Published online before print August 1, 2003

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1202626

Received for publication December 28, 2002.
Revised June 18, 2003.
Accepted for publication June 20, 2003.

Article

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

Sumiko Iho ^*@, Yukie Tanaka , Rumiko Takauji , Chino Kobayashi , Ikunobu Muramatsu ^¶, Hiromichi Iwasaki ^**, Kishiko Nakamura , Yutaka Sasaki , Kazuwa Nakao , and Takayuki Takahashi ^¶¶

*Department of Immunology and Medical Zoology, Forensic Medicine, Anesthesiology & Reanimatology, and Pharmacology, Central Research Laboratories, and ¶Division of Transfusion Medicine, **Fukui Medical University; College of Medical Technology, Kyoto University; Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine; and ^¶¶Department of Hematology and Clinical Immunology, Kobe City General Hospital

^@ To whom correspondence should be addressed. E-mail: ihosumik{at} fmsrsa.fukui-med.ac.jp.

Abstract

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-B in its production, in association with the possible production of reactive oxygen intermediates that activate NF-B; 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 IB-/ proteins and an activity of NF-B 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, N-Nitro-L-arginine methyl ester, prevented nicotine-induced IL-8 production, with an entire abrogation of DHR oxidation, IB degradation, and NF-B 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-B 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-B activation, and the IL-8 appears to contribute to leukocytosis in tobacco smokers.

Key Words: chemokine • reactive oxygen intermediates • leukocytosis • tobacco smoker • IB

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