Progesterone inhibits inducible nitric oxide synthase mRNA expression in human intestinal epithelial cells

Progesterone inhibits the transcription of inducible nitric oxide (NO) synt hase (iNOS) in murine macrophages. The effect of female sex steroids on the regulation of the human iNOS gene, which shares no identity in the 5' and 3' non-coding regions with its murine homolog, is unknown. Pretreatment of the human enterocytic cells DLD-1 and Caco-2BBe with estradiol ol dexametha sone had no effect on NO production induced by IL-1 beta, LPS, and IFN-gamm a. In contrast, NO production was inhibited by progesterone when administer ed as a pre-treatment or as a post-treatment 6 h after cytokine exposure (I C50 in DLD-1 and Caco-2BBe cells = 66 and 45 mu M) Progesterone pre-treatme nt inhibited cytokine-induced iNOS mRNA expression by 66% and 58% in DLD-1 and Caco-2BBe cells, respectively. Nuclear run-on analysis demonstrated tha t progesterone did not inhibit cytokine-induced iNOS transcription. These d ata imply that progesterone inhibits iNOS mRNA expression at a posttranscri ptional level, which is the dominant mode of iNOS regulation in human enter ocytes. Since iNOS-derived NO production has been related to the inflammato ry and tumorigenic response of progesterone-receptor bearing tissues, the r epression of iNOS mRNA expression by a female sex steroid could play an imp ortant role in the regulation of a broad range of physiologic processes.