1476-5381/asset/olbannerleft.gif?v=1&s=198ba9e64c782a75183a18cb494f9d10ecc901ea)
1476-5381/asset/olbannerright.gif?v=1&s=0b2124237bd4227e7991f1ea05cd4bed2496a9ae)
RESEARCH PAPER
IFN-γ synergistically enhances LPS signalling in alveolar macrophages from COPD patients and controls by corticosteroid-resistant STAT1 activation
Article first published online: 9 JUL 2012
DOI: 10.1111/j.1476-5381.2012.01907.x
© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society
Additional Information
How to Cite
Southworth, T., Metryka, A., Lea, S., Farrow, S., Plumb, J. and Singh, D. (2012), IFN-γ synergistically enhances LPS signalling in alveolar macrophages from COPD patients and controls by corticosteroid-resistant STAT1 activation. British Journal of Pharmacology, 166: 2070–2083. doi: 10.1111/j.1476-5381.2012.01907.x
Publication History
- Issue published online: 9 JUL 2012
- Article first published online: 9 JUL 2012
- Accepted manuscript online: 21 FEB 2012 11:45AM EST
- Received; 9 June 2011; Revised; 3 February 2012; Accepted; 7 February 2012
Keywords:
- COPD;
- alveolar macrophage;
- IFN-γ priming;
- corticosteroid insensitivity;
- JAK/STAT;
- IP-10;
- TNF-α;
- IL-6;
- toll-like receptors
BACKGROUND AND PURPOSE IFN-γ levels are increased in chronic obstructive airway disease (COPD) patients compared with healthy subjects and are further elevated during viral exacerbations. IFN-γ can ‘prime’ macrophages to enhance the response to toll-like receptor (TLR) ligands, such as LPS. The aim of this study was to examine the effect IFN-γ on corticosteroid sensitivity in alveolar macrophages (AM).
EXPERIMENTAL APPROACH AM from non-smokers, smokers and COPD patients were stimulated with IFN-γ and/or LPS with or without dexamethasone. IL-6, TNF-α and IFN-γ-induced protein 10 kDa (IP-10) levels were measured by elisa, and Western blots were used to investigate the IFN-γ-stimulated Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling pathway. Real-time PCR and flow cytometry were used to investigate TLR levels following IFN-γ treatment.
KEY RESULTS In all three subject groups, IFN-γ alone had no effect on IL-6 and TNF-α production but enhanced the effects of LPS on these cytokines. In contrast, IFN-γ alone increased the production of IP-10. IFN-γ increased TLR2 and TLR4 expression in AM. Cytokine induction and STAT1 activation by IFN-γ were insensitive to dexamethasone for all groups. The inhibition of JAK and STAT1 repressed all these IFN-γ effects.
CONCLUSIONS AND IMPLICATIONS Our results demonstrate that IFN-γ–induced STAT-1 signalling is corticosteroid resistant in AMs, and that targeting IFN-γ signalling by JAK inhibitors is a potentially novel anti-inflammatory strategy in COPD.