RAGE is the receptor for pro-inflammatory molecules and causes an amplification of the inflammatory response. S100A12, a ligand for RAGE, was recently found to be increased in the amniotic fluid of women with intra-amniotic infection. We determined the expression of the receptor through gestation in cervix (CX) and uterus (UT) and then used an in vivo model to assess if the activation of RAGE by its ligand (HMGB1) causes preterm birth (PTB).
3 sets of experiments were performed: 1) CX and UT tissue were harvested from CD-1 pregnant mice on E15, E17, E19 (n=3-6 mice/group) 2) CD-1 mice were randomized to intrauterine LPS or saline. For these studies, CX and UT were harvested 6 hrs later to assess RAGE and HMGB1 (a ligand to RAGE) expression by QPCR. 3) Recombinant HMGB1 was injected intrauterine (IU) on E15 and mice were monitored for preterm birth (low dose = 5ug/dam, n=6/group; high dose = 20ug/dam, n=5/group).
RAGE mRNA was 2.5 fold increased in the UT(p=<0.05) and 1.4 fold in CX (p=0.03) commpared to NP. Endogenous HMGB1 was up-regulated 1.6 fold (p=0.04) in the UT in intrauterine inflammation. Recombinant HMGB1 did not cause PTB or fetal loss.
RAGE and its ligand are differentially regulated in reproductive tissues during pregnancy. HMGB1, at 4-times the dose sufficient to cause a profound inflammatory response in other models, is insufficient to cause PTB. RAGE or its ligands may be biomarkers of PTB but are unlikely to be a critical mechanism in the pathogenesis of PTB.
© 2008 Mosby, Inc. Published by Elsevier Inc. All rights reserved.