The receptor for advanced glycation end products (RAGE) system in women with intraamniotic infection and inflammation.
OBJECTIVE
Receptor for advanced glycation end products (RAGE) is a multiligand cell-surface receptor part of the immunoglobulin superfamily with crucial roles in inflammation. S100A12/ENRAGE, a biomarker of amniotic fluid (AF) inflammation, is a ligand for RAGE. sRAGE, a competitive soluble RAGE receptor, inhibits RAGE ligands. Here we aimed to investigate the presence and changes in components of the RAGE system in women with intra-amniotic infection and inflammation.


METHODS
AF was retrieved by amniocentesis in 113 women stratified as follows: (1) positive AF culture (+AFC; GA = 27 [20-33] wk; n = 27); (2) negative AF culture (-AFC; GA = 30 [20-36] wk; n = 27); (3) second trimester control (2T-CRL; GA = 19 [15-25] wk; n = 31); (4) third trimester control (3T-CRL; GA = 36 [31-38] wk; n = 28). We used mass spectrometry (SELDI) to detect S100A12/ENRAGE in AF. sRAGE levels were measured using specific immunoassays. Placental pathology was interpreted in relationship to the presence or absence of histologic acute inflammation and immunoreactivity of S100A12/ENRAGE and RAGE. mRNA expression of S100A12/ENRAGE, sRAGE, and RAGE in amniochorion and placental villous tissue was investigated using quantitative real-time polymerase chain reaction (PCR).


RESULTS
Presence of the S100A12/ENRAGE biomarker SELDI peak was confirmed in 70% of the +AFC but in only 10% of the -AFC samples (P < .001). The inflammatory biomarker was absent in all control samples. We further determined that the competitive inhibitor sRAGE is temporally regulated during gestation and that its AF levels are not influenced by the presence of either intra-amniotic infection or inflammation. Histologic choriamnionitis associated with intense staining for S100A12/ENRAGE, particularly in inflammatory cells. The immunoreactivity for extracellular domain of RAGE was localized exclusively to amnion epithelial, decidual, and extravillous trophoblast cells. Yet, acute histologic chorioamnionitis was related to increased gene expression of S100A12/ENRAGE in fetal membranes and decreased sRAGE and RAGE in the placenta.


CONCLUSIONS
The S100A12/ENRAGE system is markedly upregulated in women with intra-amniotic infection and correlates with the degree of inflammation. Further studies remain to elucidate whether the gestational age dependence of the inhibitor molecule sRAGE may explain the higher incidence of infection-related preterm deliveries and especially rupture of the membranes at earlier gestational age.
Buhimschi
Irina A
IA
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA. irina.buhimschi@yale.edu
Zhao
Guomao
G
Pettker
Christian M
CM
Bahtiyar
Mert O
MO
Magloire
Lissa K
LK
Thung
Stephen
S
Fairchild
Tracy
T
Buhimschi
Catalin S
CS
D000328:Adult; D000653:Amniotic Fluid / Q000737:chemistry*; D015415:Biomarkers / Q000032:analysis; D002821:Chorioamnionitis / Q000276:immunology*; D005260:Female; D006801:Humans; D009504:Neutrophils / Q000276:immunology; D011247:Pregnancy; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000032:analysis* / Q000276:immunology; D009418:S100 Proteins / Q000032:analysis* / Q000276:immunology; D000067616:S100A12 Protein; D015854:Up-Regulation
D015415:Biomarkers; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D009418:S100 Proteins; D000067616:S100A12 Protein; C090441:S100A12 protein, human