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Cigarette smoke induces pro-inflammatory cytokine release by activation of NF-kappaB and posttranslational modifications of histone deacetylase as seen in macrophages

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Prevention: Research & Programs, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Frontiers in Cardiology and Cardiovascular Disorders, inflammation independent of lipid levels, Metabolomics, Nutrigenomics, Nutrition, Personalized and Precision Medicine & Genomic Research, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Systemic Inflammatory Response Related Disorders, tagged Chronic obstructive pulmonary disease, Cigarette smoke, Histone deacetylase, Hydroxyl radicals, NF-kappaB, Posttranslational modifications, pro-inflammatory cytokine, Reactive oxygen species on May 19, 2013| 2 Comments »

Cigarette smoke induces pro-inflammatory cytokine release by activation of NF-kappaB and posttranslational modifications of histone deacetylase as seen in macrophages

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Abbreviations:

Chronic obstructive pulmonary disease (COPD)

Reactive oxygen species (ROS)

Hydroxyl radicals (·OH)

Glutathione (GSH)

Histone deacetylase (HDAC)

TNF (Tumour necrosis factor)

IκB kinase complex (IKK)

Interleukin (IL)

Cigarette smoking is the major etiologic factor in the pathogenesis of chronic obstructive pulmonary disease (COPD), which is characterized by an abnormal inflammatory response in the lungs to cigarette smoke with a progressive and irreversible airflow limitation. Chronic airway inflammation is an archetypal feature of COPD, and increased oxidative stress has been suggested to be responsible for triggering inflammatory events observed within the lungs of smokers and COPD patients. Although the precise mechanisms behind the pathogenesis of COPD are yet to be fully dissected, the current hypothesis suggests that cigarette smoke causes airway inflammation by activating macrophages, neutrophils, and T lymphocytes, which release proteases and reactive oxygen species (ROS) leading to cellular injury. As a consequence, chronic inflammatory processes are triggered that lead to small airway obstruction. An increased oxidant burden in smokers may be derived from the fact that cigarette smoke contains an estimated 1017 oxidants/free radicals and 4,700 chemical compounds, including reactive aldehydes (carbonyls) and quinones, per puff. Many of these are relatively long-lived, such as tar-semiquinone, which can generate hydroxyl radicals (·OH) and H2O2 by the Fenton reaction. One consequence of this increased oxidative stress is activation of redox-sensitive transcription factors, such as NF-κB and activator protein-1 (AP-1), which are critical to transcription of proinflammatory genes (IL-8, IL-6, and TNF-α). However, the precise transcriptional mechanisms leading to enhanced gene expression in response to cigarette smoke are still not clearly understood.

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 theNF-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.

Source References:

http://ajplung.physiology.org/content/291/1/L46.long

http://carcin.oxfordjournals.org/content/23/9/1511.abstract?ijkey=3ea9eff65782ab8153fac166b1d85336efb795b8&keytype2=tf_ipsecsha

http://www.ncbi.nlm.nih.gov/pubmed/101105?dopt=Abstract

http://www.sciencemag.org/content/293/5535/1653.abstract?ijkey=cde39cb6af6142beff66405c8aed965e998d48c1&keytype2=tf_ipsecsha

http://www.ncbi.nlm.nih.gov/pubmed/8319604?dopt=Abstract