Oostendorp Jaap, Postma Dirkje S, Volders Haukeline, Jongepier Hajo, Kauffman Henk F, Boezen H Marike, Meyers Deborah A, Bleecker Eugene R, Nelemans S Adriaan, Zaagsma Johan, Meurs Herman
Department of Molecular Pharmacology, University of Groningen, The Netherlands.
Am J Respir Crit Care Med. 2005 Aug 1;172(3):322-8. doi: 10.1164/rccm.200409-1162OC. Epub 2005 May 5.
Single-nucleotide polymorphisms of the beta(2)-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 beta(2)-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 beta(2)-adrenergic receptor sequestration and downregulation were measured in relation to beta(2)-adrenergic receptor-mediated inhibition of IFN-gamma and interleukin-5 production. We observed that lymphocytes of individuals bearing the CysGlyGln haplotype were more susceptible to desensitization of the beta-agonist-induced cAMP response than those of individuals with the ArgGlyGlu or CysArgGln haplotype. The haplotype-dependent desensitization of beta-agonist-induced cAMP response was not associated with haplotype-dependent beta(2)-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 (alphaCD3/alphaCD28). This is the first study demonstrating haplotype-related differences in agonist-induced beta(2)-adrenergic receptor desensitization in primary human cells. This haplotype-related desensitization of the beta(2)-adrenergic receptor in lymphocytes might have consequences regarding the regulation of helper T-cell type 2 inflammatory responses.
β₂-肾上腺素能受体基因及其5'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所报道的单个多态性效应的不一致性。因此，我们研究了β₂-肾上腺素能受体的三种最常见纯合单倍型（5'前导顺反子的第19位[半胱氨酸/精氨酸]以及受体的第16位[精氨酸/甘氨酸]和第27位[谷氨酰胺/谷氨酸]）在激动剂诱导的脱敏作用方面的假定差异。分离出了明确的非哮喘、非过敏受试者中分别为半胱氨酸-甘氨酸-谷氨酰胺、精氨酸-甘氨酸-谷氨酸或半胱氨酸-精氨酸-谷氨酰胺纯合单倍型的淋巴细胞。相对于β₂-肾上腺素能受体介导的对γ-干扰素和白细胞介素-5产生的抑制作用，测量了（-）-异丙肾上腺素诱导的环磷酸腺苷（cAMP）积累、β₂-肾上腺素能受体隔离和下调的脱敏情况。我们观察到，携带半胱氨酸-甘氨酸-谷氨酰胺单倍型的个体的淋巴细胞比具有精氨酸-甘氨酸-谷氨酸或半胱氨酸-精氨酸-谷氨酰胺单倍型的个体的淋巴细胞对β-激动剂诱导的cAMP反应脱敏更敏感。β-激动剂诱导的cAMP反应的单倍型依赖性脱敏与单倍型依赖性β₂-肾上腺素能受体隔离或下调无关。此外，我们的数据表明，在携带半胱氨酸-甘氨酸-谷氨酰胺单倍型的受试者的淋巴细胞中，用抗T细胞受体-CD3复合物和共刺激分子CD28（αCD3/αCD28）抗体处理诱导的白细胞介素-5产生的抑制作用降低。这是第一项证明原代人细胞中激动剂诱导的β₂-肾上腺素能受体脱敏存在单倍型相关差异的研究。淋巴细胞中β₂-肾上腺素能受体的这种单倍型相关脱敏可能对辅助性T细胞2型炎症反应的调节产生影响。
