Advanced glycation endproducts mediate pro-inflammatory actions in human gestational tissues via nuclear factor-κB and extracellular signal-regulated kinase 1/2

Processes of human labour include increased oxidative stress, formation of inflammatory mediators (e.g. cytokines) and uterotonic phospholipid metabolites (e.g. Prostaglandins). In non-gestational tissues, advanced glycation endproducts (AGE) induce the expression of pro-inflammatory molecules through mitogen-activated protein kinase and nuclear factor kappa B (NF-kappa B)-dependent pathways. Thus, the aim of this study was to investigate the effects of AGE on 8-isoprostane (a marker of oxidative stress), pro-inflammatory cytokine and prostaglandin release in human gestational tissues, and to define the signalling pathways involved. Human placenta and gestational membranes (amnion and choriodecidua combined; n=5) were incubated in the absence or presence of AGE-BSA (0 center dot 25, 0 center dot 5, 1 and 2 mg/ml) for 18 h. AGE significantly increased in vitro release of tumour necrosis factor-alpha, interleukin (IL)-1 beta, IL-6, IL-8, prostaglandin (PG)E-2, PGF(2 alpha), and 8-isoprostane from human placenta and gestational membranes. This was associated with a concomitant increase in NF-kappa B p65 activation and ERK 1/2 phosphorylation. AGE-stimulated 8-isoprostane, cytokine and prostaglandin production was significantly suppressed by the ERK 1/2 inhibitor U0126 and the NF-kappa B inhibitor BAY 11-7082. In conclusion, AGE mediates inflammatory actions in human gestational tissues. Protein kinases and the NF-kappa B pathway play an essential role in AGE signalling in human gestational tissues.