Inhibition of Pim1 kinase, new therapeutic approach in virus-induced asthma exacerbations
Inhibition of Pim1 kinase, new therapeutic approach in virus-induced asthma exacerbations
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-?-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-?, 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.
783-791
De Vries, Maaike
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Bedke, N.
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Smithers, N.P.
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Loxham, M.
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Howarth, P.H.
ff19c8c4-86b0-4a88-8f76-b3d87f142a21
Nawijn, M.C.
631fd378-8e95-48cc-8bd7-6d56cca3cd8b
Davies, D.E.
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1 March 2016
De Vries, Maaike
b618585d-dc70-4fd7-9544-574d399aec98
Bedke, N.
65c06421-e3b9-4907-bd16-6e2f25f44fd1
Smithers, N.P.
4f48f59c-d9bc-4596-90f0-ad63d414db3d
Loxham, M.
8ef02171-9040-4c1d-8452-2ca34c56facb
Howarth, P.H.
ff19c8c4-86b0-4a88-8f76-b3d87f142a21
Nawijn, M.C.
631fd378-8e95-48cc-8bd7-6d56cca3cd8b
Davies, D.E.
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
De Vries, Maaike, Bedke, N., Smithers, N.P., Loxham, M., Howarth, P.H., Nawijn, M.C. and Davies, D.E.
(2016)
Inhibition of Pim1 kinase, new therapeutic approach in virus-induced asthma exacerbations.
European Respiratory Journal, 47 (3), .
(doi:10.1183/13993003.00171-2015).
(PMID:26869670)
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-?-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-?, 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.
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Accepted/In Press date: 9 December 2015
e-pub ahead of print date: 12 February 2016
Published date: 1 March 2016
Organisations:
Clinical & Experimental Sciences
Identifiers
Local EPrints ID: 390317
URI: http://eprints.soton.ac.uk/id/eprint/390317
ISSN: 0903-1936
PURE UUID: 767bfa3d-47ee-4224-a1d7-3fecb4511ce9
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Date deposited: 23 Mar 2016 12:36
Last modified: 15 Mar 2024 03:50
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Contributors
Author:
Maaike De Vries
Author:
N. Bedke
Author:
N.P. Smithers
Author:
M.C. Nawijn
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