Tocilizumab inhibits interleukin-6-mediated matrix metalloproteinase-2 and -9 secretions from human amnion cells in preterm premature rupture of membranes.
OBJECTIVE
In the present study, we investigated the participation of inflammatory cytokine-induced mediated matrix metalloproteinase (MMP) expressions and inhibition of interleukin (IL)-6-induced MMP secretion in amniotic epithelial cells by tocilizumab.


METHODS
To investigate the role of MMP expressions, immunohistochemical staining was performed using membranes obtained from 10 patients with preterm premature rupture of membranes (PPROM) and from 10 patients who underwent a nonlabor cesarean section. We also investigated the regulation of MMP expression by inflammatory cytokines in human amnion cells.


RESULTS
Immunohistochemical staining showed a significantly higher expression of MMP-2 and -9 in PPROM. Treatment of cultured WISH and primary amniotic epithelial cells with 10(-8) or 10(-7)M IL-6 or tumor necrosis factor (TNF)-alpha clearly increased the secretion of MMP-2 and -9. Treatment with 10(-8)M TNF-alpha or IL-6 significantly increased the invasion of WISH or primary amniotic epithelial cells, respectively, compared with the control. At a low concentration of 1 microg/ml, tocilizumab (anti-human IL-6 receptor monoclonal antibody) inhibited the IL-6-induced MMP secretion.


CONCLUSIONS
This paper is the 1st report of tocilizumab inhibiting IL-6-induced MMP-2 and MMP-9 secretions from human amnion cells in PPROM.
Mano
Yukio
Y
Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
Shibata
Kiyosumi
K
Sumigama
Seiji
S
Hayakawa
Hiromi
H
Ino
Kazuhiko
K
Yamamoto
Eiko
E
Kajiyama
Hiroaki
H
Nawa
Akihiro
A
Kikkawa
Fumitaka
F
D000650:Amnion / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D015153:Blotting, Western; D002460:Cell Line; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D005260:Female; D005322:Premature Rupture of Fetal Membranes / Q000201:enzymology*; D006801:Humans; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D016209:Interleukin-8 / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D010446:Peptide Fragments / Q000494:pharmacology; D011247:Pregnancy; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000093242:Interleukin-6 Inhibitors
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D010446:Peptide Fragments; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C052994:interleukin-1beta (163-171); C502936:tocilizumab