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

Abstract

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. 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 α-BGT treated group (PTL+N+A). Rats were administered RU486 (1.0mg/kg) by subcutaneous injection on gestational day (GD) 18 to establish PTL model. Subcutaneous injection of nicotine (1mg/kg) was administered daily from GD 16 to 18. α-BGT (1µg/kg) was administrated subcutaneously in two sessions and each session was 30min prior to nicotine. TNF-α, IL-1β, IL-4, IL-6, IL-10 in myometrium and serum were detected by Luminex. Macrophage infiltration and α7nAChR were detected by IHC. 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 α-BGT treatment reversed the prolonged interval (P<0.05). The cytokines all markedly elevated at 12h, but deceased after delivery (P<0.05). The IL-1β and TNF-α 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-1β, IL-4, IL-6, IL-10 and TNF-α in myometrium increased as the same trend as in serum. Nicotine treatment also downregulated the expression of α7nAChR in pregnant tissue. 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 α7nAChR through CAP. This study provides a novel evidence supporting the future development of therapeutic target for preterm birth.