B-lymphocytes from malignant hyperthermia-susceptible patients have an increased sensitivity to skeletal muscle ryanodine receptor activators
B-lymphocytes from malignant hyperthermia-susceptible patients have an increased sensitivity to skeletal muscle ryanodine receptor activators
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DOI：
10.1074/jbc.m107134200
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发表时间：
2001-12-21
影响因子：
4.8
通讯作者：
Treves, S
中科院分区：
文献类型：
--
作者：
Girard, T;Cavagna, D;Treves, S
恶性高热（MH）是一种药物遗传性疾病，由遗传易感个体中的挥发性麻醉剂和琥珀胆碱引发。 MH 的根本特征是肌浆网钙释放机制的超敏性，在许多情况下，这是骨骼肌兰尼碱受体钙释放通道 (RYR1) 点突变的结果。 RYR1 主要在骨骼肌中表达，但最近的一份报告证明了这种亚型在人类 B 淋巴细胞中的存在。由于 B 细胞可以产生多种细胞因子，包括内源性热原，我们研究了 MH 期间出现的一些症状是否与免疫系统的参与有关。我们的结果表明，(i) 来自携带 V2168M RYR1 基因突变的 MH 易感个体的 Epstein-Barr 病毒永生化 B 细胞对 RYR 激活剂 4-氯间甲酚更敏感，并且 (ii) 与来自 RYR 激活剂咖啡因和 4-氯间甲酚的细胞相比，其外周血白细胞在用 RYR 激活剂咖啡因和 4-氯间甲酚处理后产生更多的白细胞介素 (IL)-1 β健康的控制。我们的结果表明，RYR1 介导的钙信号传导参与 B 淋巴细胞释放 IL-1 β，并表明 MH 发作期间出现的一些症状可能是由于 IL-1 β 的产生。
Malignant hyperthemia (MH) is a pharmacogenetic disease triggered by volatile anesthetics and succinylcholine in genetically predisposed individuals. The underlying feature of MH is a hypersensitivity of the calcium release machinery of the sarcoplasmic reticulum, and in many cases this is a result of point mutations in the skeletal muscle ryanodine receptor calcium release channel (RYR1). RYR1 is mainly expressed in skeletal muscle, but a recent report demonstrated the existence of this isoform in human B-lymphocytes. As B-cells can produce a number of cytokines, including endogenous pyrogens, we investigated whether some of the symptoms seen during MH could be related to the involvement of the immune system. Our results show that (i) Epstein-Barr virus-immortalized B-cells from MH-susceptible individuals carrying the V2168M RYR1 gene mutation were more sensitive to the RYR activator 4-chloro-m-cresol and (ii) their peripheral blood leukocytes produce more interleukin (IL)-1 beta after treatment with the RYR activators caffeine and 4-chloro-m-cresol, compared with cells from healthy controls. Our result demonstrate that RYR1-mediated calcium signaling is involved in release of IL-1 beta from B-lymphocytes and suggest that some of the symptoms seen during an MH episode may be due to IL-1 beta production.