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.

Distinct Signaling Patterns of Allosteric Antagonism at the P2Y1 Receptor

“…For example, Muniz-Medina et al (2009) demonstrated that the allosteric antagonists of CCR5 maraviroc and aplaviroc have a dramatic difference in potency in blocking human immunodeficiency virus entry and CCR5 internalization. Nadeau-Vallée et al (2015) reported that some interleukin-1 inhibitors inhibit c-jun and RhoGTPase/Rho-associated coiledcoil-containing protein kinase but not nuclear factor-kB signaling, which could prevent inflammation-related conditions without the potential side effects caused by balanced antagonists.…”

Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development

“…55 Indeed delivery of a synthetic peptide to pregnant mice that is a selective IL-1 receptor modulator, delays IL-1β delays and LPS-induced preterm birth. 56 Unlike most other cytokines, IL-1β production involves a two-step process. The first step requires induction of pro-IL-1β expression.…”

Sterile inflammation and pregnancy complications: a review

“…Additionally, IL-1 is known to exacerbate inflammation in placenta (Baergen et al 1994, Nadeau-Vallee et al 2015b, the key organ in PE. Accordingly, variation in the IL-1α and IL-1Ra genes has been associated with increased risk of PE (Hefler et al 2001, Ghasemi et al 2015.…”

“…(1) stimulation of IL-1R induces the transcription of numerous pro-labor genes via MAPK p38, JNK, c-jun and small GTPase Rho in myometrial smooth muscle cells, which results in increased myometrial contractility (Tribe et al 2003, Chevillard et al 2007, Nadeau-Vallee et al 2015b; and preterm labor in mice and non-human primates (Romero et al 1991, Sadowsky et al 2006; (2) antagonism of IL-1R prevents all of these events (Romero & Tartakovsky 1992, Nadeau-Vallee et al 2015b; (3) IL-1α amniotic fluid levels are elevated in women that deliver preterm (Figueroa et al 2005); (4) preterm labor is associated with increased IL-1α activity in amniotic fluids (Romero et al 1989); and (5) maternal polymorphisms and haplotypes in the IL-1α gene (Sata et al 2009), as well as fetal polymorphism in the endogenous IL-1R antagonist (Witkin et al 2003), have been associated with increased risk of preterm birth. The critical role of IL-1 in preterm labor has been reviewed elsewhere (Nadeau-Vallee et al 2015a).…”