Nicotine induces human neutrophils to produce IL-8 through the generation of peroxynitrite and subsequent activation of NF-κB

• Published in: Journal of leukocyte biology Vol. 74; no. 5; pp. 942 - 951
• Main Authors: Iho, Sumiko, Tanaka, Yukie, Takauji, Rumiko, Kobayashi, Chino, Muramatsu, Ikunobu, Iwasaki, Hiromichi, Nakamura, Kishiko, Sasaki, Yutaka, Nakao, Kazuwa, Takahashi, Takayuki
• Format: Journal Article
• Language: English
• Published: Society for Leukocyte Biology 01.11.2003
• Subjects: chemokine; IκB; leukocytosis; reactive oxygen intermediates; tobacco smoker
• ISSN: 0741-5400; 1938-3673
• DOI: 10.1189/jlb.1202626

Leukocytosis in tobacco smokers has been well recognized; however, the exact cause has not been elucidated. To test the hypothesis that tobacco nicotine stimulates neutrophils in the respiratory tract to produce IL‐8, which causes neutrophilia in vivo, we examined whether nicotine induces neutrophil‐IL‐8 production in vitro; the causative role of NF‐κB in its production, in association with the possible production of reactive oxygen intermediates that activate NF‐κB; and the nicotinic acetylcholine receptors (nAChRs) involved in IL‐8 production. Nicotine stimulated neutrophils to produce IL‐8 in both time‐ and concentration‐dependent manners with a 50% effective concentration of 1.89 mM. A degradation of IκB‐α/β proteins and an activity of NF‐κB p65 and p50 were enhanced following nicotine treatment. The synthesis of superoxide and the oxidation of dihydrorhodamine 123 (DHR) were also enhanced. The NOS inhibitor, nω‐Nitro‐l‐arginine methyl ester, prevented nicotine‐induced IL‐8 production, with an entire abrogation of DHR oxidation, IκB degradation, and NF‐κB activity. Neutrophils spontaneously produced NO whose production was not increased, but rather decreased by nicotine stimulation, suggesting that superoxide, produced by nicotine, generates peroxynitrite by reacting with preformed NO, which enhances the NF‐κB activity, thereby producing IL‐8. The nAChRs seemed to be involved in IL‐8 production. In smokers, blood IL‐8 levels were significantly higher than those in nonsmokers. In conclusion, nicotine stimulates neutrophil‐IL‐8 production via nAChR by generating peroxynitrite and subsequent NF‐κB activation, and the IL‐8 appears to contribute to leukocytosis in tobacco smokers.