title: Endoplasmic reticulum stress is increased after spontaneous labor in human fetal membranes and myometrium where it regulates the expression of prolabor mediators.
abstract: Increasing evidence indicates that endoplasmic reticulum (ER) stress is involved in various diseases. In nongestational tissues, several markers of the unfolded protein response (UPR) have been shown to regulate the inflammatory response. Thus, the aim of this study was to determine the effect of human labor on markers of ER stress in fetal membranes and myometrium. In addition, the effect of ER stress inhibition on the expression and secretion of proinflammatory and prolabor mediators was also assessed. The markers of ER stress, GRP78, IRE1, and spliced XBP1 (XBP1s), were significantly increased in fetal membranes and myometrium after term and preterm labor compared to nonlaboring samples. Given that inflammation is considered to be one of the leading causes of spontaneous preterm birth, here we used bacterial endotoxin lipopolysaccharide (LPS) as a model for infection-induced preterm birth. In term nonlabored fetal membranes and myometrium, LPS induced UPR activation as evidenced by a significant increase in the expression of GRP78, IRE1, and XBP1s in fetal membranes and myometrium. The use of the chemical chaperones 4-phenylbutyric acid (4-PBA) and tauroursodeoxycholic acid (TUDCA) alleviated ER stress induced by LPS. 4-PBA and TUDCA also ameliorated the increase in LPS-induced prolabor mediators. Our data suggest that the UPR may regulate the inflammatory responses associated with labor or infection in fetal membranes and myometrium of pregnant term and preterm women. Thus, the use of ER stress inhibitors, in particular 4-PBA or TUDCA, may be a potential therapeutic strategy for the prevention of infection-mediated spontaneous preterm birth.
authors.affiliation: Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, AustraliaMercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Victoria, Australia.
authors.forename: Stella
authors.initials: S
authors.lastname: Liong
authors.affiliation: Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, AustraliaMercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Victoria, Australia mlappas@unimelb.edu.au.
authors.forename: Martha
authors.initials: M
authors.lastname: Lappas
mesh_terms: D000328:Adult; D017398:Alternative Splicing; D015415:Biomarkers / Q000378:metabolism; D002585:Cesarean Section; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D005321:Extraembryonic Membranes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007743:Labor, Obstetric / Q000378:metabolism*; D009215:Myometrium / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007752:Obstetric Labor, Premature / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010654:Phenylbutyrates / Q000494:pharmacology; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D046509:Tissue Culture Techniques; D015149:Tocolytic Agents / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D000071717:X-Box Binding Protein 1
chemical_list: D015415:Biomarkers; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D010654:Phenylbutyrates; D000071701:Regulatory Factor X Transcription Factors; D015149:Tocolytic Agents; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; C075773:4-phenylbutyric acid; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases
keywords: endoplasmic reticulum stress; fetal membranes; human labor; inflammation; myometrium; preterm labor