title: Impact of tobacco-smoke on key signaling pathways in the innate immune response in lung macrophages.
abstract: Many of the healthcare consequences of cigarette smoking could be due to its ability to compromise the immune system, and in respiratory diseases like chronic obstructive pulmonary disease (COPD), a constant low level of infection could be responsible for some of the symptoms/pathology. The aim was to assess the impact of cigarette smoke (CS) on the release of innate effector cytokines in THP-1 cells and human lung macrophages, and to determine the molecular mechanism behind the altered response. Cells were exposed to CS with and without endotoxin stimulus, cytokines, glutathione, mitogen-activated protein kinase (MAPK) phosphorylation, IkappaB kinase-2 (IKK-2) activity, nuclear factor kappa B (NF-kappaB), and activator protein-1 (AP-1) pathway activation was measured. Attempts were made to mimic or block the effect of CS by using nicotine, nitric oxide donors/inhibitors, prostanoid inhibitors, and anti-oxidants. Results showed that CS initially delayed the production of "innate" cytokines (e.g., IL-1beta and IL-6) and reduced glutathione levels. This was associated with a reduction in NF-kappaB pathway activation, which suggested a causative link. CS also increased the phosphorylation of MAPK's and the production of IL-8 but interestingly only in stimulated cells. Exogenous glutathione treatment reversed both these effects of CS, which suggests that this molecule may play a central role. In conclusion, this data provides a novel mechanistic explanation for why smokers have increased prevalence/severity of respiratory infections. In addition, the suppression of the innate response is accompanied by an increase in the neutrophil chemoattractant, IL-8, which may suggest a link to the pathogenesis of smoking-related inflammatory disease.
authors.affiliation: Respiratory Pharmacology, Airway Disease Section, Imperial College, National Heart and Lung Institute, London, UK.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Birrell
authors.forename: Sissie
authors.initials: S
authors.lastname: Wong
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Catley
authors.forename: Maria G
authors.initials: MG
authors.lastname: Belvisi
mesh_terms: D000328:Adult; D002021:Buffers; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism*; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005978:Glutathione / Q000032:analysis; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007113:Immunity, Innate / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000166:cytology; D016676:Macrophages, Alveolar / Q000166:cytology / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D012015:Reference Standards; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D012906:Smoke; D012907:Smoking / Q000009:adverse effects* / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D002021:Buffers; D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D012906:Smoke; D018808:Transcription Factor AP-1; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; D020928:Mitogen-Activated Protein Kinases; D005978:Glutathione