β-肾上腺素能受体作为黑素瘤潜在的免疫抑制剂。
β -Adrenoceptor as a potential immuno-suppressor agent in melanoma.
机构信息
Oncohematology Unit, Department of Pediatric Oncology, Meyer University Children's University Hospital, Florence, Italy.
Department of Health Sciences, University of Florence, Florence, Italy.
出版信息
Br J Pharmacol. 2019 Jul;176(14):2509-2524. doi: 10.1111/bph.14660. Epub 2019 May 9.
BACKGROUND AND PURPOSE
Stress-related catecholamines have a role in cancer and β-adrenoceptors; specifically, β -adrenoceptors have been identified as new targets in treating melanoma. Recently, β -adrenoceptors have shown a pleiotropic effect on melanoma micro-environment leading to cancer progression. However, the mechanisms by which β -adrenoceptors promote this progression remain poorly understood. Catecholamines affect the immune system by modulating several factors that can alter immune cell sub-population homeostasis. Understanding the mechanisms of cancer immune-tolerance is one of the most intriguing challenges in modern research. This study investigates the potential role of β -adrenoceptors in immune-tolerance regulation.
EXPERIMENTAL APPROACH
A mouse model of melanoma in which syngeneic B16-F10 cells were injected in C57BL-6 mice was used to evaluate the effect of β-adrenoceptor blockade on the number and activity of immune cell sub-populations (Treg, NK, CD8, MDSC, macrophages, and neutrophils). Pharmacological and molecular approaches with β-blockers (propranolol and SR59230A) and specific β-adrenoceptor siRNAs targeting β - or β -adrenoceptors were used.
KEY RESULTS
Only β -, but not β -adrenoceptors, were up-regulated under hypoxia in peripheral blood mononuclear cells and selectively expressed in immune cell sub-populations including Treg, MDSC, and NK. SR59230A and β -adrenoceptor siRNAs increased NK and CD8 number and cytotoxicity, while they attenuated Treg and MDSC sub-populations in the tumour mass, blood, and spleen. SR59230A and β -adrenoceptor siRNAs increased the ratio of M1/M2 macrophages and N1 granulocytes.
CONCLUSIONS AND IMPLICATIONS
Our data suggest that β -adrenoceptors are involved in immune-tolerance, which opens the way for new strategic therapies to overcome melanoma growth.
LINKED ARTICLES
This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc.
背景与目的
应激相关儿茶酚胺在癌症和β-肾上腺素能受体中起作用；具体来说，β-肾上腺素能受体已被确定为治疗黑色素瘤的新靶点。最近，β-肾上腺素能受体在黑色素瘤微环境中表现出多效性作用，导致癌症进展。然而，β-肾上腺素能受体促进这种进展的机制仍知之甚少。儿茶酚胺通过调节几种可以改变免疫细胞亚群稳态的因素影响免疫系统。了解癌症免疫耐受的机制是现代研究中最引人关注的挑战之一。本研究探讨了β-肾上腺素能受体在免疫耐受调节中的潜在作用。
实验方法
使用将同源 B16-F10 细胞注射到 C57BL-6 小鼠中建立的黑色素瘤小鼠模型，评估β-肾上腺素能受体阻断对免疫细胞亚群（Treg、NK、CD8、MDSC、巨噬细胞和中性粒细胞）数量和活性的影响。使用β-阻滞剂（普萘洛尔和 SR59230A）和针对β-或β-肾上腺素能受体的特异性β-肾上腺素能受体 siRNA 的药理学和分子方法。
主要结果
只有β-肾上腺素能受体而非β-肾上腺素能受体在周围血单核细胞中受到缺氧的上调，并在包括 Treg、MDSC 和 NK 在内的免疫细胞亚群中选择性表达。SR59230A 和β-肾上腺素能受体 siRNA 增加了 NK 和 CD8 的数量和细胞毒性，同时减弱了肿瘤块、血液和脾脏中的 Treg 和 MDSC 亚群。SR59230A 和β-肾上腺素能受体 siRNA 增加了 M1/M2 巨噬细胞和 N1 粒细胞的比例。
结论和意义
我们的数据表明，β-肾上腺素能受体参与免疫耐受，这为克服黑色素瘤生长的新战略疗法开辟了道路。
相关文章
本文是关于肾上腺素能受体-旧角色的新角色的专题部分的一部分。要查看本节中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc。
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