title: A Role for the Inflammasome in Spontaneous Preterm Labor With Acute Histologic Chorioamnionitis.
abstract: Inflammasomes are cytosolic multiprotein complexes that orchestrate inflammation in response to pathogens and endogenous danger signals. Herein, we determined whether the chorioamniotic membranes from women in spontaneous preterm labor with acute histologic chorioamnionitis (1) express major inflammasome components; (2) express caspase (CASP)-1 and CASP-4 as well as their active forms; (3) exhibit apoptosis-associated speck-like protein containing a CARD (ASC)/CASP-1 complex formation; and (4) release the mature forms of interleukin (IL)-1β and IL-18. We utilized quantitative reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, immunoblotting, and immunohistochemistry to determine the messenger RNA (mRNA) and protein expression of major inflammasome components, nucleotide-binding oligomerization domain (NOD) proteins, and the pro- and mature/active forms of CASP-1, CASP-4, IL-1β, and IL-18. The ASC/CASP-1 complex formation was determined using an in situ proximity ligation assay. When comparing the chorioamniotic membranes from women in spontaneous preterm labor with acute histologic chorioamnionitis to those without this placental lesion, we found that (1) the mRNA of NLR family pyrin domain-containing protein ( NLRP) 1, NLRP3, NLR family CARD domain-containing protein 4 ( NLRC4), and NOD2 were higher; (2) the NLRP3 protein was increased; (3) the mRNA and active form (p10) of CASP-1 were greater; (4) the mRNA and active form of CASP-4 were increased; (5) the mRNA and mature form of IL-1β were higher; (6) the mature form of IL-18 was elevated; and (7) ASC/CASP-1 complex formation was increased. In conclusion, spontaneous preterm labor with acute histologic chorioamnionitis is characterized by an upregulation of NLRP3 and the active form of CASP-4, as well as increased ASC/CASP-1 complex formation, which may participate in the activation of CASP-1 and the maturation of IL-1β and IL-18 in the chorioamniotic membranes. These findings provide the first evidence that supports a role for the inflammasome in the pathological inflammation implicated in spontaneous preterm labor with acute histologic chorioamnionitis.
authors.affiliation: 1 Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI, USA.|2 Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.|3 Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Nardhy
authors.initials: N
authors.lastname: Gomez-Lopez
authors.affiliation: 1 Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI, USA.|4 Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA.|5 Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, USA.|6 Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Romero
authors.affiliation: 1 Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI, USA.|2 Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xu
authors.affiliation: 1 Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI, USA.|2 Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Olesya
authors.initials: O
authors.lastname: Plazyo
authors.affiliation: 1 Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI, USA.|2 Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Unkel
authors.affiliation: 1 Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI, USA.|2 Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Yaozhu
authors.initials: Y
authors.lastname: Leng
authors.affiliation: 1 Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI, USA.|7 Systems Biology of Reproduction Lendulet Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.|8 Maternity Private Department, Kutvolgyi Clinical Block, Semmelweis University, Budapest, Hungary.|9 First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
authors.forename: Nandor Gabor
authors.initials: NG
authors.lastname: Than
authors.affiliation: 1 Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI, USA.|2 Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Tinnakorn
authors.initials: T
authors.lastname: Chaiworapongsa
authors.affiliation: 1 Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI, USA.|2 Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Panaitescu
authors.affiliation: 1 Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI, USA.|2 Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Dong
authors.affiliation: 1 Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI, USA.|2 Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Adi L
authors.initials: AL
authors.lastname: Tarca
authors.affiliation: 10 Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Vikki M
authors.initials: VM
authors.lastname: Abrahams
authors.affiliation: 1 Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI, USA.|2 Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Lami
authors.initials: L
authors.lastname: Yeo
authors.affiliation: 1 Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI, USA.|2 Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Sonia S
authors.initials: SS
authors.lastname: Hassan
mesh_terms: D000328:Adult; D000650:Amnion / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000502:physiology*; D018925:Chemokines / Q000378:metabolism; D002821:Chorioamnionitis / Q000378:metabolism*; D002823:Chorion / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D007743:Labor, Obstetric / Q000378:metabolism; D007752:Obstetric Labor, Premature / Q000378:metabolism*; D011247:Pregnancy; D055815:Young Adult
chemical_list: D018925:Chemokines; D016207:Cytokines; D058847:Inflammasomes; D020169:Caspases
keywords: PYD and CARD domain containing (PYCARD) protein; apoptosis-associated speck-like protein containing a CARD (ASC); caspase-1; caspase-4; cytokines; fetal inflammatory response; fever; funisitis; inflammasome assembly; intraamniotic inflammation; microbial invasion of the amniotic cavity; neutrophil; parturition; pregnancy; prematurity; preterm birth; pyroptosis