Interleukin 1β Regulates Progesterone Metabolism in Human Cervical Fibroblasts

Progesterone plays a critical role in regulating cervical structure necessary for pregnancy maintenance. Preterm labor and early cervical ripening are often associated with localized infection. We hypothesized that proinflammatory cytokines enhance progesterone metabolism in human cervical fibroblasts (HCFs) in vitro, through the regulation of the expression of 20 alpha-hydroxysteroid dehydrogenases (aldo-keto reductase [AKR]1C1, AKR1C2, or AKR1C3), 5 alpha-reductase type 1 (5 alpha-RDT1), and/or 17 beta-hydroxysteroid dehyrogenases (17 beta-HSD) type 1 and 2. The expression of both progesterone receptor (PR) and estrogen receptor alpha (ER alpha) was also studied. Human cervical fibroblasts were found to express AKR1C1, C2, and C3, with AKR1C1 exhibiting the greatest expression. These cells also expressed 5 alpha-RDT1 and 17 beta-HSD1 and 2, albeit to a lesser level compared to the aldo-keto reductases. The fibroblasts also expressed both PR and ER alpha. Interleukin 1 beta (IL-1 beta) significantly increased the expression of AKR1C1 and C2 but not C3 but did not alter 5 alpha-RDT1 nor 17 beta-HSD1 or 2 expression. Interleukin 1 beta treatment significantly increased progesterone metabolism by these cells. Use of specific inhibitors for aldo-keto reductases or 5 alpha reductases confirmed that the increased progesterone metabolism was a consequence of the increased expression and/or activity of AKR1C1/2. Our results indicate that a major proinflammatory cytokine, IL-1 beta, can facilitate local progesterone metabolism in a cell type critical for maintaining cervical structure via regulating expression of AKR1C1 and 2.