Nicotine inhibits Fc epsilon RI-induced cysteinyl leukotrienes and cytokine production without affecting mast cell degranulation through alpha 7/alpha 9/alpha 10-nicotinic receptors.
Nicotine inhibits Fc epsilon RI-induced cysteinyl leukotrienes and cytokine production without affecting mast cell degranulation through alpha 7/alpha 9/alpha 10-nicotinic receptors.
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DOI：
10.4049/jimmunol.0902227
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发表时间：
2010-07-01
期刊：
影响因子：
--
通讯作者：
Sopori ML
中科院分区：
文献类型：
--
作者：
Mishra NC;Rir-sima-ah J;Boyd RT;Singh SP;Gundavarapu S;Langley RJ;Razani-Boroujerdi S;Sopori ML
吸烟者不太可能患上一些炎症和过敏性疾病。在Brown-Norway大鼠中，尼古丁抑制过敏性哮喘的几个参数，包括Th 2细胞因子和半胱氨酰白三烯LTC 4的产生。半胱氨酰白三烯主要由肥大细胞产生，并且这些细胞在过敏性哮喘中起核心作用。肥大细胞表达高亲和力的IgE受体（FcεRI）。在其交联之后，细胞降解并释放预先形成的炎症介质（早期），并合成和分泌细胞因子/趋化因子和白三烯（晚期）。尼古丁调节肥大细胞活化的机制尚不清楚。使用α-银环蛇毒素结合、qPCR和PCR产物测序，我们发现大鼠肥大/嗜碱性粒细胞系RBL-2 H3表达烟碱乙酰胆碱受体（nAChRs）α7、α9和α10，并且暴露于极低浓度的尼古丁（纳摩尔），而无生物活性的代谢产物可替宁在≥8h内对晚期相无抑制作用（白三烯/细胞因子产生）但不脱粒（组胺和氨基己糖苷酶释放）。这些作用与尼古丁对细胞内游离钙离子浓度的影响无关，而与尼古丁抑制cPLA 2活性和PI 3 K/ERK/NF-κB通路（包括Akt和ERK磷酸化以及NF-κB核转位）有关。尼古丁对晚期反应的抑制作用被α7/α9-nAChRs拮抗剂甲基可可碱和α-银环蛇毒素阻断，并被α7、α9或α10 nAChRs的siRNA敲低阻断，表明α 7、α 9和α 10 nAChRs之间存在功能性相互作用，这可能解释了RBL对纳摩尔浓度尼古丁的反应。这种“杂合”受体可能作为一个新的抗过敏/哮喘治疗的目标。
Smokers are less likely to develop some inflammatory and allergic diseases. In Brown-Norway rats, nicotine inhibits several parameters of allergic asthma including the production of Th2 cytokines and the cysteinyl leukotriene LTC4. Cysteinyl leukotrienes are primarily produced by mast cells, and these cells play a central role in allergic asthma. Mast cells express a high affinity receptor for IgE (FcεRI). Following its cross-linking, cells degranulate and release preformed inflammatory mediators (early phase), and synthesize and secrete cytokines/chemokines and leukotrienes (late phase). The mechanism by which nicotine modulates mast cell activation is unclear. Using α-bungarotoxin binding, qPCR, and PCR product sequencing, we show that the rat mast/basophil cell line RBL-2H3 express nicotinic acetylcholine receptors (nAChRs) α7, α9, and α10, and exposure to exceedingly low concentrations of nicotine (nanomolar), but not the biologically inactive metabolite cotinine for ≥8h suppressed the late phase (leukotriene/cytokine production) but not degranulation (histamine and hexosaminidase release). These effects were unrelated to those of nicotine on intracellular free calcium concentration but causally associated with the inhibition of cPLA2 activity and PI3K/ERK/NF-κB pathway, including phosphorylation of Akt and ERK, and nuclear translocation of NF-κB. The suppressive effect of nicotine on the late-phase response was blocked by the α7/α9-nAChRs antagonist methyllycaconitine and α-bungarotoxin, and by siRNA knockdown of α7, α9, or α10 nAChRs, suggesting a functional interaction between α7, α9, and α10 nAChRs that might explain the response of RBL to nanomolar concentrations of nicotine. This “hybrid” receptor might serve as a target for novel anti-allergic/asthmatic therapies.
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影响因子：
4
作者：
Bray, C;Son, JH;Meizel, S
通讯作者：
Meizel, S
影响因子：
64.8
作者：
Ali, K;Bilancio, A;Vanhaesebroeck, B
通讯作者：
Vanhaesebroeck, B
影响因子：
4.7
作者：
Alkondon, M;Pereira, EFR;Albuquerque, EX
通讯作者：
Albuquerque, EX
影响因子：
10
作者：
Burr, ML;Wat, D;Doull, IJM
通讯作者：
Doull, IJM
影响因子：
64.8
作者：
DAHLEN, SE;HEDQVIST, P;SAMUELSSON, B
通讯作者：
SAMUELSSON, B