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.