Cigarette smoke induces proinflammatory cytokine release by activation of NF-kappaB and posttranslational modifications of histone deacetylase in macrophages.
Cigarette smoke-mediated oxidative stress induces an inflammatory response in the lungs by stimulating the release of proinflammatory cytokines. Chromatin remodeling due to histone acetylation and deacetylation is known to play an important role in transcriptional regulation of proinflammatory genes. The aim of this study was to investigate the molecular mechanism(s) of inflammatory responses caused by cigarette smoke extract (CSE) in the human macrophage-like cell line MonoMac6 and whether the treatment of these cells with the antioxidant glutathione (GSH) monoethyl ester, or modulation of the thioredoxin redox system, can attenuate cigarette smoke-mediated IL-8 release. Exposure of MonoMac6 cells to CSE (1% and 2.5%) increased IL-8 and TNF-alpha production vs. control at 24 h and was associated with significant depletion of GSH levels associated with increased reactive oxygen species release in addition to activation of NF-kappaB. Inhibition of IKK ablated the CSE-mediated IL-8 release, suggesting that this process is dependent on the NF-kappaB pathway. CSE also reduced histone deacetylase (HDAC) activity and HDAC1, HDAC2, and HDAC3 protein levels. This was associated with posttranslational modification of HDAC1, HDAC2, and HDAC3 protein by nitrotyrosine and aldehyde-adduct formation. Pretreatment of cells with GSH monoethyl ester, but not thioredoxin/thioredoxin reductase, reversed cigarette smoke-induced reduction in HDAC levels and significantly inhibited IL-8 release. Thus cigarette smoke-induced release of IL-8 is associated with activation of NF-kappaB via IKK and reduction in HDAC levels/activity in macrophages. Moreover, cigarette smoke-mediated proinflammatory events are regulated by the redox status of the cells.
Yang
Se-Ran
SR
Dept. of Environmental Medicine, Lung Biology and Disease Program, Univ. of Rochester Medical Center, 601 Elmwood Ave., Rochester, NY 14642, USA.
Chida
Asiya S
AS
Bauter
Mark R
MR
Shafiq
Nusrat
N
Seweryniak
Kathryn
K
Maggirwar
Sanjay B
SB
Kilty
Iain
I
Rahman
Irfan
I
D045744:Cell Line, Tumor; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism*; D007948:Leukemia, Monocytic, Acute; D008264:Macrophages / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism*; D016877:Oxidants / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000276:immunology; D011499:Protein Processing, Post-Translational / Q000276:immunology; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D012907:Smoking / Q000009:adverse effects* / Q000276:immunology; D013880:Thioredoxin-Disulfide Reductase / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016209:Interleukin-8; D016328:NF-kappa B; D016877:Oxidants; D014409:Tumor Necrosis Factor-alpha; C042431:S-ethyl glutathione; D013880:Thioredoxin-Disulfide Reductase; D051550:I-kappa B Kinase; D006655:Histone Deacetylases; D005978:Glutathione