Imperial College London
Alternate

RESEARCH TECHNICIAN

Faculty of Medicine, National Heart & Lung Institute

Research Technician
 
 
 
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Contact

 

+44 (0)20 7594 7897p.fenwick

 
 
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Location

 

Technician Room 229BGuy Scadding BuildingRoyal Brompton Campus

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Summary

 

Publications

Citation

BibTex format

@article{Fenwick:2015:10.1371/journal.pone.0128757,
author = {Fenwick, PS and Macedo, P and Barnes, PJ and Donnelly, LE},
doi = {10.1371/journal.pone.0128757},
journal = {PLOS One},
title = {Effect of JAK inhibitors on release of CXCL9, CXCL10 and CXCL11 from human airway epithelial cells},
url = {http://dx.doi.org/10.1371/journal.pone.0128757},
volume = {10},
year = {2015}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - BackgroundCD8+ T-cells are located in the small airways of COPD patients and may contribute to pathophysiology. CD8+ cells express the chemokine receptor, CXCR3 that binds CXCL9, CXCL10 and CXCL11, which are elevated in the airways of COPD patients. These chemokines are released from airway epithelial cells via activation of receptor associated Janus kinases (JAK). This study compared the efficacy of two structurally dissimilar pan-JAK inhibitors, PF956980 and PF1367550, and the glucocorticosteroid dexamethasone, in BEAS-2B and human primary airway epithelial cells from COPD patients and control subjects.MethodsCells were stimulated with either IFNγ alone or with TNFα, and release of CXCL9, CXCL10 and CXCL11 measured by ELISA and expression of CXCL9, CXCL10 and CXCL11 by qPCR. Activation of JAK signalling was assessed by STAT1 phosphorylation and DNA binding.ResultsThere were no differences in the levels of release of CXCL9, CXCL10 and CXCL11 from primary airway epithelial cells from any of the subjects or following stimulation with either IFNγ alone or with TNFα. Dexamethasone did not inhibit CXCR3 chemokine release from stimulated BEAS-2B or primary airway epithelial cells. However, both JAK inhibitors suppressed this response with PF1367550 being ~50-65-fold more potent than PF956980. The response of cells from COPD patients did not differ from controls with similar responses regardless of whether inhibitors were added prophylactically or concomitant with stimuli. These effects were mediated by JAK inhibition as both compounds suppressed STAT1 phosphorylation and DNA-binding of STAT1 and gene transcription.ConclusionsThese data suggest that the novel JAK inhibitor, PF1367550, is more potent than PF956980 and that JAK pathway inhibition in airway epithelium could provide an alternative anti-inflammatory approach for glucocorticosteroid-resistant diseases including COPD.
AU  - Fenwick,PS
AU  - Macedo,P
AU  - Barnes,PJ
AU  - Donnelly,LE
DO  - 10.1371/journal.pone.0128757
PY  - 2015///
SN  - 1932-6203
TI  - Effect of JAK inhibitors on release of CXCL9, CXCL10 and CXCL11 from human airway epithelial cells
T2  - PLOS One
UR  - http://dx.doi.org/10.1371/journal.pone.0128757
UR  - http://hdl.handle.net/10044/1/24106
VL  - 10
ER  -
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