title: Targeting interleukin-6 receptor inhibits preterm delivery induced by inflammation.
abstract: Intrauterine infection is still a common trigger of preterm delivery (PTD) and also a determinant risk factor for the subsequent development of neurodevelopmental abnormalities in neonates. In this study, we examined the expressional pattern of various inflammatory cytokines such as interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) in placentae complicated with severe chorioamnionitis (CAM) and found that IL-6 is mainly expressed in macrophages in villous mesenchyme by immunohistochemical analysis with anti-CD-68 antibody. Using an experimental lipopolysaccharide (LPS)-induced PTD model, the therapeutic potential of targeting this cytokine was investigated. Anti-IL-6 receptor antibody (MR16-1) was delivered 6 h before LPS treatment. Mice in the MR16-1 group had a significantly lower rate of PTD (17%) than in the controls (53%, P = 0.026). As a result, MR16-1 treatment significantly prolonged the gestational period (control; 18.4 ± 1.7d, MR16-1; 19.8 ± 1.5d, P = 0.007) without any apparent adverse events on the mice and their pups. In primary human amniotic epithelial cells, pretreatment with a humanized anti-human IL-6 receptor antibody, tocilizumab, significantly inhibited the production of prostaglandin E2 induced by IL-6. In conclusion, IL-6 was strongly expressed mainly in macrophages in villous mesenchyme in placentae complicated with CAM. Anti-IL-6R antibody significantly decreased the rate of PTD in LPS-induced inflammatory model in mice, and inhibited PGE2 production from human primary amniotic epithelial cells. Targeting IL-6 signaling could be a promising option for the prevention of PTD and needs to be further explored for future clinical application.
authors: Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Atsuko
authors: A
authors: Wakabayashi
authors: Kenjiro
authors: K
authors: Sawada
authors: Masahiro
authors: M
authors: Nakayama
authors: Aska
authors: A
authors: Toda
authors: Akihito
authors: A
authors: Kimoto
authors: Seiji
authors: S
authors: Mabuchi
authors: Yasuto
authors: Y
authors: Kinose
authors: Koji
authors: K
authors: Nakamura
authors: Kazuhiro
authors: K
authors: Takahashi
authors: Hirohisa
authors: H
authors: Kurachi
authors: Tadashi
authors: T
authors: Kimura
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology* / Q000627:therapeutic use; D016022:Case-Control Studies; D002478:Cells, Cultured; D002824:Chorionic Villi / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000150:complications*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D011247:Pregnancy; D047928:Premature Birth / Q000209:etiology / Q000517:prevention & control*; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D000906:Antibodies; D015850:Interleukin-6; D019947:Receptors, Interleukin-6
keywords: chorioamnionitis; interleukin-6; macrophage; preterm delivery; tocilizumab