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
© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society
British Journal of Pharmacology
Volume 166, Issue 7, pages 2070–2083, August 2012
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
- 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
- alveolar macrophage;
- IFN-γ priming;
- corticosteroid insensitivity;
- 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.