Advanced glycation endproducts mediate pro-inflammatory actions in human gestational tissues via nuclear factor-kappaB 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 kappaB (NF-kappaB)-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 (0.25, 0.5, 1 and 2 mg/ml) for 18 h. AGE significantly increased in vitro release of tumour necrosis factor-alpha, interleukin (IL)-1beta, IL-6, IL-8, prostaglandin (PG)E(2), PGF(2alpha) and 8-isoprostane from human placenta and gestational membranes. This was associated with a concomitant increase in NF-kappaB 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-kappaB inhibitor BAY 11-7082. In conclusion, AGE mediates inflammatory actions in human gestational tissues. Protein kinases and the NF-kappaB pathway play an essential role in AGE signalling in human gestational tissues.
Lappas
Martha
M
Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Level 4/163 Studley Road, Heidelberg, Victoria, Australia. mlappas@unimelb.edu.au
Permezel
Michael
M
Rice
Gregory E
GE
D000704:Analysis of Variance; D015415:Biomarkers / Q000032:analysis; D002070:Butadienes / Q000494:pharmacology; D015237:Dinoprost / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism; D015232:Dinoprostone / Q000032:analysis / Q000378:metabolism; D005321:Extraembryonic Membranes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D005260:Female; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D006801:Humans; D007375:Interleukin-1 / Q000032:analysis / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D010920:Placenta / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D011247:Pregnancy / Q000378:metabolism*; D013268:Stimulation, Chemical; D013450:Sulfones / Q000494:pharmacology; D046509:Tissue Culture Techniques; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D015415:Biomarkers; D002070:Butadienes; D017127:Glycation End Products, Advanced; D007375:Interleukin-1; D016328:NF-kappa B; D009570:Nitriles; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; C113580:U 0126; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; D048052:Mitogen-Activated Protein Kinase 3; D015232:Dinoprostone