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Evidence for participation of rage (receptor for advanced glycation end products), soluble rage (sRAGE) and S100A12 proteins, in control of the inflammatory response of amniotic cavity during pregnancy

      Objective

      RAGE (NF-B activator) is a novel membrane cell-surface receptor with role in inflammation. S100A12 (proteomic biomarker of inflammation) is a ligand for RAGE. sRAGE competitively inhibits RAGE ligands. Studies were conducted to understand the relationships among RAGE, sRAGE and S100A12 in the amniotic fluid (AF) and fetal tissues of women with PTL in the presence or absence of intra-AF infection/inflammation (IAI/I).

      Study design

      AF was retrieved by amniocentesis in 93 consecutive women stratified as follows: i) +AFC: positive AF culture, n=20, GA=27.1±0.7wks; ii) −AFC: negative AF culture, n=30, GA=28.7±0.9 wks; iii) 2nd trim. control, n=15, GA=18.5±0.4wks; iv) 3rd trim. control, n=28, GA=36.7±0.4wks. sRAGE and IL-6 levels were measured by highly specific immunoassay. Each sample was subjected to mass spectrometry (SELDI) for detection of S100A12. Fetal membranes, cord and placenta were stained for RAGE and S100A12 protein.

      Results

      The S100A12 [10.4kDa] biomarker was present in 70%(14/20) of women with +AFC but only in 10%(3/30) of women with –AFC(p<0.001). Its presence correlated with AF levels of IL-6 (r=0.63, p<0.001) and AF WBC count (r=0.71, p<0.001). No control had the S100A12 SELDI biomarker peak. Levels of the inhibitor sRAGE were not influenced by presence or absence of IAI/I but increased directly with increasing GA (r=0.67, p<0.001) [Figure]. Staining for RAGE was present in all fetal membranes, and did not vary with IAI/I. Staining for S100A12 was selectively and markedly increased in the amnion and chorio-decidua of patients with IAI/I.
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      Conclusion

      The proinflammatory ligand S100A12 is upregulated in the presence of IAI/I. Its receptor RAGE and inhibitor sRAGE are selectively present in fetal membranes and AF, respectively. The GA dependence of sRAGE may explain the higher incidence of IAI/I-related prematurity at earlier GAs.