HMGB1 Induces an Inflammatory Response in the Chorioamniotic Membranes That Is Partially Mediated by the Inflammasome.
Spontaneous preterm labor occurs in two subsets of patients with sterile intra-amniotic inflammation, a process induced by alarmins such as high-mobility group box-1 (HMGB1). Inflammasomes are implicated in the process of spontaneous preterm labor. Therefore, we investigated whether HMGB1 initiates an inflammasome-associated inflammatory response in the chorioamniotic membranes. Incubation of the chorioamniotic membranes with HMGB1 1) induced the release of mature IL-1beta and IL-6; 2) upregulated the mRNA expression of the pro-inflammatory mediators NFKB1, IL6, TNF, IL1A, IFNG, and HMGB1 receptors RAGE and TLR2; 3) upregulated the mRNA expression of the inflammasome components NLRP3 and AIM2 as well as NOD proteins (NOD1 and NOD2); 4) increased the protein concentrations of NLRP3 and NOD2; 5) increased the concentration of caspase-1 and the quantity of its active form (p20); and 6) upregulated the mRNA expression and active form of MMP-9. In addition, HMGB1 concentrations in chorioamniotic membrane extracts from women who underwent spontaneous preterm labor were greater than in those from women who had undergone spontaneous labor at term. Collectively, these results show that HMGB1 can induce an inflammatory response in the chorioamniotic membranes, which is partially mediated by the inflammasome. These results provide insight into the mechanisms whereby HMGB1 induces preterm labor and birth in mice and explain why the concentration of this alarmin is increased in women who undergo spontaneous preterm labor.
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, Maryland, and Detroit, Michigan.|Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan.
Olesya
O
Plazyo
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, Maryland, and Detroit, Michigan.|Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan.|Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, Michigan.|Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan.
Roberto
R
Romero
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, Maryland, and Detroit, Michigan.|Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan.
Ronald
R
Unkel
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, Maryland, and Detroit, Michigan.|Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan.
Amapola
A
Balancio
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, Maryland, and Detroit, Michigan.|Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan.
Tara N
TN
Mial
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, Maryland, and Detroit, Michigan.|Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan.
Yi
Y
Xu
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, Maryland, and Detroit, Michigan.|Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan.
Zhong
Z
Dong
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, Maryland, and Detroit, Michigan.|Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan.
Sonia S
SS
Hassan
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, Maryland, and Detroit, Michigan ngomezlo@med.wayne.edu.|Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan.|Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, Michigan.
Nardhy
N
Gomez-Lopez
D000328:Adult; D000650:Amnion / Q000187:drug effects* / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D002823:Chorion / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D024243:HMGB1 Protein / Q000494:pharmacology*; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism*; D010766:Phosphorylation; D047928:Premature Birth / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D055815:Young Adult
D024243:HMGB1 Protein; D058847:Inflammasomes; D018836:Inflammation Mediators; D020170:Caspase 1
AIM2; DAMPs; MMP-9; NLRP3; NOD2; RAGE; TLR-2; alarmins; caspase-1; interleukin-1β; interleukin-6; parturition; pregnancy; preterm birth; preterm labor; sterile inflammation; sterile intra-amniotic inflammation