title: Glucocorticoids sensitize rat placental inflammatory responses via inhibiting lipoxin A4 biosynthesis.
abstract: Inflammation dysregulation in placenta is implicated in the pathogenesis of numerous pregnancy complications. Glucocorticoids (GCs), universally considered anti-inflammatory, can also exert proinflammatory actions under some conditions, whereas whether and how GCs promote placental inflammation have not been intensively investigated. In this paper we report the opposing regulation of rat placental inflammation by synthetic GC dexamethasone (Dex). When Dex was subcutaneously injected 1 h after we administered an intraperitoneal lipopolysaccharide (LPS) challenge, neutrophil infiltration and proinflammatory Il1b, Il6, and Tnfa expression in rat placenta were significantly reduced. In contrast, Dex pretreatment for 24 h potentiated rat placental proinflammatory response to LPS and delayed inflammation resolution, which involved MAPKs and NF-kappaB activation. Mechanically, Dex pretreatment promoted 5-lipoxygenase (ALOX5) activation and increased leukotriene B4 production, whereas it inhibited the anti-inflammatory and proresolving lipid mediator lipoxin A4 (LXA4) biosynthesis in rat placenta via downregulating ALOX15 and ALOX15B expression. Moreover, LXA4 supplementation dampened Dex-potentiated placental inflammation and suppressed Dex-mediated ALOX5 activation in vivo and in vitro. Taken together, these findings suggest that GCs exposure could promote placental inflammation initiation and delay resolution via disrupting LXA4 biosynthesis.
authors.affiliation: Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Dongxin
authors.initials: D
authors.lastname: Zhang
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Li
authors.forename: Huizhen
authors.initials: H
authors.lastname: Peng
authors.forename: Haojing
authors.initials: H
authors.lastname: Liu
authors.forename: Qiong
authors.initials: Q
authors.lastname: Cheng
authors.forename: Xue
authors.initials: X
authors.lastname: Cheng
authors.forename: Pan
authors.initials: P
authors.lastname: Zeng
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.forename: Hongxiang
authors.initials: H
authors.lastname: Chen
authors.forename: Yinping
authors.initials: Y
authors.lastname: Huang
authors.forename: Duyun
authors.initials: D
authors.lastname: Ye
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000276:immunology / Q000378:metabolism; D016718:Arachidonic Acid / Q000276:immunology; D002460:Cell Line; D003907:Dexamethasone / Q000276:immunology / Q000494:pharmacology*; D015232:Dinoprostone / Q000276:immunology / Q000378:metabolism; D005260:Female; D005938:Glucocorticoids / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D007975:Leukotriene B4 / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D044045:Lipoxins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D010920:Placenta / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D005938:Glucocorticoids; D008070:Lipopolysaccharides; D044045:Lipoxins; D016328:NF-kappa B; C040527:lipoxin A4; D007975:Leukotriene B4; D016718:Arachidonic Acid; D003907:Dexamethasone; D001094:Arachidonate 5-Lipoxygenase; D015232:Dinoprostone
keywords: arachidonic acid; eicosanoids; glucocorticoids; inflammation; placenta