REGULATION OF INTESTINAL CHOLECYSTOKININ GENE-EXPRESSION BY GLUCOCORTICOIDS

The effect of glucocorticoids on the expression of intestinal cholecys tokinin (CCK) was investigated both in vivo and in cell culture system s. In vivo, 2-day administration of methylprednisolone to adult male r ats induced a decrease in CCK-like immunoreactivity (CCK-LI) and CCK m RNA levels in mucosal extracts. In two CCK-producing cell lines, RIN 1 056E and STC-1 of pancreatic and intestinal origin respectively, dexam ethasone induced dose-dependent decreases in both CCK-LI and steady-st ate CCK mRNA levels. The decrease in CCK mRNA was totally prevented by incubation of cells with an excess of RU 38486, a competitive inhibit or for the binding of glucocorticoids to their receptor. Actinomycin D , used to prevent RNA synthesis, did not modify CCK mRNA stability in dexamethasone-pretreated cells as compared with cells not exposed to d examethasone. When cells were first incubated with actinomycin D, subs equent addition of dexamethasone left the steady-state CCK mRNA levels unaltered in both cell lines. Nuclear run-on assays performed in RIN 1056E cells showed that glucocorticoids decreased the rate of transcri ption of the CCK gene. In addition, cycloheximide, used to prevent pro tein synthesis, abolished the inhibitory effects of dexamethasone on s teady-state CCK mRNA levels. These results demonstrate that glucocorti coids down-regulate CCK gene expression in the rat intestinal mucosa a nd in two CCK-producing cell lines. The effect is blocked by a glucoco rticoid receptor antagonist. Inhibition of CCK gene expression may res ult from a decrease in the transcription rate, and probably involves o ne or several steps that depend on protein synthesis.