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Type: Journal article
Title: Novel noncompetitive IL-1 receptor-biased ligand prevents infection- and inflammation-induced preterm birth
Author: Nadeau-Vallée, M.
Quiniou, C.
Palacios, J.
Hou, X.
Erfani, A.
Madaan, A.
Sanchez, M.
Leimert, K.
Boudreault, A.
Duhamel, F.
Rivera, J.
Zhu, T.
Noueihed, B.
Robertson, S.
Ni, X.
Olson, D.
Lubell, W.
Girard, S.
Chemtob, S.
Citation: Journal of Immunology, 2015; 195(7):3402-3415
Publisher: American Association of Immunologists
Issue Date: 2015
ISSN: 1550-6606
Statement of
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
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.
Keywords: Myometrium
Cell Line
Premature Birth
rho GTP-Binding Proteins
JNK Mitogen-Activated Protein Kinases
p38 Mitogen-Activated Protein Kinases
NF-kappa B
Receptors, Interleukin-1
Toll-Like Receptor 2
Toll-Like Receptor 4
rho-Associated Kinases
Rights: Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved.
DOI: 10.4049/jimmunol.1500758
Appears in Collections:Aurora harvest 3
Pathology publications

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