title: HMGB1 promotes a p38MAPK associated non-infectious inflammatory response pathway in human fetal membranes.
abstract: OBJECTIVE
  Spontaneous preterm birth (PTB) and preterm prelabor rupture of membranes (pPROM) are major pregnancy complications often associated with a fetal inflammatory response. Biomolecular markers of this fetal inflammatory response to both infectious and non-infectious risk factors and their contribution to PTB and pPROM mechanism are still unclear. This study examined fetal membrane production, activation and mechanistic properties of high mobility group box 1 (HMGB1) as a contributor of the non-infectious fetal inflammatory response.
  
  
  METHODS
  HMGB1 transcripts and active HMGB1 were profiled in fetal membranes and amniotic fluids collected from PTB and normal term birth. In vitro, normal term not in labor fetal membranes were exposed to lipopolysaccharide (LPS) and water soluble cigarette smoke extract (CSE). HMGB1-transcripts and its protein concentrations were documented by RT-PCR and ELISA. Recombinant HMGB1 treated membranes and media were subjected to RT-PCR for HMGB1 receptors, mitogen activated protein kinase pathway analysis, cytokine levels, and Western blot for p38MAPK.
  
  
  RESULTS
  HMGB1 expression and its active forms were higher in PTB and pPROM than normal term membranes and amniotic fluid samples. Both LPS and CSE enhanced HMGB1 expression and release in vitro. Fetal membrane exposure to HMGB1 resulted in increased expression of TLR2 and 4 and dose-dependent activation of p38MAPK-mediated inflammation.
  
  
  CONCLUSIONS
  HMGB1 increase by fetal membrane cells in response to either oxidative stress or infection can provide a positive feedback loop generating non-infectious inflammatory activation. Activation of p38MAPK by HMGB1 promotes development of the senescence phenotype and senescence associated sterile inflammation. HMGB1 activity is an important regulator of the fetal inflammatory response regardless of infection.
authors.affiliation: Division of Maternal-Fetal Medicine and Perinatal Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bredeson
authors.affiliation: Department of Biochemistry and Molecular Biology, NHLBI Proteomics Center on Airway Inflammation and UTMB Biomolecular Resource Facility, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Papaconstantinou
authors.affiliation: Department of Biochemistry and Molecular Biology, NHLBI Proteomics Center on Airway Inflammation and UTMB Biomolecular Resource Facility, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: James H
authors.initials: JH
authors.lastname: Deford
authors.affiliation: Division of Maternal-Fetal Medicine and Perinatal Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America.
authors.forename: Talar
authors.initials: T
authors.lastname: Kechichian
authors.affiliation: Division of Maternal-Fetal Medicine and Perinatal Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America.
authors.forename: Tariq A
authors.initials: TA
authors.lastname: Syed
authors.affiliation: Division of Maternal-Fetal Medicine and Perinatal Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America.
authors.forename: George R
authors.initials: GR
authors.lastname: Saade
authors.affiliation: Division of Maternal-Fetal Medicine and Perinatal Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America.
authors.forename: Ramkumar
authors.initials: R
authors.lastname: Menon
mesh_terms: D000653:Amniotic Fluid / Q000166:cytology / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005321:Extraembryonic Membranes / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005322:Premature Rupture of Fetal Membranes / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007231:Infant, Newborn; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D007744:Obstetric Labor Complications / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D047928:Premature Birth; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D016207:Cytokines; D024243:HMGB1 Protein; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D051197:Toll-Like Receptor 4; D048051:p38 Mitogen-Activated Protein Kinases