Antenatal Suppression of IL-1 Protects against Inflammation-Induced Fetal Injury and Improves Neonatal and Developmental Outcomes in Mice.
Preterm birth (PTB) is commonly accompanied by in utero fetal inflammation, and existing tocolytic drugs do not target fetal inflammatory injury. Of the candidate proinflammatory mediators, IL-1 appears central and is sufficient to trigger fetal loss. Therefore, we elucidated the effects of antenatal IL-1 exposure on postnatal development and investigated two IL-1 receptor antagonists, the competitive inhibitor anakinra (Kineret) and a potent noncompetitive inhibitor 101.10, for efficacy in blocking IL-1 actions. Antenatal exposure to IL-1β inducedTnfa,Il6,Ccl2,Pghs2, andMpges1expression in placenta and fetal membranes, and it elevated amniotic fluid IL-1β, IL-6, IL-8, and PGF2α, resulting in PTB and marked neonatal mortality. Surviving neonates had increasedIl1b,Il6,Il8,Il10,Pghs2,Tnfa, andCrpexpression in WBCs, elevated plasma levels of IL-1β, IL-6, and IL-8, increased IL-1β, IL-6, and IL-8 in fetal lung, intestine, and brain, and morphological abnormalities: e.g., disrupted lung alveolarization, atrophy of intestinal villus and colon-resident lymphoid follicle, and degeneration and atrophy of brain microvasculature with visual evoked potential anomalies. Late gestation treatment with 101.10 abolished these adverse outcomes, whereas Kineret exerted only modest effects and no benefit for gestation length, neonatal mortality, or placental inflammation. In a LPS-induced model of infection-associated PTB, 101.10 prevented PTB, neonatal mortality, and fetal brain inflammation. There was no substantive deviation in postnatal growth trajectory or adult body morphometry after antenatal 101.10 treatment. The results implicate IL-1 as an important driver of neonatal morbidity in PTB and identify 101.10 as a safe and effective candidate therapeutic.
Department of Pediatrics, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.|Department of Ophthalmology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.|Department of Pharmacology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.|Department of Pharmacology, University of Montreal, Montreal, Quebec H3T 1J4, Canada.
Mathieu
M
Nadeau-Vallée
Department of Obstetrics and Gynecology, Adelaide Medical School and Robinson Research Institute, University of Adelaide, Adelaide, South Australia 5005, Australia.
Peck-Yin
0000-0002-0923-0553
PY
Chin
Department of Pediatrics, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.|Department of Ophthalmology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.|Department of Pharmacology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.
Lydia
L
Belarbi
Department of Obstetrics and Gynecology, University of Montreal, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1J4, Canada.|Department of Microbiology, Infectiology, and Immunology, University of Montreal, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1J4, Canada.
Marie-Ève
MÈ
Brien
Department of Pediatrics, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.|Department of Ophthalmology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.|Department of Pharmacology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.|Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada.
Sheetal
S
Pundir
Department of Neurosciences, CHU Sainte-Justine Research Center, University of Montreal, Montreal, Quebec H3T 1J4, Canada.
Martin H
MH
Berryer
Department of Pediatrics, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.|Department of Ophthalmology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.|Department of Pharmacology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.
Alexandra
0000-0002-5974-8916
A
Beaudry-Richard
Department of Pediatrics, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.|Department of Ophthalmology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.|Department of Pharmacology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.|Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada.
Ankush
A
Madaan
Department of Obstetrics and Gynecology, Adelaide Medical School and Robinson Research Institute, University of Adelaide, Adelaide, South Australia 5005, Australia.
David J
0000-0002-4831-7950
DJ
Sharkey
Department of Neurosciences, CHU Sainte-Justine Research Center, University of Montreal, Montreal, Quebec H3T 1J4, Canada.
Alexis
0000-0003-2735-3554
A
Lupien-Meilleur
Department of Pediatrics, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.|Department of Ophthalmology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.|Department of Pharmacology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.
Xin
X
Hou
Department of Pediatrics, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.|Department of Ophthalmology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.|Department of Pharmacology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.
Christiane
C
Quiniou
Department of Pediatrics, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.|Department of Ophthalmology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.|Department of Pharmacology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.
Alexandre
A
Beaulac
Department of Obstetrics and Gynecology, University of Montreal, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1J4, Canada.|Department of Microbiology, Infectiology, and Immunology, University of Montreal, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1J4, Canada.
Ines
I
Boufaied
Department of Pediatrics, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.|Department of Ophthalmology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.|Department of Pharmacology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.
Amarilys
A
Boudreault
Department of Obstetrics and Gynecology, University of Montreal, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1J4, Canada.|Department of Microbiology, Infectiology, and Immunology, University of Montreal, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1J4, Canada.
Adriana
A
Carbonaro
Department of Chemistry, University of Montreal, Montreal, Quebec H3T 1J4, Canada.
Ngoc-Duc
ND
Doan
Department of Pediatrics, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.|Department of Ophthalmology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.|Department of Pharmacology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.|Department of Pharmacology, University of Montreal, Montreal, Quebec H3T 1J4, Canada.
Jean-Sebastien
0000-0003-3877-9614
JS
Joyal
Department of Chemistry, University of Montreal, Montreal, Quebec H3T 1J4, Canada.
William D
0000-0002-3080-2712
WD
Lubell
Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta T6G 2R3, Canada.|Department of Pediatrics, University of Alberta, Edmonton, Alberta T6G 2R3, Canada; and.|Department of Physiology, University of Alberta, Edmonton, Alberta T6G 2R3, Canada.
David M
DM
Olson
Department of Obstetrics and Gynecology, Adelaide Medical School and Robinson Research Institute, University of Adelaide, Adelaide, South Australia 5005, Australia; sylvain.chemtob@umontreal.ca sylvie.girard@recherche-ste-justine.qc.ca sarah.robertson@adelaide.edu.au.
Sarah A
SA
Robertson
Department of Obstetrics and Gynecology, University of Montreal, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1J4, Canada; sylvain.chemtob@umontreal.ca sylvie.girard@recherche-ste-justine.qc.ca sarah.robertson@adelaide.edu.au.|Department of Microbiology, Infectiology, and Immunology, University of Montreal, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1J4, Canada.
Sylvie
S
Girard
Department of Pediatrics, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada; sylvain.chemtob@umontreal.ca sylvie.girard@recherche-ste-justine.qc.ca sarah.robertson@adelaide.edu.au.|Department of Ophthalmology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.|Department of Pharmacology, CHU Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.|Department of Pharmacology, University of Montreal, Montreal, Quebec H3T 1J4, Canada.|Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada.
Sylvain
S
Chemtob
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology*; D018836:Inflammation Mediators / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000627:therapeutic use; D010920:Placenta / Q000187:drug effects / Q000276:immunology*; D011247:Pregnancy / Q000276:immunology*; D047928:Premature Birth / Q000188:drug therapy / Q000276:immunology*
C529594:101.10 peptide; D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D010455:Peptides