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Novel Noncompetitive IL-1 Receptor-Biased Ligand Prevents Infection- and Inflammation-Induced Preterm Birth

Mathieu Nadeau-Vallée, Christiane Quiniou, Julia Palacios, Xin Hou, Atefeh Erfani, Ankush Madaan, Mélanie Sanchez, Kelycia Leimert, Amarilys Boudreault, François Duhamel, José Carlos Rivera, Tang Zhu, Baraa Noueihed, Sarah A. Robertson, Xin Ni, David M. Olson, William Lubell, Sylvie Girard and Sylvain Chemtob
J Immunol August 24, 2015, 1500758; DOI: https://doi.org/10.4049/jimmunol.1500758
Mathieu Nadeau-Vallée
*Department of Pediatrics, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
†Department of Ophthalmology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
‡Department of Pharmacology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
§Department of Pharmacology, University of Montreal, Montreal, Quebec H3C 3J7, Canada;
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Christiane Quiniou
*Department of Pediatrics, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
†Department of Ophthalmology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
‡Department of Pharmacology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
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Julia Palacios
*Department of Pediatrics, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
†Department of Ophthalmology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
‡Department of Pharmacology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
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Xin Hou
*Department of Pediatrics, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
†Department of Ophthalmology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
‡Department of Pharmacology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
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Atefeh Erfani
*Department of Pediatrics, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
†Department of Ophthalmology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
‡Department of Pharmacology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
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Ankush Madaan
*Department of Pediatrics, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
†Department of Ophthalmology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
‡Department of Pharmacology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
¶Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada;
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Mélanie Sanchez
*Department of Pediatrics, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
†Department of Ophthalmology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
‡Department of Pharmacology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
¶Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada;
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Kelycia Leimert
‖Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta TG6 2S2, Canada;
#Department of Pediatrics, University of Alberta, Edmonton, Alberta TG6 2S2, Canada;
**Department of Physiology, University of Alberta, Edmonton, Alberta TG6 2S2, Canada;
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Amarilys Boudreault
*Department of Pediatrics, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
†Department of Ophthalmology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
‡Department of Pharmacology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
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François Duhamel
*Department of Pediatrics, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
†Department of Ophthalmology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
‡Department of Pharmacology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
§Department of Pharmacology, University of Montreal, Montreal, Quebec H3C 3J7, Canada;
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José Carlos Rivera
*Department of Pediatrics, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
†Department of Ophthalmology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
‡Department of Pharmacology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
††Maisonneuve-Rosemont Hospital, Research Center, Montreal, Quebec H1T 2M4, Canada;
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Tang Zhu
*Department of Pediatrics, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
†Department of Ophthalmology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
‡Department of Pharmacology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
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Baraa Noueihed
*Department of Pediatrics, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
†Department of Ophthalmology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
‡Department of Pharmacology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
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Sarah A. Robertson
‡‡Department of Obstetrics and Gynecology, University of Adelaide, Adelaide, South Australia 5005, Australia;
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Xin Ni
§§Department of Obstetrics and Gynecology, Second Military Medical University, Shanghai 200433, China;
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David M. Olson
‖Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta TG6 2S2, Canada;
#Department of Pediatrics, University of Alberta, Edmonton, Alberta TG6 2S2, Canada;
**Department of Physiology, University of Alberta, Edmonton, Alberta TG6 2S2, Canada;
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William Lubell
¶¶Department of Chemistry, University of Montreal, Montreal, Quebec H3C 3J7, Canada;
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Sylvie Girard
*Department of Pediatrics, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
‖‖Department of Obstetrics and Gynecology, CHU Sainte-Justine Research Centre, Montreal, Quebec H3T 1C5, Canada; and
##Department of Physiology, CHU Sainte-Justine Research Centre, Montreal, Quebec H3T 1C5, Canada
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Sylvain Chemtob
*Department of Pediatrics, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
†Department of Ophthalmology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
‡Department of Pharmacology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada;
††Maisonneuve-Rosemont Hospital, Research Center, Montreal, Quebec H1T 2M4, Canada;
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Abstract

Preterm birth (PTB) is firmly linked to inflammation regardless of the presence of infection. Proinflammatory cytokines, including IL-1β, are produced in gestational tissues and can locally upregulate uterine activation proteins. Premature activation of the uterus by inflammation may lead to PTB, and IL-1 has been identified as a key inducer of this condition. However, all currently available IL-1 inhibitors are large molecules that exhibit competitive antagonism properties by inhibiting all IL-1R signaling, including transcription factor NF-κB, which conveys important physiological roles. We hereby demonstrate the efficacy of a small noncompetitive (all-d peptide) IL-1R–biased ligand, termed rytvela (labeled 101.10) in delaying IL-1β–, TLR2-, and TLR4-induced PTB in mice. The 101.10 acts without significant inhibition of NF-κB, and instead selectively inhibits IL-1R downstream stress-associated protein kinases/transcription factor c-jun and Rho GTPase/Rho-associated coiled-coil–containing protein kinase signaling pathways. The 101.10 is effective at decreasing proinflammatory and/or prolabor genes in myometrium tissue and circulating leukocytes in all PTB models independently of NF-κB, undermining NF-κB role in preterm labor. In this work, biased signaling modulation of IL-1R by 101.10 uncovers a novel strategy to prevent PTB without inhibiting NF-κB.

Footnotes

  • This work was supported by the Global Alliance for the Prevention of Prematurity and Stillbirth (an initiative of Seattle Children's) and the Canadian Institute of Health Research. M.N.-V. was supported by a scholarship from the Suzanne Veronneau-Troutman Funds associated with the Department of Ophthalmology of University of Montreal and by the Vision Research Network; J.P. was sponsored by the National Council for Scientific and Technological Development under an agreement with the Canadian Bureau for International Education; A.M. was recipient of the Canadian Institute of Health Research Drug Design Training Program and Systems Biology Training Program; F.D. was recipient of the Canadian Institute of Health Research Frederick Banting and Charles Best Canada Graduate Scholarships (Ph.D.), the Fonds de la Recherche en Santé du Québec Ph.D. Scholarship for Health Professional, the Stars Foundation, the CHU Sainte-Justine's Foundation (Ph.D.), and the Hydro-Québec Scholarship for Excellence (Ph.D.); and S.C. holds a Canada Research Chair (Vision Science) and the Leopoldine Wolfe Chair in translational research in age-related macular degeneration.

  • The online version of this article contains supplemental material.

  • Received March 31, 2015.
  • Accepted July 22, 2015.
  • Copyright © 2015 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 208 (11)
The Journal of Immunology
Vol. 208, Issue 11
1 Jun 2022
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Novel Noncompetitive IL-1 Receptor-Biased Ligand Prevents Infection- and Inflammation-Induced Preterm Birth
Mathieu Nadeau-Vallée, Christiane Quiniou, Julia Palacios, Xin Hou, Atefeh Erfani, Ankush Madaan, Mélanie Sanchez, Kelycia Leimert, Amarilys Boudreault, François Duhamel, José Carlos Rivera, Tang Zhu, Baraa Noueihed, Sarah A. Robertson, Xin Ni, David M. Olson, William Lubell, Sylvie Girard, Sylvain Chemtob
The Journal of Immunology August 24, 2015, 1500758; DOI: 10.4049/jimmunol.1500758

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Novel Noncompetitive IL-1 Receptor-Biased Ligand Prevents Infection- and Inflammation-Induced Preterm Birth
Mathieu Nadeau-Vallée, Christiane Quiniou, Julia Palacios, Xin Hou, Atefeh Erfani, Ankush Madaan, Mélanie Sanchez, Kelycia Leimert, Amarilys Boudreault, François Duhamel, José Carlos Rivera, Tang Zhu, Baraa Noueihed, Sarah A. Robertson, Xin Ni, David M. Olson, William Lubell, Sylvie Girard, Sylvain Chemtob
The Journal of Immunology August 24, 2015, 1500758; DOI: 10.4049/jimmunol.1500758
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