Melatonin is associated with cell-type-specific inflammatory and oxidative stress responses at the maternal-fetal interface.

Melatonin regulates inflammation and oxidative stress at the placenta, but its effects on specific placental cell types remain unclear. This study investigated how melatonin influences inflammatory and oxidative stress responses, cytokine secretion, NRF2-associated antioxidant responses, and transcriptomic responses in JEG-3 trophoblast-like cells and primary decidual macrophages exposed to lipopolysaccharide (LPS). Melatonin reduced LPS-induced inflammatory cytokine production and intracellular reactive oxygen species accumulation, with pretreatment producing the strongest anti-inflammatory effects. Although NLRP3 transcript expression differed according to treatment sequence, melatonin was associated with reduced inflammatory cytokine secretion despite limited changes in total NLRP3 protein expression. Melatonin also differentially influenced antioxidant responses across placental cell types, with decidual macrophages exhibiting broader functional and transcriptional changes than JEG-3 trophoblast-like cells. Transcriptomic profiling revealed dose- and cell type-dependent effects, with decidual macrophages exhibiting altered expression of genes and pathways associated with inflammatory signaling, oxidative phosphorylation, and reactive oxygen species regulation. In contrast, JEG-3 trophoblast-like cells demonstrated limited transcriptional remodeling and more modest engagement of inflammatory signaling pathways than primary decidual macrophages. These findings suggest that melatonin differentially modulates inflammatory and oxidative stress responses across placental cell types at the maternal-fetal interface. Collectively, these data support the potential role of melatonin in promoting placental redox-inflammatory balance during inflammatory stress and provide a foundation for future studies in physiologically relevant models.