Differential desensitization of homozygous haplotypes of the beta2-adrenergic receptor in lymphocytes.
Differential desensitization of homozygous haplotypes of the beta2-adrenergic receptor in lymphocytes.
复制标题
淋巴细胞中β2-肾上腺素能受体纯合单倍型的差异脱敏。
DOI：
10.1164/rccm.200409-1162oc
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发表时间：
2005
影响因子：
24.7
通讯作者：
Meurs,Herman
中科院分区：
文献类型：
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作者：
Oostendorp,Jaap;Postma,DirkjeS;Volders,Haukeline;Jongepier,Hajo;Kauffman,HenkF;Boezen,HMarike;Meyers,DeborahA;Bleecker,EugeneR;Nelemans,SAdriaan;Zaagsma,Johan;Meurs,Herman
β2肾上腺素能受体基因及其5‘端启动子的单核苷酸多态性与受体功能和脱敏作用的差异有关。连锁不平衡可能解释了报道的孤立多态效应的不一致。因此，我们研究了β2-肾上腺素能受体的三种最常见的纯合单倍型(5‘前导顺反子的第19位[Cys/Arg]和受体的第16位[Arg/Gly]和27位[Gln/Glu])在激动剂诱导的脱敏中可能的差异。分离了明确定义的非哮喘、非过敏性受试者的单倍型CysGlyGln、ArgGlyGlu或CysArgGln纯合子的淋巴细胞。观察了异丙肾上腺素(−)诱导的环磷酸腺苷(CAMP)蓄积的脱敏作用、β2肾上腺素能受体的滞留和下调与β2肾上腺素能受体介导的干扰素γ和白介素5产生抑制的关系。我们观察到，携带CysGlyGln单倍型的人的淋巴细胞比携带CysGlyGln单倍型的人更容易对β激动剂诱导的cAMP反应脱敏。β激动剂诱导的cAMP反应的单倍型依赖脱敏与单倍型依赖的β2肾上腺素能受体隔离或下调无关。此外，我们的数据表明，在CysGlyGln单倍型受试者的淋巴细胞中，T细胞受体-CD3复合体和共刺激分子CD28(αCD3/αCD28)的抗体诱导的白细胞介素5的产生受到的抑制减少。这是第一个表明激动剂诱导原代人类细胞β2-肾上腺素能受体脱敏与单倍型相关的差异的研究。淋巴细胞中β2-肾上腺素能受体的这种与单倍型相关的脱敏可能与辅助T细胞2型炎症反应的调节有关。
Single-nucleotide polymorphisms of the β2-adrenergic receptor gene and its 5′ promoter have been associated with differences in receptor function and desensitization. Linkage disequilibrium may account for inconsistencies in reported effects of isolated polymorphisms. Therefore, we have investigated the three most common homozygous haplotypes of the β2-adrenergic receptor (position 19 [Cys/Arg] of the 5′ leader cistron and positions 16 [Arg/Gly] and 27 [Gln/Glu] of the receptor) for putative differences in agonist-induced desensitization. Lymphocytes of well defined nonasthmatic, nonallergic subjects homozygous for the haplotype CysGlyGln, ArgGlyGlu, or CysArgGln were isolated. Desensitization of (−)-isoproterenol–induced cyclic adenosine monophosphate (cAMP) accumulation and β2-adrenergic receptor sequestration and downregulation were measured in relation to β2-adrenergic receptor-mediated inhibition of IFN-γ and interleukin-5 production. We observed that lymphocytes of individuals bearing the CysGlyGln haplotype were more susceptible to desensitization of the β-agonist–induced cAMP response than those of individuals with the ArgGlyGlu or CysArgGln haplotype. The haplotype-dependent desensitization of β-agonist–induced cAMP response was not associated with haplotype-dependent β2-adrenergic receptor sequestration or downregulation. In addition, our data suggest reduced inhibition, in lymphocytes of subjects with the CysGlyGln haplotype, of interleukin-5 production induced by treatment with antibodies to the T-cell receptor–CD3 complex and to costimulatory molecule CD28 (αCD3/αCD28). This is the first study demonstrating haplotype-related differences in agonist-induced β2-adrenergic receptor desensitization in primary human cells. This haplotype-related desensitization of the β2-adrenergic receptor in lymphocytes might have consequences regarding the regulation of helper T-cell type 2 inflammatory responses.