Abstract
Pregnancy-induced hypertension (PIH), also known as preeclampsia, is one of the major causes of maternal and fetal death. While the precise cause of PIH is not known, aberrant cytokine production and placenta participation are considered to be important factors. Gestational cigarette smoking, which is widely accepted to be harmful to both the mother and fetus, is protective against PIH. Based on the antiinflammatory activity of nicotine, the major component of cigarettes, we examined the effect of nicotine and other cholinergic agonists on placental inflammatory responses ex vivo. We observed that nicotine and other cholinergic agonists significantly suppress placenta cytokine production following stimulation. Placenta cells express the alpha7 nicotinic acetylcholine receptor (alpha7nAChR), and using cholinergic antagonists, we demonstrated that the antiinflammatory effect of nicotine and other cholinergic agonists is, in part, mediated through the nAChR pathway. By contrast, cholinergic stimulation had no effect on the expression of soluble fms-like tyrosine kinase (sFlt), an antiangiogenic substance implicated in maternal vascular dysfunction during PIH. Mechanistic studies reveal that cholinergic agonists exert their antiinflammatory effects through the NFkappaB pathway. Taken together, our results suggest that cholinergic agonists, including nicotine, may reduce cytokine production by placenta cells via NFkappaB to protect against PIH.
Highlights
Despite the many detrimental effects of smoking on maternal and fetal health, several studies show that maternal smoking is protective against pregnancyinduced hypertension (PIH), known as preeclampsia [1,2,3,4,5,6]
Based on the observations that smoking protects against PIH and nicotine exerts antiinflammatory effects, we examined the effects of cholinergic agonists, including nicotine, on placental inflammatory responses ex vivo
The concentrations of nicotine and Dex mRNA and protein, as determined by with PIH, human placenta cells were treated with LPS to induce TNF production
Summary
Despite the many detrimental effects of smoking on maternal and fetal health, several studies show that maternal smoking is protective against pregnancyinduced hypertension (PIH), known as preeclampsia [1,2,3,4,5,6]. PIH is characterized by maternal hypertension, proteinuria, and edema during the second half of pregnancy [7,8]. While the association between angiogenic factors and PIH has been recently discovered [9,10,11], numerous reports highlight the proposed contribution of leukocyte activation and several proinflammatory cytokines to the development of PIH, including TNFα (TNF), IL-6, IL-1 receptor antagonist, and IL-8 [12,13,14,15,16,17,18]. Further studies implicate a generalized phenomenon of maternal immune cell activation via NFκB, a critical regulator of inflammation [19,20]
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