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Cigarette smoke induces proinflammatory cytokine release by activation of NF-B and posttranslational modifications of histone deacetylase in macrophages

¹Department of Environmental Medicine and Lung Biology and Disease Program and ²Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York; and ³Pfizer Global Research and Development, Sandwich, United Kingdom

Submitted 3 June 2005 ; accepted in final form 16 January 2006

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- 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-B. Inhibition of IKK ablated the CSE-mediated IL-8 release, suggesting that this process is dependent on the NF-B 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-B 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.

oxidants; glutathione; MonoMac6 cells; IB kinase; chronic obstructive pulmonary disease

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