Novel Noncompetitive IL-1 Receptor-Biased Ligand Prevents Infection-and Inflammation-Induced Preterm Birth

作者：Nadeau Vallee Mathieu; Quiniou Christiane; Palacios Julia; Hou Xin; Erfani Atefeh; Madaan Ankush; Sanchez Melanie; Leimert Kelycia; Boudreault Amarilys; Duhamel Francois; Rivera Jose Carlos; Zhu Tang; Noueihed Baraa; Robertson Sarah A; Ni Xin; Olson David M; Lubell William; Girard Sylvie; Chemtob Sylvain^*

来源：The Journal of Immunology, 2015, 195(7): 3402-3415.

DOI：10.4049/jimmunol.1500758

Preterm birth (PTB) is firmly linked to inflammation regardless of the presence of infection. Proinflammatory cytokines, including IL-1 beta, 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-kappa B, 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-1 beta-, TLR2-, and TLR4-induced PTB in mice. The 101.10 acts without significant inhibition of NF-kappa B, 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-kappa B, undermining NF-kappa B 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-kappa B.

• 出版日期2015-10-1
• 单位McGill; 中国人民解放军第二军医大学