A novel modulator of IL-6R prevents inflammation-induced preterm birth and improves newborn outcome
Abstract Preterm birth (PTB) is a major cause of neonatal mortality and morbidity. Evidence supports a determinant role for interleukin-6 (IL-6) in the pathophysiology of PTB. Our group developed a small peptide, HSJ633, that antagonizes the interleukin-6 receptor (IL-6R). Binding assays performed o...
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Springer Nature
2025-07-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.1038/s44321-025-00257-9 |
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| author | France Côté Elizabeth Prairie Estefania Marin Sierra Christiane Quiniou Tiffany Habelrih Wendy Xu Béatrice Ferri Xin Hou Isabelle Lahaie Nadia Côté Sarah-Eve Loiselle Laurence Gobeil Kevin Sawaya Aurélie Faucher Amélie Beaulieu Sandrine Delisle Marie-Pénélope Simard Mohammad Ali Mohammad Nezhady Véronique Laplante Allan Reuben Sidi Mohamed Kalaidji Emmanuel Bajon Gael Cagnone Kelycia B Leimert Jean-François Gauchat Luc Gaudreau Sarah Robertson William D Lubell David M Olson Sylvain Chemtob |
| author_facet | France Côté Elizabeth Prairie Estefania Marin Sierra Christiane Quiniou Tiffany Habelrih Wendy Xu Béatrice Ferri Xin Hou Isabelle Lahaie Nadia Côté Sarah-Eve Loiselle Laurence Gobeil Kevin Sawaya Aurélie Faucher Amélie Beaulieu Sandrine Delisle Marie-Pénélope Simard Mohammad Ali Mohammad Nezhady Véronique Laplante Allan Reuben Sidi Mohamed Kalaidji Emmanuel Bajon Gael Cagnone Kelycia B Leimert Jean-François Gauchat Luc Gaudreau Sarah Robertson William D Lubell David M Olson Sylvain Chemtob |
| author_sort | France Côté |
| collection | DOAJ |
| description | Abstract Preterm birth (PTB) is a major cause of neonatal mortality and morbidity. Evidence supports a determinant role for interleukin-6 (IL-6) in the pathophysiology of PTB. Our group developed a small peptide, HSJ633, that antagonizes the interleukin-6 receptor (IL-6R). Binding assays performed on HEK-Blue IL-6 cells reveal that HSJ633 appears to bind to IL-6R on a site remote from the IL-6 binding domain. Concordantly, HSJ633 selectively inhibits STAT3 phosphorylation while preserving the activation of cytoprotective AKT, p38, and ERK 1/2. In vivo, in a murine model of LPS-induced PTB, HSJ633 reduces inflammation in gestational and fetal tissues, preserves the integrity of fetal organs, and improves the survival of neonatal progeny when administered before and after the induction of labor by an inflammatory stimulus. Relevantly, the pharmacological inhibition of STAT3 in mice is sufficient to prevent PTB. Findings reveal first-in-class efficacy of a small peptide inhibitor of IL-6R, namely HSJ633, in impeding the inflammatory cascade associated with PTB and mitigating adverse neonatal outcomes. |
| format | Article |
| id | doaj-art-2006da86e9f54f79baa1a75df3f7815c |
| institution | DOAJ |
| issn | 1757-4684 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-2006da86e9f54f79baa1a75df3f7815c2025-08-20T03:05:53ZengSpringer NatureEMBO Molecular Medicine1757-46842025-07-011781950198210.1038/s44321-025-00257-9A novel modulator of IL-6R prevents inflammation-induced preterm birth and improves newborn outcomeFrance Côté0Elizabeth Prairie1Estefania Marin Sierra2Christiane Quiniou3Tiffany Habelrih4Wendy Xu5Béatrice Ferri6Xin Hou7Isabelle Lahaie8Nadia Côté9Sarah-Eve Loiselle10Laurence Gobeil11Kevin Sawaya12Aurélie Faucher13Amélie Beaulieu14Sandrine Delisle15Marie-Pénélope Simard16Mohammad Ali Mohammad Nezhady17Véronique Laplante18Allan Reuben19Sidi Mohamed Kalaidji20Emmanuel Bajon21Gael Cagnone22Kelycia B Leimert23Jean-François Gauchat24Luc Gaudreau25Sarah Robertson26William D Lubell27David M Olson28Sylvain Chemtob29Department of Pharmacology and Physiology, Université de MontréalDepartment of Pharmacology and Physiology, Université de MontréalCHU Sainte-Justine Research CenterCHU Sainte-Justine Research CenterDepartment of Pharmacology and Physiology, Université de MontréalDepartment of Obstetrics and Gynaecology, University of AlbertaDepartment of Pharmacology and Physiology, Université de MontréalCHU Sainte-Justine Research CenterCHU Sainte-Justine Research CenterDepartment of Biology, Université de SherbrookeDepartment of Pharmacology and Physiology, Université de MontréalDepartment of Biology, Université de SherbrookeDepartment of Microbiology and Immunology, McGill UniversityDepartment of Biology, Université de SherbrookeDepartment of Pharmacology and Physiology, Université de MontréalDepartment of Biochemistry, Université de MontréalDepartment of Pharmacology and Physiology, Université de MontréalCHU Sainte-Justine Research CenterDepartment of Pharmacology and Physiology, Université de MontréalDepartment of Electrical and Computer Engineering, McGill UniversityCHU Sainte-Justine Research CenterCHU Sainte-Justine Research CenterCHU Sainte-Justine Research CenterDepartment of Obstetrics and Gynaecology, University of AlbertaDepartment of Pharmacology and Physiology, Université de MontréalDepartment of Biology, Université de SherbrookeMedical Sciences, The University of AdelaideDepartment of Chemistry, Université de MontréalDepartment of Obstetrics and Gynaecology, University of AlbertaDepartment of Pharmacology and Physiology, Université de MontréalAbstract Preterm birth (PTB) is a major cause of neonatal mortality and morbidity. Evidence supports a determinant role for interleukin-6 (IL-6) in the pathophysiology of PTB. Our group developed a small peptide, HSJ633, that antagonizes the interleukin-6 receptor (IL-6R). Binding assays performed on HEK-Blue IL-6 cells reveal that HSJ633 appears to bind to IL-6R on a site remote from the IL-6 binding domain. Concordantly, HSJ633 selectively inhibits STAT3 phosphorylation while preserving the activation of cytoprotective AKT, p38, and ERK 1/2. In vivo, in a murine model of LPS-induced PTB, HSJ633 reduces inflammation in gestational and fetal tissues, preserves the integrity of fetal organs, and improves the survival of neonatal progeny when administered before and after the induction of labor by an inflammatory stimulus. Relevantly, the pharmacological inhibition of STAT3 in mice is sufficient to prevent PTB. Findings reveal first-in-class efficacy of a small peptide inhibitor of IL-6R, namely HSJ633, in impeding the inflammatory cascade associated with PTB and mitigating adverse neonatal outcomes.https://doi.org/10.1038/s44321-025-00257-9InflammationInterleukin-6Neonatal MortalityNon-competitive ModulatorPreterm Birth |
| spellingShingle | France Côté Elizabeth Prairie Estefania Marin Sierra Christiane Quiniou Tiffany Habelrih Wendy Xu Béatrice Ferri Xin Hou Isabelle Lahaie Nadia Côté Sarah-Eve Loiselle Laurence Gobeil Kevin Sawaya Aurélie Faucher Amélie Beaulieu Sandrine Delisle Marie-Pénélope Simard Mohammad Ali Mohammad Nezhady Véronique Laplante Allan Reuben Sidi Mohamed Kalaidji Emmanuel Bajon Gael Cagnone Kelycia B Leimert Jean-François Gauchat Luc Gaudreau Sarah Robertson William D Lubell David M Olson Sylvain Chemtob A novel modulator of IL-6R prevents inflammation-induced preterm birth and improves newborn outcome EMBO Molecular Medicine Inflammation Interleukin-6 Neonatal Mortality Non-competitive Modulator Preterm Birth |
| title | A novel modulator of IL-6R prevents inflammation-induced preterm birth and improves newborn outcome |
| title_full | A novel modulator of IL-6R prevents inflammation-induced preterm birth and improves newborn outcome |
| title_fullStr | A novel modulator of IL-6R prevents inflammation-induced preterm birth and improves newborn outcome |
| title_full_unstemmed | A novel modulator of IL-6R prevents inflammation-induced preterm birth and improves newborn outcome |
| title_short | A novel modulator of IL-6R prevents inflammation-induced preterm birth and improves newborn outcome |
| title_sort | novel modulator of il 6r prevents inflammation induced preterm birth and improves newborn outcome |
| topic | Inflammation Interleukin-6 Neonatal Mortality Non-competitive Modulator Preterm Birth |
| url | https://doi.org/10.1038/s44321-025-00257-9 |
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