In vivo beta-adrenergic stimulation suppresses natural killer activity and compromises resistance to tumor metastasis in rats.
In vivo beta-adrenergic stimulation suppresses natural killer activity and compromises resistance to tumor metastasis in rats.
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DOI：
10.4049/jimmunol.160.7.3251
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发表时间：
1998-04
影响因子：
4.4
通讯作者：
G. Shakhar;S. Ben-Eliyahu
中科院分区：
文献类型：
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作者：
G. Shakhar;S. Ben-Eliyahu
交感神经系统参与介导应激诱导的NK细胞活性改变，特别是通过刺激β-肾上腺素能受体。然而，由于儿茶酚胺诱导NK细胞分布的时间依赖性改变，β-肾上腺素能刺激对个体NK细胞细胞毒性的影响尚不清楚，其对宿主抵抗转移扩散的影响也不清楚。为了解决这些问题，我们在F344大鼠中使用β-肾上腺素能激动剂，metaproterenol（MP）。MP给药后10分钟内，血液NK细胞数量增加一倍，并在1小时内恢复至基线水平。此时，MP以剂量依赖性方式抑制血液NK活性。两种β-肾上腺素能拮抗剂普萘洛尔和纳多洛尔阻断了这种抑制作用，普萘洛尔能穿过血脑屏障，纳多洛尔不能穿过血脑屏障。使用NK敏感的肿瘤模型MADB 106获得相应的发现。MP引起高达10倍的肿瘤细胞的数量增加，保留在肺部接种后1天，并在随后的肺转移检测3周后的数量类似的上升。这些作用呈剂量依赖性，纳多洛尔可逆。NK细胞似乎在介导MP的肿瘤增强作用中发挥核心作用，因为它们的选择性耗竭几乎消除了这种作用。总体而言，我们的研究结果表明，独立于血液NK细胞数量的短暂增加，体内β-肾上腺素能刺激抑制大鼠NK活性。这种抑制是外周诱导的，可以损害宿主对NK敏感性肿瘤的抗性。同源性研究在人类和临床意义进行了讨论。
The sympathetic nervous system has been implicated in mediating stress-induced alterations in NK cell activity, particularly through stimulation of beta-adrenergic receptors. However, because catecholamines induce time-dependent alterations in the distribution of NK cells, the impact of beta-adrenergic stimulation on individual NK cell cytotoxicity is not clear, nor are its implications regarding host resistance to metastatic spread. To address these issues, we used the beta-adrenergic agonist, metaproterenol (MP), in F344 rats. The number of blood NK cells doubled within 10 min of MP administration and returned to baseline levels within 1 h. By this time, MP suppressed blood NK activity in a dose-dependent manner. Two beta-adrenergic antagonists, propranolol, which crosses the blood-brain barrier, and nadolol, which does not, blocked this suppression. Corresponding findings were obtained using an NK-sensitive tumor model, the MADB106. MP caused an up to 10 times increase in the number of tumor cells retained in the lungs 1 day after inoculation and a similar rise in the number of consequent lung metastases detected 3 wk later. These effects were dose dependent and nadolol reversible. NK cells appear to play a central role in mediating the tumor-enhancing effects of MP because their selective depletion nearly abolished this effect. Overall, our findings suggest that independent of the transitory increase in numbers of blood NK cells, in vivo beta-adrenergic stimulation suppresses NK activity in the rat. This suppression is induced peripherally and can compromise host resistance to NK-sensitive tumors. Homologies to studies in humans and clinical relevance are discussed.