title: Inhibition of Pim1 kinase, new therapeutic approach in virus-induced asthma exacerbations.
abstract: Therapeutic options to treat virus-induced asthma exacerbations are limited and urgently needed. Therefore, we tested Pim1 kinase as potential therapeutic target in human rhinovirus (HRV) infections. We hypothesised that inhibition of Pim1 kinase reduces HRV replication by augmenting the interferon-induced anti-viral response due to increased activity of the janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway.Air-liquid interface (ALI) cultures of primary bronchial epithelial cells (PBECs) from healthy individuals and moderate-to-severe asthmatic volunteers were infected with HRV-16 with or without a specific Pim1 inhibitor; viral replication and induction of anti-viral responses were measured using RT-qPCR. Viral titres were measured by 50% tissue culture infective dose and release of interferon-γ-induced protein 10 (IP-10) and RANTES protein assessed by ELISA. Phosphorylation of STAT-1 was determined using western blotting.Viral replication was reduced in ALI cultures of healthy and asthmatic PBECs treated with the Pim1 inhibitor. Using cultures from healthy donors, enhanced STAT-1 phosphorylation upon inhibition of Pim1 kinase activity resulted in increased mRNA expression of interferon-β, interleukin-29, IP-10 and RANTES 12 h after infection and increased protein levels of IP-10 and RANTES 24 h after infection.We have identified Pim1 kinase as novel target to reduce viral replication in ALI cultures of PBECs. This may open new avenues for therapeutic interventions in virus-induced asthma exacerbations.
authors: University of Groningen, University Medical Center Groningen, Experimental Pulmonology and Inflammation Research, Dept of Pathology and Medical Biology, Groningen, The Netherlands Brooke Laboratory, Academic Unit of Clinical and Experimental Sciences, University of Southampton, Faculty of Medicine, University Hospital Southampton, Southampton, UK University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands m.de.vries04@umcg.nl.
authors: Maaike de
authors: Md
authors: Vries
authors: Brooke Laboratory, Academic Unit of Clinical and Experimental Sciences, University of Southampton, Faculty of Medicine, University Hospital Southampton, Southampton, UK.
authors: Nicole
authors: N
authors: Bedke
authors: Brooke Laboratory, Academic Unit of Clinical and Experimental Sciences, University of Southampton, Faculty of Medicine, University Hospital Southampton, Southampton, UK.
authors: Natalie P
authors: NP
authors: Smithers
authors: Brooke Laboratory, Academic Unit of Clinical and Experimental Sciences, University of Southampton, Faculty of Medicine, University Hospital Southampton, Southampton, UK.
authors: Matthew
authors: M
authors: Loxham
authors: Brooke Laboratory, Academic Unit of Clinical and Experimental Sciences, University of Southampton, Faculty of Medicine, University Hospital Southampton, Southampton, UK National Institute for Health Research, Respiratory Biomedical Research Unit, University Hospital Southampton, Southampton, UK.
authors: Peter H
authors: PH
authors: Howarth
authors: University of Groningen, University Medical Center Groningen, Experimental Pulmonology and Inflammation Research, Dept of Pathology and Medical Biology, Groningen, The Netherlands University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands.
authors: Martijn C
authors: MC
authors: Nawijn
authors: Brooke Laboratory, Academic Unit of Clinical and Experimental Sciences, University of Southampton, Faculty of Medicine, University Hospital Southampton, Southampton, UK National Institute for Health Research, Respiratory Biomedical Research Unit, University Hospital Southampton, Southampton, UK.
authors: Donna E
authors: DE
authors: Davies
mesh_terms: D001249:Asthma / Q000821:virology*; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism*; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors*; D012229:Rhinovirus / Q000502:physiology*; D014779:Virus Replication
chemical_list: C483024:CCL5 protein, human; D018946:Chemokine CCL5; D016207:Cytokines; C573415:IFNG protein, human; D016899:Interferon-beta; D007371:Interferon-gamma; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1