Absence of Receptor Mediated Functional Progesterone Withdrawal in the Decidua During Labor‐like Inflammatory Conditions

Abstrakt

ABSTRACT Problem : Preterm birth and dysregulated labor remain the leading causes of neonatal morbidity, yet the mechanisms governing progesterone (P4) signaling and inflammatory regulation within the decidua parietalis at the feto‐maternal interface are poorly understood. In particular, the roles of progesterone receptor membrane components PGRMC1 and PGRMC2 in maintaining decidual immune homeostasis during pregnancy and labor remain undefined. Methods : of Study:Human decidua parietalis cells were cultured under pregnancy‐ and labor‐like conditions, with and without immune cell co‐culture. Expression of PGRMC1, PGRMC2, and PR‐A/B and their interaction with P4 were assessed. Labor‐associated inflammation was modeled using lipopolysaccharide (LPS). SiRNA targeted knockdown of PGRMC2 was performed to evaluate effects on progesterone receptor expression, cell‐cycle progression, progesterone metabolism (AKR1C1/2) and inflammatory cytokine production. Results : PGRMC1, PGRMC2, and PR‐A/B expression remained stable across gestational conditions, and P4 robustly interacted with PGRMCs. LPS‐induced inflammation was not suppressed by P4 despite preserved receptor expression. PGRMC2 knockdown did not alter progesterone receptor expression, cell‐cycle progression, or progesterone metabolism; however, it significantly increased baseline and stimulus‐induced IL‐6 and TNF levels. Under labor‐like inflammatory conditions, loss of PGRMC2 markedly amplified cytokine production. Conclusions : These findings identify PGRMC2 as an important regulator of decidual immune homeostasis; however, the translational relevance of this role remains limited, as neither our pregnancy nor labor models produced a physiologically meaningful downregulation of PGRMC2 expression. Instead, our data support a model in which parturition‐associated changes in decidua are driven primarily by inflammatory cues rather than by loss of progesterone receptor signaling, demonstrating tissue‐specific progesterone signaling.