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.

Alginate-liposomal construct for bupivacaine delivery and MSC function regulation

“…The molecular signatures evaluated in our studies for overall cell function (IL-6), anti-inflammatory function (PGE2), and regenerative function (TGF-β1) shared molecular mediators such as p38-MAPK, ROS, and Ca 2+ that in the presence of bupivacaine should increase their expression and secretion [39–42]. Some were regulators of each other, such as PGE2 increasing the expression of TGF-β1 [43, 44] and IL-6 [45, 46] in addition to TGF-β1 and IL-6 increasing the production of PGE2 [47, 48]. However, the secretion patterns observed in our studies differed for each cytokine and bupivacaine formulation over time.…”

Interleukin (IL)‐1 in rat parturition: IL‐1 receptors 1 and 2 and accessory proteins abundance in pregnant rat uterus at term – regulation by progesterone

“…) or receptor inhibition by the specific antibody, tocilizumab, (Wakabayashi et al. ) or administration of the naturally occurring IL‐1 receptor antagonist (IL‐1RA) (Romero and Tartakovsky ) or 101.10, a specific small peptide allosteric receptor antagonist to IL‐1R accessory protein (IL‐1R AcP) (Nadeau‐Vallée et al. ), delay term or preterm delivery in mouse models (Romero et al.…”

“…It is widely accepted that the process of parturition utilizes inflammatory mediators (Christiaens et al 2008;Fang et al 2000;Liggins et al 1977;Romero et al 1989). Interleukin-1 (IL-1a and b forms) (Romero et al 1991) and IL-6, (Gomez-Lopez et al 2016;Robertson et al 2010) for instance, are essential for on-time delivery as IL-6 gene deletion (Robertson et al 2010) or receptor inhibition by the specific antibody, tocilizumab, (Wakabayashi et al 2013) or administration of the naturally occurring IL-1 receptor antagonist (IL-1RA) (Romero and Tartakovsky 1992) or 101.10, a specific small peptide allosteric receptor antagonist to IL-1R accessory protein (IL-1R AcP) (Nadeau-Vall ee et al 2015), delay term or preterm delivery in mouse models (Romero et al 1989). Mouse models are exquisitely sensitive to lipopolysaccharide (LPS), a gram-negative, toll-like receptor (TLR) 4 agonist, lipoteichoic acid (LTA) a gram-positive TLR2 agonist or IL-1b induction of preterm delivery (Hirsch et al 2002;Nadeau-Vall ee et al 2015).…”

Nrf2 regulates gene-environment interactions in an animal model of intrauterine inflammation: Implications for preterm birth and prematurity

“…Additionally, cytokine levels of IL-6 and TNFα were significantly elevated in Nrf2 −/− placentas after LPS treatment. Inhibitors of IL-6 and TNFα have both been shown to attenuate preterm delivery, fetal death, and intrauterine growth restriction in mice515253. Interestingly, the transcriptional analysis also observed a significant increase in prostanglandin D2 synthase (Ptgds), which is a marker of preterm labor in women and promotes PTB in mice54.…”