Interaction Between Progesterone and Interleukin-1β in Modulating Progesterone Receptor Expression and the Inflammatory Phenotype in Human Cervical Fibroblasts.

Abstract

Progesterone helps maintain cervical structure during pregnancy via the progesterone receptor (PR). Two PR isoforms exist, PR-A and PR-B, which have overlapping as well as isoform-specific target genes. During late gestation, leukocytes infiltrate the cervical stroma accompanied by increased cervical cytokine levels, resembling an inflammatory process. We examined interleukin (IL)-1β regulation of the expression of PR-A, PR-B, and genes governing prostaglandin synthesis in human cervical fibroblasts (HCFs). Since progesterone has been shown to exert anti-inflammatory actions, we also examined the capacity of progesterone (R5020) to ameliorate the actions of IL-1β in HCFs. Interleukin-1β induced both PR-A and PR-B mRNA in HCFs. Interleukin-1β induced a rapid and transient loss of both PR-A and PR-B protein, followed by a latent (24 hours) increase in both PR isoforms. R5020 negated the IL-1β-induced increase in PR-A and PR-B mRNA and protein as well as the rapid IL-1β-induced downregulation of nuclear PR. Interleukin-1β induced prostaglandin G/H synthase-2 (PGHS-2), but not prostaglandin G/H synthase-1 (PGHS-1), as well as prostaglandin E synthase-1 (PGES-1), but not prostaglandin F synthase (PGFS). R5020 did not ameliorate IL-1β induction of PGHS-2 or PGES-1. Blockade of prostaglandin synthesis (indomethacin) prevented both the IL-1β-induced increase in PR mRNA and the acute decrease in PR-A and PR-B protein, implicating a role for prostaglandins in regulating PR expression in HCFs. Although progesterone may function to maintain PR expression in a milieu of increasing cytokines in the late gestation human cervix, it does not exert an anti-inflammatory role with regard to prostaglandin E2 (PGE2) production.