Selective inhibition of expression of the substance P receptor mRNA in pancreatic acinar AR42J cells by glucocorticoids.

The effect of glucocorticoids on the regulation of the substance P receptor (SPR) mRNA was studied in rat pancreatic acinar AR42J cells by Northern blot analysis with the cloned cDNA. After a lag period of about 1 h, dexamethasone rapidly decreased steady-state SPR mRNA to almost negligible levels by 2 h. This decrease occurred in a dose-dependent manner by dexamethasone and was caused by various steroids in accordance with their relative potencies as glucocorticoids. These results indicate that the expression of the SPR mRNA is selectively and negatively regulated by glucocorticoids through interaction with the glucocorticoid receptor. The mechanisms of reduction of SPR mRNA levels were studied by treatment of AR42J cells with actinomycin D or cycloheximide. The SPR mRNA half-life was approximately 30 min, and this rate remained unchanged by dexamethasone treatment. Furthermore, the rapid turnover of the SPR mRNA required ongoing protein synthesis. On the basis of the result of actinomycin D treatment, together with kinetics of dexamethasone-induced changes in SPR mRNA levels, we discuss the mechanism in which glucocorticoids act at transcription initiation to reduce SPR mRNA levels.