Background and aims Reg4 is a recently discovered member of the regenerating gene family with distinctive expression profiles in primary
cancers. To date, the physiological function of Reg4 is poorly understood. Previously, the authors found that Reg4 was markedly upregulated during
acute pancreatitis (AP). The aim of this study was to investigate the role of Reg4 in experimental
pancreatitis. Methods AP was induced in C57BL/6 mice by administration of either
l-arginine or
caerulein, and Reg4 expression was assessed by immunofluorescence,
reverse transcriptase (RT)-PCR and western blot analyses. Recombinant
human Reg4 protein (rReg4), heat-inactivated Reg4, neutralising antibody and vehicle were also administered to mice by
subcutaneous injection. The severity of AP was determined by measuring
amylase and
lipase activities in the serum and histological grading. The effect of rReg4 on cell death was examined and
epidermal growth factor receptor (EGFR), p-EGFR, Akt, p-Akt, Bcl-2 and Bcl-xL expression were assessed by western blot analysis of isolated murine acinar cells treated with
l-arginine. Results Reg4
mRNA and
protein were markedly upregulated during
arginine-induced
pancreatitis. Reg4 was widely expressed in residual acinar cells around the islets and regenerating metaplastic epithelium. rReg4 could protect against
arginine-induced
necrosis of acinar cells both in vivo and in vitro. This protective effect was also confirmed in the
caerulein-induced murine model of AP. It was shown that
arginine induced expression of Bcl-2 and Bcl-xL, while rReg4 upregulated Bcl-2 and Bcl-xL expression by activating the EGFR/Akt pathway. The upregulation of Bcl-xL correlated inversely with cell
necrosis in isolated pancreatic acinar cells. Conclusions The data suggest that Reg4 may protect against acinar cell
necrosis in experimental
pancreatitis by enhancing the expression of Bcl-2 and Bcl-xL via activation of the EGFR/Akt signalling pathway.