IL-6R blockade reduces neonatal mortality

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In a recently published study, Dr eBiomedicineResearchers from the United States of America (USA) analyzed human data to investigate the role of interleukin (IL)-6 and IL-1α in sterile intraamniotic inflammation (SIAI), a condition associated with preterm birth (PTB).

Further, they examined the effect of anti-IL-6 receptor monoclonal antibody (aIL-6R) in preventing preterm birth and adverse neonatal outcomes in mouse models.

They found that IL-6 played an important role in human SIAI, and treatment with aIL-6R could significantly reduce IL-1α-induced preterm birth in mice.

Study: Blockade of IL-6R prevents preterm birth and adverse neonatal outcomes.  Image credit: Mircea Moira/Shutterstock.comStudy: Blockade of IL-6R prevents preterm birth and adverse neonatal outcomes. Image credit: Mircea Moira/


PTB is a leading cause of child mortality worldwide and is associated with several long-term consequences in early and adult life. Evidence suggests that intraamniotic inflammation is causally related to preterm labor and birth.

When such an inflammatory response is triggered by an increase in “alarmins” normally in the absence of microbes, the condition is called SIAI, which currently has no approved treatment.

IL-6 is a cytokine that regulates the time of birth that is also used as a reliable marker for intraamniotic inflammation, and IL-1α is an alarmin associated with PTB.

Although cytokine analysis studies have revealed that SIAI correlates with increased levels of IL-6 and IL-1α in amniotic fluid, the mechanisms underlying SIAI and the benefits of blocking IL-6 signaling to prevent PTB remain to be explored.

This blocking-based approach has previously been used to treat other inflammatory conditions in pregnant women. Therefore, researchers in the present study evaluated the translational value of this approach in treating patients with SIAI to prevent PTB and examined the role of IL-1α and IL-6 as mediators of SIAI.

About the study

To study the expression of IL-6 in the chorioamniotic membrane, the researchers analyzed publicly available single-cell ribonucleic acid sequencing (scRNA-seq) data of samples from PTB patients and preterm labor mouse models.

In the experimental part of the study, pregnant female rats were randomized into control (n = 6) and test groups (n = 6). Murine models of SIAI-induced preterm birth were generated by ultrasound-guided intraamniotic injection of IL-1α in C57BL/6 mice.

Similarly, of lipopolysaccharide (LPS). E coli Origin was injected into mice to model germ-induced intraamniotic inflammation. Six hours post-injection with IL-1α or LPS, mice in the test group were intraperitoneally injected with aIL-6R.

Rates of PTB in mother mice and mortality of offspring were measured by video monitoring. Neonatal outcomes of the children were measured in terms of survival, weight, head biparietal diameter and neuromotor behavior.

Free radical levels in the fetal brain were measured using diagnostic-assisted magnetic resonance imaging (QUEST MRI). Gene expression profiling recovered and analyzed maternal-fetal tissue (before PTB) and neonatal tissue (on day 21). The neonatal gut microbiome was characterized using metagenomics tools and bacterial community analysis.

Concentrations of IL-6, IL-1β, and tumor necrosis factor (TNF) were measured in amniotic fluid samples. Statistical analysis involved Fisher’s exact test, Mann-Whitney U-test, Kaplan-Meier survival curve, principal component analysis, and Gehan-Breslow-Wilcoxon test.

Results and discussion

Research shows that different cells express within the chorioamniotic membrane IL6, And the expression varies in preterm and term labor. Corresponding with previous evidence, IL-1α levels were found to be elevated in patients with SIAI versus those without the condition. Intraamniotic injection of IL-1α in mice induces PTB and neonatal death in a dose-dependent manner.

Further, the adverse perinatal effects of elevated IL-1α levels were mitigated by blocking IL-6R using antibody aIL-6R. Although neonatal mortality was reduced by 34%, PTB was reduced by 43%, resulting in an extended gestational length of experimental mice similar to that of control mice.

According to the study, the mechanism underlying the prevention of PTB by IL-6R blockade is the possible dampening of normal labor pathways induced by IL-1α in the uterus, cervix, and fetal membranes.

Notably, injection of LPS increased neonatal mortality and PTB, but aIL-6R treatment did not alter these findings. Fetal brain oxidative stress was observed in LPS-injected mice but not in IL-1α-injected mice, indicating the need for distinct therapeutic approaches to germ-induced and alarmin-induced intraamniotic inflammation.

Treatment with aIL-6R has also been found to protect against fetal growth restriction, enabled by the ability of aIL-6R to transfer from mother to fetus. Moreover, homeostasis of the neonatal gut microbiome was restored, and adverse neonatal outcomes were found to be prevented by aIL-6R treatment.


In conclusion, the study provides mechanistic evidence that adverse fetal and neonatal outcomes associated with SIAI can be prevented by blocking IL-6R through treatment with an antibody.

The findings emphasize the critical role of IL-6 signaling in SIAI-associated PTB and the need and utility of repurposing pregnancy-safe anti-inflammatory drugs to prevent SIAI and PTB.

Further studies are needed to confirm these findings and support the potential utility of aIL-6R treatment in clinical settings.

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