Impact of tobacco-smoke on key signaling pathways in the innate immune response in lung macrophages

J Cell Physiol. 2008 Jan;214(1):27-37. doi: 10.1002/jcp.21158.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Buffers
  • Cell Line
  • Cells, Cultured
  • Cytokines / biosynthesis
  • Cytokines / metabolism*
  • Enzyme Activation
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Glutathione / analysis
  • Humans
  • I-kappa B Kinase / metabolism
  • Immunity, Innate / immunology*
  • Lipopolysaccharides / pharmacology
  • Lung / cytology
  • Macrophages, Alveolar / cytology
  • Macrophages, Alveolar / immunology*
  • Male
  • Middle Aged
  • Mitogen-Activated Protein Kinases / metabolism
  • Monocytes / metabolism
  • NF-kappa B / metabolism
  • Phosphorylation
  • RNA, Messenger / metabolism
  • Reference Standards
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Smoke*
  • Smoking / adverse effects*
  • Smoking / immunology
  • Transcription Factor AP-1 / metabolism


  • Buffers
  • Cytokines
  • Lipopolysaccharides
  • NF-kappa B
  • RNA, Messenger
  • Smoke
  • Transcription Factor AP-1
  • I-kappa B Kinase
  • IKBKB protein, human
  • Mitogen-Activated Protein Kinases
  • Glutathione