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

Abstract

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.

Cigarette smoke exacerbates mouse allergic asthma through Smad proteins expressed in mast cells

“…Cigarette smoke elevates the numbers of prominent inflammatory cells such as macrophages and neutrophils or goblet cells, and it enhances release of inflammatory cytokines [3,4,40]. As smoke has adjuvant property [5,7,8], these cells play important roles in the exacerbation of asthmatic airway inflammation [4,5].…”

“…Cigarette smoke induces NF-κB and AP-1 in a variety of cells [2,3,47], and it up-regulates the expressions of inflammatory cytokines [3,4,41] and extracellular molecules [48]. Moreover, cytokine genes are regulated by NF-κB and AP-1.…”

“…Cigarette smoke contains many toxic substances and a strong pro-inflammatory stimulus [1-3]. It is widely recognized as a significant risk factor for a number of diseases including emphysema, chronic obstructive pulmonary disease, cardiovascular disease, lung cancer and allergic diseases [1].…”

Nicotine and oxidative cigarette smoke constituents induce immune-modulatory and pro-inflammatory dendritic cell responses

“…Several other studies have alluded to the importance of cigarette smoke-induced oxidative stress in the pathogenesis of chronic airway inflammation in smokers (Barnes, 2003;Kluchova et al, 2007;Pierrou et al, 2007;Tkacova et al, 2007). Oxidative stress induces CXCL8/IL-8 by macrophages and epithelial cells (Mio et al, 1997;Yang et al, 2006), and has been implicated in the induction of adhesion molecules involved in the recruitment of monocytes and neutrophils to sites of inflammation (Shen et al, 1996). The current study implies that cigarette smoke-induced oxidative stress on myeloid DCs results in an additional major contribution to the generation of neutrophilic airway inflammation in smokers.…”

Pathogenesis of Emphysema: From the Bench to the Bedside

“…The major consequence of the oxidative stress is the activation of the transcription factor nuclear factor-kB, which activates proinflammatory cytokine transcription (5,6). Recent evidence suggests that cigarette smoke inhibits histone deacetylase, further promoting the release of proinflammatory cytokines (7).…”