Nicotine induces human neutrophils to produce IL-8 through the generation of peroxynitrite and subsequent activation of NF-κB
Nicotine induces human neutrophils to produce IL-8 through the generation of peroxynitrite and subsequent activation of NF-κB
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DOI：
10.1189/jlb.1202626
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发表时间：
2003-11-01
影响因子：
5.5
通讯作者：
Takahashi, T
中科院分区：
文献类型：
--
作者：
Iho, S;Tanaka, Y;Takahashi, T
吸烟的人白细胞增多已经得到了很好的认识；然而，确切的原因尚不清楚。为了验证烟草尼古丁刺激呼吸道中性粒细胞产生IL-8并引起体内中性粒细胞的假设，我们在体外研究了尼古丁是否诱导中性粒细胞IL-8的产生；NF-kappaB在其产生中的致病作用，与激活NF-kappaB的活性氧中间体的可能产生有关；以及参与IL-8产生的烟碱乙酰胆碱受体（nAChRs）。尼古丁刺激嗜中性粒细胞产生IL-8，产生时间和浓度依赖性，50%有效浓度为1.89 mM。尼古丁处理后，ikappab - α / β蛋白降解和NF-kappaB p65和p50活性增强。超氧化物的合成和二氢膦胺123 （DHR）的氧化也得到了促进。NOS抑制剂n(omega)-硝基- l -精氨酸甲酯（n(omega)-硝基- l -精氨酸甲酯）可以阻止尼古丁诱导的IL-8产生，同时完全消除DHR氧化、IkappaB降解和NF-kappaB活性。中性粒细胞在尼古丁刺激下自发产生NO，而NO的生成非但没有增加，反而减少，这说明尼古丁产生的超氧化物与预形成的NO反应生成过氧亚硝酸盐，从而增强NF-kappaB活性，从而产生IL-8。nachr似乎参与了IL-8的产生。吸烟者的血液IL-8水平明显高于非吸烟者。总之，尼古丁通过nAChR产生过氧亚硝酸盐和随后的NF-kappaB激活来刺激中性粒细胞IL-8的产生，IL-8似乎有助于吸烟者的白细胞增多。
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-kappaB in its production, in association with the possible production of reactive oxygen intermediates that activate NF-kappaB; and the nicotinic acetylcholine receptors (nAChRs) involved in IL-8 production. Nicotine stimulated nentrophils to produce IL-8 in both time- and concentration-dependent manners with a 50% effective concentration of 1.89 mM. A degradation of IkappaB-alpha/beta proteins and an activity of NF-kappaB 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(omega)-Nitro-L-arginine methyl ester, prevented nicotine-induced IL-8 production, with an entire abrogation of DHR oxidation, IkappaB degradation, and NF-kappaB 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-kappaB 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-kappaB activation, and the IL-8 appears to contribute to leukocytosis in tobacco smokers.