Advanced glycation end products induce secretion of chemokines and apoptosis in human first trimester trophoblasts.
BACKGROUND
We studied the effects of advanced glycation end products (AGEs), which are known to accumulate in patients with diabetes, autoimmune diseases, or that smoke, on human trophoblasts.


METHODS
First trimester human chorionic villi of 6-10 week gestation were obtained. Expression and localization of the receptor for AGEs (RAGE) was examined by western blotting and immunohistochemistry. Macrophage inflammatory protein (MIP)-1alpha and MIP-1beta, regulated upon activation, normal T-cell expressed and secreted (RANTES), and human chorionic gonadotropin (hCG) in culture medium were measured by ELISA. Trophoblastic apoptosis was evaluated by the Hoechst 33258 staining and the in situ nick end labeling technique.


RESULTS
RAGE was localized in trophoblasts. AGEs significantly stimulated secretion of both MIP-1alpha and MIP-1beta from trophoblasts in a time- and dose-dependent manner. AGEs significantly induced apoptosis and reduced secretion of hCG. Increased secretions of MIP-1alpha and MIP-1beta by AGEs were significantly suppressed by inhibitors of nitric oxide synthase (NOS) or nafamostat mesilate, a synthetic serine protease inhibitor and a suppressor of transcription factor, NF-kappaB activation. These agents also suppressed the effects of AGEs on hCG secretion and trophoblastic apoptosis.


CONCLUSIONS
These AGE-mediated changes in trophoblasts may lead to impairment of implantation and placentation. NOS inhibitors or nafamostat mesilate may modify these effects.
Konishi
H
H
Department of Obstetrics and Gynecology, Okayama University Medical School, 2-5-1 Shikata, Okayama City, Okayama, 700-8558, Japan.
Nakatsuka
M
M
Chekir
C
C
Noguchi
S
S
Kamada
Y
Y
Sasaki
A
A
Hiramatsu
Y
Y
D017209:Apoptosis / Q000187:drug effects*; D001550:Benzamidines; D002478:Cells, Cultured; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D006063:Chorionic Gonadotropin / Q000378:metabolism; D002824:Chorionic Villi / Q000378:metabolism; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011480:Protease Inhibitors / Q000494:pharmacology; D020033:Protein Isoforms / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D014327:Trophoblasts / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*
D001550:Benzamidines; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D018925:Chemokines; D006063:Chorionic Gonadotropin; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D006146:Guanidines; D019402:Macrophage Inflammatory Proteins; D011480:Protease Inhibitors; D020033:Protein Isoforms; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D012710:Serum Albumin, Bovine; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester; C032855:nafamostat