Targeting interleukin-6 receptorinhibits 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 subsequentdevelopment 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-a (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 1/4 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 1/4 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-6was strongly expressed mainly in macrophages in villous mesenchyme in placentae complicated withCAM. Anti-IL-6Rantibody significantly decreased the rate of PTD in LPS-induced inflammatory model in mice, and inhibited PGE2 production from human primaryamniotic epithelial cells. Targeting IL-6 signaling could be a promising option for the prevention ofPTDand needs to be further explored for future clinical application. © The Author 2013. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.