Nicotine ameliorates inflammatory mediators in RU486 induced preterm labor model through activating cholinergic anti-inflammatory pathway

Background: Preterm birth is a global public health threat. Inflammatory reaction is thought to mediate preterm birth. The role of nicotine, an anti-inflammatory agent that is mediated by cholinergic anti-inflammatory pathways (CAP), remains unclear in the pathogenesis.Methods: Pregnant rats were randomly divided into four groups (20 rats each): pregnant control group (P), RU486-treated group (PTL), RU486 and nicotine-treated group (PTL + N), RU486, nicotine and alpha-BGT treated group (PTL + N + A). Rats were administered RU486 (1.0 mg/kg) by subcutaneous injection on gestational day (GD) 18 to establish PTL model. Subcutaneous injection of nicotine (1 mg/kg) was administered daily from GD 16 to 18. alpha-BGT (1 mu g/kg) was administrated subcutaneously in two sessions and each session was 30 min prior to nicotine. TNF-alpha, IL-18, IL-4, IL-6, IL-10 in myometrium and serum were detected by Luminex. Macrophage infiltration and alpha 7nAChR were detected by IHC.Results: We established a RU486-induced preterm labor rat model. Preterm labor was associated with a striking upregulation inflammatory mediators and increased macrophage infiltration. Nicotine significantly prolonged gestation (P < 0.05) and alpha-BGT treatment reversed the prolonged interval (P < 0.05). The cytokines all markedly elevated at 12 h, but deceased after delivery (P < 0.05). The IL-18 and TNF-alpha in serum were significantly increased in PTL group vs P group (P < 0.05), and decreased after nicotine treatment (P < 0.05). The cytokines IL-18, IL-4, IL-6, IL-10 and TNF-alpha in myometrium increased as the same trend as in serum. Nicotine treatment also downregulated the expression of alpha 7nAChR in pregnant tissue.Conclusion: We confirmed the increased inflammation in preterm birth. Nicotine was able to down-regulate the inflammatory mediates and prolong the pregnant duration in PTL model, which might be induced by activating alpha 7nAChR through CAP. This study provides a novel evidence supporting the future development of therapeutic target for preterm birth.