Premium
IFN‐γ synergistically enhances LPS signalling in alveolar macrophages from COPD patients and controls by corticosteroid‐resistant STAT1 activation
Author(s) -
Southworth T,
Metryka A,
Lea S,
Farrow S,
Plumb J,
Singh D
Publication year - 2012
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2012.01907.x
Subject(s) - stat1 , janus kinase , stat protein , immunology , medicine , cytokine , dexamethasone , jak stat signaling pathway , stat3 , interferon , receptor , signal transduction , biology , tyrosine kinase , microbiology and biotechnology
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.