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IFN-? synergistically enhances LPS signalling in alveolar macrophages from COPD patients and controls by corticosteroid-resistant STAT1 activation.


ABSTRACT: BACKGROUND AND PURPOSE: IFN-? levels are increased in chronic obstructive airway disease (COPD) patients compared with healthy subjects and are further elevated during viral exacerbations. IFN-? 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-? on corticosteroid sensitivity in alveolar macrophages (AM). EXPERIMENTAL APPROACH: AM from non-smokers, smokers and COPD patients were stimulated with IFN-? and/or LPS with or without dexamethasone. IL-6, TNF-? and IFN-?-induced protein 10?kDa (IP-10) levels were measured by elisa, and Western blots were used to investigate the IFN-?-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-? treatment. KEY RESULTS: In all three subject groups, IFN-? alone had no effect on IL-6 and TNF-? production but enhanced the effects of LPS on these cytokines. In contrast, IFN-? alone increased the production of IP-10. IFN-? increased TLR2 and TLR4 expression in AM. Cytokine induction and STAT1 activation by IFN-? were insensitive to dexamethasone for all groups. The inhibition of JAK and STAT1 repressed all these IFN-? effects. CONCLUSIONS AND IMPLICATIONS: Our results demonstrate that IFN-?-induced STAT-1 signalling is corticosteroid resistant in AMs, and that targeting IFN-? signalling by JAK inhibitors is a potentially novel anti-inflammatory strategy in COPD.

SUBMITTER: Southworth T 

PROVIDER: S-EPMC3402772 | BioStudies | 2012-01-01

REPOSITORIES: biostudies

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