The effect of bile acids on human pancreatic duct cells

Abstract

We have previously shown that exposure of intact guinea pig pancreatic ducts to bile acids, which may occur e.g. in acute pancreatitis, induces intracellular acidification and a marked increase in intracellular Ca2+ concentration ([Ca2+]i). Moreover, a low dose of chenodeoxycholate (CDC) stimulates the luminal anion exchanger which suggests a possible role of cystic fibrosis transmembrane conductance regulator (CFTR) in this effect. There are no available data concerning the effect of bile acids on human pancreatic duct cells. The aim of our study was to examine the effects of CDC or glycochenodeoxycholate (GCDC) in human cystic fibrosis CFPAC-1 pancreatic duct cells which are homozygous for the most common delF508 cystic fibrosis transmembrane conductance regulator (CFTR) mutation or in CFPAC-1 cells which are corrected for the defective CFTR. Methods: We transduced polarized CFPAC-1 cells (n=4–6) with recombinant Sendai virus (SeV) constructs (multiplicity of infection=3) containing the CFTR or β-galactosidase (LacZ) cDNA. 48–72h after infection, the intracellular pH (pHi) and [Ca2+]i of the cells were recorded by microfluorimetry. Results: Both apical and basolateral administration of CDC or GCDC caused dose-dependent (100–1000µM) reversible intracellular acidification. Our results did not show significant differences in the rate of intracellular acidification caused by bile acids in SeV-CFTR and SeV-LacZ transduced cells. The exposure of cell lines to bile acids induced a marked increase in [Ca2+]i and CDC caused the largest response. Similarly to that observed in primary ducts, the effect of CDC administration from the apical membrane was greater than from the basolateral membrane. Furthermore, glycine conjugated bile acids also resulted in Ca2+ signalling when administered from either membrane of the cells. Conclusions: Human pancreatic duct cells respond similarly to administration of bile acids compared to that observed in guinea pigs. CFTR expression is not necessary for pHi changes and Ca2+ signalling caused by bile acids.