Cannabinoids modulate inflammatory tone and attenuate inflammatory responses in human placental explants

Abstract Background With increasing cannabis use during pregnancy, understanding how cannabinoids affect placental immune function is fundamental. The placenta maintains a regulated immune environment through innate immune pathways, including nuclear factor kappa B (NF-κB)–dependent cytokine production and inflammasome-related mechanisms. We examined whether major and minor cannabinoids modulate basal inflammatory tone and responses to an acute inflammatory stimulus in human placental explants. Methods Human term villous explants from uncomplicated pregnancies were exposed to Δ⁹-tetrahydrocannabinol (THC), cannabigerol (CBG), cannabinol (CBN), or cannabivarin (CBV) (2.5–20 µg/mL) for 48 h, with or without stimulation with lipopolysaccharide (LPS; 1 µg/mL) for 4 h in the continued presence of cannabinoids. Explant viability and endocrine function were assessed. Expression of interleukin (IL)-6 ( IL6 ), IL1B , IL18 , tumor necrosis factor ( TNF ), NFKB1 , NLR family pyrin domain containing 3 ( NLRP3 ), caspase 1 ( CASP1 ), toll-like receptor 4 ( TLR4 ), and prostaglandin-endoperoxide synthase 2 ( PTGS2 ) was quantified by RT-qPCR. Secretion of IL-6, TNF-α, and IL-1β was measured by ELISA. Data were analyzed using Kruskal–Wallis or Friedman tests followed by Dunn’s multiple-comparisons test, as appropriate. Results Cannabinoid exposure did not affect viability or endocrine function. Under basal conditions, cannabinoids reduced expression of IL1B and NLRP3 and decreased secretion of IL-6 and IL-1β. Under LPS stimulation, CBG, CBN, and CBV attenuated the induction of IL6 , IL1B , NFKB1 , and NLRP3 and all four cannabinoids reduced cytokine secretion. THC selectively increased PTGS2 in healthy placentas, whereas CBG and CBN reduced LPS-induced PTGS2 expression. Conclusions THC, CBG, CBN, and CBV altered inflammation-related gene expression and reduced pro-inflammatory cytokine secretion in human term placental explants under both basal conditions and LPS stimulation. These findings suggest that cannabinoids modulate placental inflammatory responses and provide a basis for further studies of their impact on placental function and pregnancy.