). Four groups of animals were sacrificed at day 1, day 7, and day 14 after induction of inflammation. Control group had no TNBS administered (n = 3 for all groups). Tissue from colon, as well as serum was harvested. mRNA expression of PAP was measured by real time quantitative RT-PCR. Serum levels of C-reactive protein and histopathology of colon tissue were evaluated. Results: Expression of PAP is minimal in normal colon. PAP I expression in colon was dramatically upregulated by 22.0 ± 1.2-fold at seven days after induction of inflammation when compared to untreated control group. Our time course results show that PAP I mRNA levels initially decreased at day one (by 4.2 fold), peaked at day seven (22.0 fold), and declined to baseline by day fourteen when compared to untreated control (p < 0.05 for day 1 and day 7). Similar changes in PAP II gene regulation were also observed. Serum C-reactive protein levels, increased from 1.73 ± 0.2 mg/dL at day one to 2.36 ± 0.21 mg/dL at day seven (p < 0.05). Changes in expression of PAP I corresponded to changes in serum C-reactive protein levels. Both PAP I expression and C-reactive protein levels decreased at day one, peaked at day seven, and dropped back to baseline at day fourteen when compared to untreated control group. Histopathological evaluation showed extensive intestinal wall damage characterized by epithelial exfoliation, mucosal hemorrhage, submucosal infiltration with leukocytes and transmural edema at day 7. Conclusion: Transcriptional profiling of PAP gene expression identified that it is highly upregulated in a rat model of chronic IBD. Significant changes in PAP expression, that parallel changes of CRP levels, indicate physiological relevance of PAP to inflammatory processes in the colon.