Role of cathepsin E in decidual macrophage of patients with recurrent miscarriage.
In a previous study, we reported that the cathepsin-cystatin system caused endometrial dysfunction in early pregnancy. Here, we investigated the existence and contribution of cathepsin E in early pregnancy in patients with recurrent miscarriage (RM). The effect of cathepsin deficiency on fertility and female reproductive organs were also analyzed in CatE(-/-) mice. Human studies were conducted in a hospital setting, with informed consent. Cervical mucus was collected from RM patients in early pregnancy (4-6 gestational weeks, n = 21), and the pregnancy outcome was compared prospectively. The cathepsin E expression in decidua of RM patients (n = 49) and normal pregnant women undergoing elective surgical abortion (n = 24) was measured using SDS-PAGE, and western blot analysis. Decidual macrophages were isolated from RM patients (n = 6) and stimulated by lipopolysaccharide (LPS) and interferon gamma (IFN-γ). Results from the mouse model showed that CatE(-/-) mice were fertile, but the litter number was significantly smaller. The uterus of CatE(-/-) mice showed granulation tissue. In human samples, protease activity of cathepsin E measured with Fluorescence-Quenching Substrate (KYS-1) in cervical mucus of patients who developed miscarriage was markedly decreased compared with patients without RM. The expression of cathepsin E in decidua, semi-quantified by SDS-PAGE, western blot analysis was significantly lower in RM patients compared with patients without RM. By double staining immunofluorescence, the staining of cathepsin E was observed in CD14 or CD68 positive cells in all deciduas. Upon stimulation with LPS and IFN-γ, the expression of cathepsin E in cell lysate of decidual macrophages was markedly reduced in RM patients compared with controls. The results suggested that decreased activity of cathepsin E produced by decidual macrophages might be responsible for the induction of miscarriages in some RM patients.
Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho, Nagoya, Aichi 467-8601, Japan.
Shinobu
S
Goto
Yasuhiko
Y
Ozaki
Nobuhiro
N
Suzumori
Atsushi
A
Yasukochi
Tomoyo
T
Kawakubo
Tadahide
T
Furuno
Mamoru
M
Nakanishi
Kenji
K
Yamamoto
Mayumi
M
Sugiura-Ogasawara
D000026:Abortion, Habitual / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D016022:Case-Control Studies; D020059:Cathepsin E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003656:Decidua / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D015536:Down-Regulation; D005260:Female; D005865:Gestational Age; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008098:Litter Size; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011247:Pregnancy; D011446:Prospective Studies; D013997:Time Factors
D008070:Lipopolysaccharides; D007371:Interferon-gamma; D020059:Cathepsin E; C533926:Ctse protein, mouse; C533925:CTSE protein, human
cathepsin E; deciduas; macrophage; proteolysis; recurrent miscarriage