IL-6 trans-signaling system in intra-amniotic inflammation, preterm birth, and preterm premature rupture of the membranes

• Published in: The Journal of immunology (1950) 2011-03, Vol.186 (5), p.3226-3236
• Main Authors: Lee, Sarah Y, Buhimschi, Irina A, Dulay, Antonette T, Ali, Unzila A, Zhao, Guomao, Abdel-Razeq, Sonya S, Bahtiyar, Mert O, Thung, Stephen F, Funai, Edmund F, Buhimschi, Catalin S
• Format: Article
• Language: English
• Subjects: Adult; Amniocentesis; Amniotic Fluid - enzymology; Amniotic Fluid - immunology; Amniotic Fluid - metabolism; Cytokine Receptor gp130 - physiology; Female; Fetal Membranes, Premature Rupture - enzymology; Fetal Membranes, Premature Rupture - immunology; Fetal Membranes, Premature Rupture - pathology; Humans; Infant, Newborn; Infant, Premature; Inflammation Mediators - antagonists & inhibitors; Inflammation Mediators - metabolism; Inflammation Mediators - physiology; Interleukin-6 - antagonists & inhibitors; Interleukin-6 - metabolism; Interleukin-6 - physiology; Matrix Metalloproteinase 9 - secretion; Matrix Metalloproteinase Inhibitors; Pregnancy; Pregnancy Complications - enzymology; Pregnancy Complications - immunology; Pregnancy Complications - pathology; Premature Birth - enzymology; Premature Birth - immunology; Premature Birth - pathology; Receptors, Interleukin-6 - antagonists & inhibitors; Receptors, Interleukin-6 - physiology; Signal Transduction - immunology; Young Adult
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1003587

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.