Mechanisms underlying cigarette smoke-induced NF-kappaB activation in human lymphocytes: the role of reactive nitrogen species.
Cigarette smoke (CS) is an important source of reactive nitrogen species (RNS). It has been demonstrated that CS constitutes the highest source of exogenous nitric oxide and peroxynitrite to which humans are exposed. NF-kappaB is a key inflammatory, redox-sensitive transcription factor, which role in CS-induced airway inflammation is unclear. Moreover, the role of RNS in the activation of NF-kappaB and in inflammation has remained vague. This study investigated CS-induced NF-kappaB activation in human lymphocytes and assessed the involvement of CS-derived RNS in NF-kappaB activation and their possible biological effects. Mild, but not high, exposure to CS induced NF-kappaB in lymphocytes through IKK activation, I-kappaBalpha degradation, and the reduction in the intracellular glutathione levels. Peroxynitrite, but not NO, mimicked the effects of CS on NF-kappaB. Reduction of intracellular peroxynitrite formation by the inhibition of the mitochondrial respiratory chain resulted in decreased activation of NF-kappaB by CS. NF-kappaB-induced iNOS levels were increased in response to CS. Low levels of CS exposure induced classical NF-kappaB activation pathway in lymphocytes via intracellular formation of peroxynitrite, through a reaction between smoke-derived NO and endogenously produced superoxide. This NF-kappaB activation resulted in inflammatory gene expression, which may contribute to CS-related airway inflammation.
Hasnis
E
E
Department of Anatomy and Cell Biology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Bar-Shai
M
M
Burbea
Z
Z
Reznick
A Z
AZ
D000328:Adult; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004790:Enzyme Induction; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008875:Middle Aged; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D018384:Oxidative Stress / Q000187:drug effects*; D030421:Peroxynitrous Acid / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000378:metabolism*; D014026:Nicotiana
D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D026361:Reactive Nitrogen Species; D012906:Smoke; D000072000:NF-KappaB Inhibitor alpha; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D051550:I-kappa B Kinase; D005978:Glutathione