title: Specific inhibition of c-Jun N-terminal kinase delays preterm labour and reduces mortality.
abstract: Preterm labour (PTL) is commonly associated with infection and/or inflammation. Lipopolysaccharide (LPS) from different bacteria can be used to independently or mutually activate Jun N-terminal kinase (JNK)/AP1- or NF-κB-driven inflammatory pathways that lead to PTL. Previous studies using Salmonella abortus LPS, which activates both JNK/AP-1 and NF-κB, showed that selective inhibition of NF-κB delays labour and improves pup outcome. Where labour is induced using Escherichia coli LPS (O111), which upregulates JNK/AP-1 but not NF-κB, inhibition of JNK/AP-1 activation also delays labour. In this study, to determine the potential role of JNK as a therapeutic target in PTL, we investigated the specific contribution of JNK signalling to S. Abortus LPS-induced PTL in mice. Intrauterine administration of S. Abortus LPS to pregnant mice resulted in the activation of JNK in the maternal uterus and fetal brain, upregulation of pro-inflammatory proteins COX-2, CXCL1, and CCL2, phosphorylation of cPLA2 in myometrium, and induction of PTL. Specific inhibition of JNK by co-administration of specific D-JNK inhibitory peptide (D-JNKI) delayed LPS-induced preterm delivery and reduced fetal mortality. This is associated with inhibition of myometrial cPLA2 phosphorylation and proinflammatory proteins synthesis. In addition, we report that D-JNKI inhibits the activation of JNK/JNK3 and caspase-3, which are important mediators of neural cell death in the neonatal brain. Our data demonstrate that specific inhibition of TLR4-activated JNK signalling pathways has potential as a therapeutic approach in the management of infection/inflammation-associated PTL and prevention of the associated detrimental effects to the neonatal brain.
authors.affiliation: Imperial College Parturition Research GroupDepartment of Reproductive Biology, Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UKGene Transfer Technology GroupInstitute for Women's Health, University College London, 86-96 Chenies Mews, London WC1E 6HX, UKProteostasis Therapeutics 200 Technology SquareSuite 402, Cambridge, Massachusetts 02139, USADepartment of Biomedical and Forensic SciencesAnglia Ruskin University, East Road, Cambridge CB1 1PT, UK grisha.pirianov@anglia.ac.uk.
authors.forename: Grisha
authors.initials: G
authors.lastname: Pirianov
authors.affiliation: Imperial College Parturition Research GroupDepartment of Reproductive Biology, Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UKGene Transfer Technology GroupInstitute for Women's Health, University College London, 86-96 Chenies Mews, London WC1E 6HX, UKProteostasis Therapeutics 200 Technology SquareSuite 402, Cambridge, Massachusetts 02139, USADepartment of Biomedical and Forensic SciencesAnglia Ruskin University, East Road, Cambridge CB1 1PT, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: MacIntyre
authors.affiliation: Imperial College Parturition Research GroupDepartment of Reproductive Biology, Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UKGene Transfer Technology GroupInstitute for Women's Health, University College London, 86-96 Chenies Mews, London WC1E 6HX, UKProteostasis Therapeutics 200 Technology SquareSuite 402, Cambridge, Massachusetts 02139, USADepartment of Biomedical and Forensic SciencesAnglia Ruskin University, East Road, Cambridge CB1 1PT, UK.
authors.forename: Yun
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Imperial College Parturition Research GroupDepartment of Reproductive Biology, Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UKGene Transfer Technology GroupInstitute for Women's Health, University College London, 86-96 Chenies Mews, London WC1E 6HX, UKProteostasis Therapeutics 200 Technology SquareSuite 402, Cambridge, Massachusetts 02139, USADepartment of Biomedical and Forensic SciencesAnglia Ruskin University, East Road, Cambridge CB1 1PT, UK.
authors.forename: Simon N
authors.initials: SN
authors.lastname: Waddington
authors.affiliation: Imperial College Parturition Research GroupDepartment of Reproductive Biology, Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UKGene Transfer Technology GroupInstitute for Women's Health, University College London, 86-96 Chenies Mews, London WC1E 6HX, UKProteostasis Therapeutics 200 Technology SquareSuite 402, Cambridge, Massachusetts 02139, USADepartment of Biomedical and Forensic SciencesAnglia Ruskin University, East Road, Cambridge CB1 1PT, UK.
authors.forename: Vasso
authors.initials: V
authors.lastname: Terzidou
authors.affiliation: Imperial College Parturition Research GroupDepartment of Reproductive Biology, Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UKGene Transfer Technology GroupInstitute for Women's Health, University College London, 86-96 Chenies Mews, London WC1E 6HX, UKProteostasis Therapeutics 200 Technology SquareSuite 402, Cambridge, Massachusetts 02139, USADepartment of Biomedical and Forensic SciencesAnglia Ruskin University, East Road, Cambridge CB1 1PT, UK.
authors.forename: Huseyin
authors.initials: H
authors.lastname: Mehmet
authors.affiliation: Imperial College Parturition Research GroupDepartment of Reproductive Biology, Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UKGene Transfer Technology GroupInstitute for Women's Health, University College London, 86-96 Chenies Mews, London WC1E 6HX, UKProteostasis Therapeutics 200 Technology SquareSuite 402, Cambridge, Massachusetts 02139, USADepartment of Biomedical and Forensic SciencesAnglia Ruskin University, East Road, Cambridge CB1 1PT, UK.
authors.forename: Phillip R
authors.initials: PR
authors.lastname: Bennett
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002003:Brucella abortus / Q000737:chemistry; D053148:Caspase 3 / Q000096:biosynthesis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D005313:Fetal Death / Q000517:prevention & control*; D054501:Group II Phospholipases A2 / Q000096:biosynthesis / Q000235:genetics; D007249:Inflammation / Q000201:enzymology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D008070:Lipopolysaccharides; D051379:Mice; D048057:Mitogen-Activated Protein Kinase 10 / Q000096:biosynthesis / Q000235:genetics; D009215:Myometrium / Q000187:drug effects / Q000201:enzymology; D007752:Obstetric Labor, Premature / Q000139:chemically induced / Q000517:prevention & control*; D011247:Pregnancy; D015398:Signal Transduction / Q000187:drug effects; D014599:Uterus / Q000187:drug effects / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D048057:Mitogen-Activated Protein Kinase 10; D048031:JNK Mitogen-Activated Protein Kinases; D054501:Group II Phospholipases A2; C505409:Casp3 protein, mouse; D053148:Caspase 3