M1 Macrophages are a Source of IL-1α: A Driver of Progesterone Metabolism and Myometrial Contraction

Progesterone (P4) withdrawal is the key trigger for labor onset. Labor is a sterile inflammatory process involving monocyte infiltration, differentiation into M1 or M2 macrophages (Macs) and contributing to the inflammatory milieu in the uterus. Premature leukocyte influx may lead to preterm birth. Inflammatory stimuli induce intracellular progesterone (P4) withdrawal in myometrial cells (MYO) through activation of P4 metabolizing enzyme 20alpha-hydroxysteroid dehydrogenase (20α-HSD). We hypothesized that; (1) the pro-inflammatory M1-Macs induce 20α-HSD in MYO, which causes P4 withdrawal and MYO contractility; and (2) IL-1α produced by M1-Macs mediate the effect of M1-Macs on intracellular P4 withdrawal in MYO. Human myometrial biopsies from women in labor (TL) and not in labor (TNL) revealed higher IL-1α in TL, with M1-Macs in TNL expressing more IL-1α than MYO. In-vitro study shows; (1) higher expression of IL-1α in M1-Macs compared to M2-Macs; (2) treatment of MYO with IL-1α or M1-Macs increased 20α-HSD and contractility; and (3) blockade of IL-1α, AP-1 transcription factors, or co-treatment with non-metabolizable progestin; R5020 inhibits these effects. Our findings highlight the role of tissue-resident M1-Macs in regulating intracellular P4 metabolism and suggest that M1-Macs-derived IL-1α may facilitate P4-withdrawal and uterine contractility associated with labor onset.