title: IL-6 trans-signaling system in intra-amniotic inflammation, preterm birth, and preterm premature rupture of the membranes.
abstract: Classic IL-6 signaling is conditioned by the transmembrane receptor (IL-6R) and homodimerization of gp130. During trans-signaling, IL-6 binds to soluble IL-6R (sIL-6R), enabling activation of cells expressing solely gp130. Soluble gp130 (sgp130) selectively inhibits IL-6 trans-signaling. To characterize amniotic fluid (AF) IL-6 trans-signaling molecules (IL-6, sIL-6R, sgp130) in normal gestations and pregnancies complicated by intra-amniotic inflammation (IAI), we studied 301 women during second trimester (n = 39), third trimester (n = 40), and preterm labor with intact (n = 131, 85 negative IAI and 46 positive IAI) or preterm premature rupture of membranes (PPROM; n = 91, 61 negative IAI and 30 positive IAI). ELISA, Western blotting, and real-time RT-PCR were used to investigate AF, placenta, and amniochorion for protein and mRNA expression of sIL-6R, sgp130, IL-6R, and gp130. Tissues were immunostained for IL-6R, gp130, CD15(+) (polymorphonuclear), and CD3(+) (T cell) inflammatory cells. The ability of sIL-6R and sgp130 to modulate basal and LPS-stimulated release of amniochorion matrix metalloprotease-9 was tested ex vivo. We showed that in physiologic gestations, AF sgp130 decreases toward term. AF IL-6 and sIL-6R were increased in IAI, whereas sgp130 was decreased in PPROM. Our results suggested that fetal membranes are the probable source of AF sIL-6R and sgp130. Immunohistochemistry and RT-PCR revealed increased IL-6R and decreased gp130 expression in amniochorion of women with IAI. Ex vivo, sIL-6R and LPS augmented amniochorion matrix metalloprotease-9 release, whereas sgp130 opposed this effect. We conclude that IL-6 trans-signaling molecules are physiologic constituents of the AF regulated by gestational age and inflammation. PPROM likely involves functional loss of sgp130.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Sarah Y
authors.initials: SY
authors.lastname: Lee
authors.forename: Irina A
authors.initials: IA
authors.lastname: Buhimschi
authors.forename: Antonette T
authors.initials: AT
authors.lastname: Dulay
authors.forename: Unzila A
authors.initials: UA
authors.lastname: Ali
authors.forename: Guomao
authors.initials: G
authors.lastname: Zhao
authors.forename: Sonya S
authors.initials: SS
authors.lastname: Abdel-Razeq
authors.forename: Mert O
authors.initials: MO
authors.lastname: Bahtiyar
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Thung
authors.forename: Edmund F
authors.initials: EF
authors.lastname: Funai
authors.forename: Catalin S
authors.initials: CS
authors.lastname: Buhimschi
mesh_terms: D000328:Adult; D000649:Amniocentesis; D000653:Amniotic Fluid / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D050822:Cytokine Receptor gp130 / Q000502:physiology; D005260:Female; D005322:Premature Rupture of Fetal Membranes / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D015850:Interleukin-6 / Q000378:metabolism / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D011247:Pregnancy; D011248:Pregnancy Complications / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D047928:Premature Birth / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology*; D055815:Young Adult; D000093242:Interleukin-6 Inhibitors
chemical_list: D050822:Cytokine Receptor gp130; D018836:Inflammation Mediators; D015850:Interleukin-6; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D019947:Receptors, Interleukin-6; D000093242:Interleukin-6 Inhibitors; C508600:IL6 protein, human