TY - JOUR
T1 - Novel noncompetitive IL-1 receptor-biased ligand prevents infection- and inflammation-induced preterm birth
AU - Nadeau-Vallée, Mathieu
AU - Quiniou, Christiane
AU - Palacios, Julia
AU - Hou, Xin
AU - Erfani, Atefeh
AU - Madaan, Ankush
AU - Sanchez, Mélanie
AU - Leimert, Kelycia
AU - Boudreault, Amarilys
AU - Duhamel, François
AU - Rivera, José Carlos
AU - Zhu, Tang
AU - Noueihed, Baraa
AU - Robertson, Sarah A.
AU - Ni, Xin
AU - Olson, David M.
AU - Lubell, William
AU - Girard, Sylvie
AU - Chemtob, Sylvain
PY - 2015/10/1
Y1 - 2015/10/1
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.1500758
DO - 10.4049/jimmunol.1500758
M3 - Article
C2 - 26304990
AN - SCOPUS:84942446686
SN - 0022-1767
VL - 195
SP - 3402
EP - 3415
JO - Journal of Immunology
JF - Journal of Immunology
IS - 7
ER -