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|Title:||Novel noncompetitive IL-1 receptor-biased ligand prevents infection- and inflammation-induced preterm birth|
|Citation:||Journal of Immunology, 2015; 195(7):3402-3415|
|Publisher:||American Association of Immunologists|
|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; Uterus; Cell Line; Animals; Mice; Premature Birth; Inflammation; rho GTP-Binding Proteins; JNK Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Peptides; NF-kappa B; Receptors, Interleukin-1; Pregnancy; Female; Toll-Like Receptor 2; Toll-Like Receptor 4; Interleukin-1beta; rho-Associated Kinases|
|Rights:||Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved.|
|Appears in Collections:||Pathology publications|
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