The natural interleukin-1 receptor antagonist prevents interleukin-l-induced preterm delivery in mice

Romero, Roberto; Tartakovsky, Boris

doi:10.1016/s0002-9378(12)80035-4

Cited by 206 publications

(112 citation statements)

References 21 publications

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“…(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).…”

Section: Preterm Labormentioning

confidence: 99%

Sterile inflammation and pregnancy complications: a review

Nadeau-Vallée¹,

Obari²,

Palacios³

et al. 2016

Reproduction

216

161

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Inflammation is essential for successful embryo implantation, pregnancy maintenance and delivery. In the last decade, important advances have been made in regard to endogenous, and therefore non-infectious, initiators of inflammation, which can act through the same receptors as pathogens. These molecules are referred to as damage-associated molecular patterns (DAMPs), and their involvement in reproduction has only recently been unraveled. Even though inflammation is necessary for successful reproduction, untimely activation of inflammatory processes can have devastating effect on pregnancy outcomes. Many DAMPs, such as uric acid, high-mobility group box 1 (HMGB1), interleukin (IL)-1 and cell-free fetal DNA, have been associated with pregnancy complications, such as miscarriages, preeclampsia and preterm birth in preclinical models and in humans. However, the specific contribution of alarmins to these conditions is still under debate, as currently there is lack of information on their mechanism of action. In this review, we discuss the role of sterile inflammation in reproduction, including early implantation and pregnancy complications. Particularly, we focus on major alarmins vastly implicated in numerous sterile inflammatory processes, such as uric acid, HMGB1, IL-1α and cell-free DNA (especially that of fetal origin) while giving an overview of the potential role of other candidate alarmins.Reproduction (2016) 152 R277-R292

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Section: Preterm Labormentioning

confidence: 99%

Sterile inflammation and pregnancy complications: a review

Nadeau-Vallée¹,

Obari²,

Palacios³

et al. 2016

Reproduction

216

161

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“…injection of either LTA (3 3 3-h interval injections of 12.5 mg/kg in 100 mL saline), LPS (a single dose of 0.5 mg in 100 mL saline), or a single intrauterine injection of IL-1b (1 mg). Doses of IL-1b, LPS, and LTA and frequencies of administration used were selected on the basis of reported documentation (8,16,26,27) and on in vivo doseresponse experiments we performed that would induce PTB in a reproducible manner. For the IL-1b-induced PTB model, animals were steadily anesthetized with an isoflurane mask.…”

Section: Cell Culturementioning

confidence: 99%

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

Nadeau-Vallée

Quiniou

Palacios

et al. 2015

The Journal of Immunology

101

123

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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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“…Uterine cytokines, especially interleukin 1 or 2, probably acting via stimulation of decidual PGE 2 production (Dudley et al 1993), are implicated in the initiation of parturition in the mouse (Romero et al 1991, Romero & Tartakovsky 1992, Fidel et al 1994, Hirsch et al 1995, Kaga et al 1996, particularly in pre-term parturition provoked by bacterial endotoxin (Kaga et al 1996); although not via direct acute actions on the myometrium (Oshiro et al 1993), there is circumstantial evidence for a role for neutrophils in the uterus in parturition onset (Kasik & Rice 1995). The pregnant mouse uterus contracts in response to PGE 2 , and depolarisation sensitivity is much greater in late pregnancy than in early pregnancy (Suzuki & Kuriyama 1975a).…”

Section: Parturition In the Mousementioning

confidence: 99%