PROGESTERONE AND ESTRADIOL INHIBIT CFTR-MEDIATED ION-TRANSPORT BY PANCREATIC EPITHELIAL-CELLS

The cystic fibrosis (CF) gene product, CF transmembrane conductance re gulator (CFTR), is responsible for adenosine 3',5'-cyclic monophosphat e (cAMP)-activated Cl- transport in epithelial cells, and mutant CFTR accounts for the pathology in the CF pancreas. We have previously show n that both isolated rabbit pancreatic acini and the human pancreatic duct cell line PANC-1 possess a cAMP-activated Cl- conductance identif ied as CFTR. We report here that preincubation in either of the female hormones progesterone or beta-estradiol inhibits activation by cAMP, but not by Ca2+ ionophore, of PANC-1 cell volume reduction under isoto nic conditions. cAMP-activated cell volume reduction is sensitive to a ntisense, but not sense, CFTR oligodeoxynucleotide. Furthermore, proge sterone inhibits cAMP-activated Cl- efflux from rabbit acinar cells. M oreover, preincubation with progesterone, but not beta-estradiol, redu ces CFTR mRNA and protein levels as measured using polymerase chain re action amplification of reverse-transcribed acinar RNA and Western blo ts of protein from acinar membranes. We conclude that female hormones inhibit CFTR functional activity in pancreatic epithelial cells by dif ferent mechanisms.