Cannabidiol reduces LPS-induced inflammatory response in the human placenta by reducing NF-κB translocation

Abstract Background Cannabidiol (CBD), a non-psychoactive cannabinoid increasingly used during pregnancy, has been proposed to modulate inflammatory processes. However, its effects on human placental immune functions remain poorly characterized. This study investigates the impact of CBD on lipopolysaccharide (LPS)-induced inflammation in human placenta explants and primary trophoblast cells, focusing on cytokine expression, receptor involvement, and underlying mechanisms. Methods Term placental explants and syncytiotrophoblast cells were exposed to LPS with or without CBD. Inflammatory cytokine levels were quantified by ELISA and RT-qPCR. Receptor involvement was assessed using selective antagonists for cannabinoid receptors type 1 and 2 (CB1 and CB2), and transient receptor potential cation channel subfamily V member 1 (TRPV1). NF-κB activation was evaluated by immunofluorescence, and caspase-1 activity was measured to explore inflammasome-related pathways. Results CBD significantly attenuated LPS-induced interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and interleukin 18 (IL-18) expression in a concentration-dependent manner, without inducing cytotoxicity. These effects were not reversed by CB1, CB2, or TRPV1 antagonists, indicating that other pathways are likely involved. CBD was associated with reduced NF-κB p65 nuclear translocation yet did not affect caspase-1 activity or transcript levels, indicating inflammasome-independent suppression. Conclusion CBD exerts anti-inflammatory effects in human placenta and trophoblasts, associated with reduced NF-κB p65 nuclear translocation and independent of CB1, CB2, and TRPV1 signaling, without evidence of canonical inflammasome activation. Given the placenta’s role in fetal programming, these findings underscore the importance of evaluating CBD's developmental impact in the context of its growing perinatal use. Graphical Abstract Graphical abstract illustrating the proposed mechanism by which CBD attenuates LPS-induced inflammation in human placental explants and primary trophoblast cells. LPS promotes NF-κB p65 nuclear translocation and increases expression of IL-6, IL-1β, and TNF-α. CBD reduces NF-κB nuclear accumulation and downstream cytokine production. Dotted trajectories denote hypothetical or unresolved intermediate signaling steps and do not imply direct molecular interactions. Functional antagonist assays indicate that CBD-mediated immunomodulation in the placenta occurs independently of CB1, CB2, and TRPV1 receptors. This schematic is presented as a working hypothesis. Created with BioRender.com.