Progesterone mediates decreases in uterine smooth muscle cell interleukin-1alpha by a mechanism involving decreased stability of IL-1alpha mRNA.

The regulation, by progesterone, of serotonin-induced interleukin-1alpha production was studied in primary cultures of rat uterine smooth muscle cells. Prior reports from this laboratory have demonstrated that these cells produce IL-1alpha and IL-1beta mRNAs in response to the hormonal action of serotonin. Results of the present study indicate that treatment of myometrial smooth muscle cells with medroxyprogesterone acetate (MPA) results in a marked decrease in IL-1alpha protein as measured by western blot analysis. These decreases occur even in the presence of maximally-inducing concentrations of serotonin. MPA-mediated changes in IL-1alpha protein are characterized by a rapid decline in IL-1alpha mRNA levels. This inhibition by medroxyprogesterone also occurs when cells are stimulated to produce IL-1alpha by PMA rather than serotonin. Thus, when cells are cultured in the presence of both inducer and inhibitor, the inhibitor, progesterone, clearly dominates in the control of IL-1alpha expression. This effect is concentration-dependent, can be mimicked by native progesterone or glucocorticoids, but is unaffected by estradiol. The ability of progestins to decrease IL-1alpha mRNA is blocked by both inhibitors of transcription and translation and by treatment with RU-486. Progesterone had no effect on chloramphenicol acetyl transferase (CAT) transcription from two different IL-1alpha promoter constructs, indicating that progesterone's action appears to be dependent on post-transcriptional rather than transcriptional regulation. Conversely, progesterone accelerated the normal rate of decay of IL-1alpha mRNA that occurs following the removal of serotonin from the cultures. These results suggest that progesterone decreases IL-1alpha levels by stimulating the production of an intracellular intermediate that decreases the stability of IL-1alpha mRNA.