Progesterone inhibits the transcription of inducible nitric oxide (NO) synthase (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 or dexamethasone had no effect on NO production induced by IL-1beta, LPS, and IFN-gamma. In contrast, NO production was inhibited by progesterone when administered as a pre-treatment or as a post-treatment 6 h after cytokine exposure (IC50 in DLD-1 and Caco-2BBe cells = 66 and 45 microM). Progesterone pre-treatment inhibited cytokine-induced iNOS mRNA expression by 66% and 58% in DLD-1 and Caco-2BBe cells, respectively. Nuclear run-on analysis demonstrated that progesterone did not inhibit cytokine-induced iNOS transcription. These data imply that progesterone inhibits iNOS mRNA expression at a post-transcriptional level, which is the dominant mode of iNOS regulation in human enterocytes. Since iNOS-derived NO production has been related to the inflammatory and tumorigenic response of progesterone-receptor bearing tissues, the repression of iNOS mRNA expression by a female sex steroid could play an important role in the regulation of a broad range of physiologic processes.
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