摘要
Intrahepatic cholestasis of pregnancy(ICP)is a cholestatic disorder with potentially deleterious consequences for fetuses.Although a clear correlation between the elevated levels of maternal serum bile acids and deficient fetal outcome has been established in clinical practice,the underlying mechanisms remain elusive.Herein,we report that bile acids induce NF-κB pathway activation via G protein-coupled bile acid receptor 1(Gpbar1),with consequent upregulation of inflammatory genes in trophoblasts,leading to aberrant leukocyte infiltration and inflammation in placenta.Ursodeoxycholic acid(UDCA),a drug used clinically to treat ICP,competes with other bile acids for binding with Gpbar1 and thus inhibits bile acid-induced inflammatory response in trophoblasts and improves fetal survival in pregnant rats with obstructive cholestasis.Notably,inhibition of NF-κB by andrographolide is more effective than UDCA in benefiting placentas and fetuses.Thus,anti-inflammation therapy targeting Gpbar1/NF-κB pathway could be effective in suppressing bile acid-induced inflammation and alleviating ICP-associated fetal disorders.
基金
supported by grants from the 973 Program(2014CB541905)
the National Natural Science Foundation of China(31525016,31471309,31190061)
Personalized Medicines-Molecular Signature-based Drug Discovery and Development,the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12000000)
the Science and Technology Commission of Shanghai Municipality(11JC1414200),SKLCB(KF2012002)
the CAS/SAFEA International Partnership Program for Creative Research Teams.
