title: Novel Noncompetitive IL-1 Receptor-Biased Ligand Prevents Infection- and Inflammation-Induced Preterm Birth.
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.
authors: 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;
authors: Mathieu
authors: M
authors: Nadeau-Vallée
authors: 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;
authors: Christiane
authors: C
authors: Quiniou
authors: 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;
authors: Julia
authors: J
authors: Palacios
authors: 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;
authors: Xin
authors: X
authors: Hou
authors: 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;
authors: Atefeh
authors: A
authors: Erfani
authors: 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;
authors: Ankush
authors: A
authors: Madaan
authors: 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;
authors: Mélanie
authors: M
authors: Sanchez
authors: 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;
authors: Kelycia
authors: K
authors: Leimert
authors: 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;
authors: Amarilys
authors: A
authors: Boudreault
authors: 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;
authors: François
authors: F
authors: Duhamel
authors: 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;
authors: José Carlos
authors: JC
authors: Rivera
authors: 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;
authors: Tang
authors: T
authors: Zhu
authors: 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;
authors: Baraa
authors: B
authors: Noueihed
authors: Department of Obstetrics and Gynecology, University of Adelaide, Adelaide, South Australia 5005, Australia;
authors: Sarah A
authors: SA
authors: Robertson
authors: Department of Obstetrics and Gynecology, Second Military Medical University, Shanghai 200433, China;
authors: Xin
authors: X
authors: Ni
authors: 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;
authors: David M
authors: DM
authors: Olson
authors: Department of Chemistry, University of Montreal, Montreal, Quebec H3C 3J7, Canada;
authors: William
authors: W
authors: Lubell
authors: 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 sylvain.chemtob@umontreal.ca sylvie.girard@recherche-ste-justine.qc.ca.
authors: Sylvie
authors: S
authors: Girard
authors: 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; sylvain.chemtob@umontreal.ca sylvie.girard@recherche-ste-justine.qc.ca.
authors: Sylvain
authors: S
authors: Chemtob
mesh_terms: D000818:Animals; D002460:Cell Line; D005260:Female; D007249:Inflammation / Q000276:immunology*; D053583:Interleukin-1beta / Q000276:immunology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D051379:Mice; D009215:Myometrium / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D011247:Pregnancy; D047928:Premature Birth / Q000517:prevention & control*; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D051195:Toll-Like Receptor 2 / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology; D014599:Uterus / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
chemical_list: C529594:101.10 peptide; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D016328:NF-kappa B; D010455:Peptides; D017472:Receptors, Interleukin-1; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D054460:rho-Associated Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020741:rho GTP-Binding Proteins