Kay L J, Rostami-Hodjegan A, Suvarna S K, Peachell P T
Academic Unit of Molecular Pharmacology, University of Sheffield, The Royal Hallamshire Hospital (Floor M), Sheffield, S Yorks S10 2JF, UK.
Br J Pharmacol. 2007 Oct;152(3):323-31. doi: 10.1038/sj.bjp.0707400. Epub 2007 Jul 23.
Previous studies have shown that beta(2)-adrenoceptor-mediated responses in human lung mast cells are highly variable. The aims of the present study were to establish whether polymorphisms of the beta (2)-adrenoceptor gene (ADRB2) influence this variability in (a) beta(2)-adrenoceptor-mediated inhibition and (b) desensitization of beta(2)-adrenoceptor-mediated responses in human lung mast cells.
Mast cells were isolated from human lung tissue. The inhibitory effects of the beta-adrenoceptor agonist, isoprenaline (10(-10)-10(-5) M), on IgE-mediated histamine release from mast cells were determined (n=92). Moreover, the inhibitory effects of isoprenaline were evaluated following a desensitizing treatment involving long-term (24 h) incubation of mast cells with isoprenaline (10(-6) M) (n=65). A potential influence of polymorphisms on these functional responses was determined by genotyping 11 positions, in the promoter and coding regions, of ADRB2 previously reported as polymorphic.
There was no influence of any of the polymorphic positions of ADRB2 on the potency of isoprenaline to inhibit histamine release from mast cells with the exception of position 491C>T (Thr164Ile). There was no influence of any of the polymorphic positions of ADRB2 on the extent of desensitization of the isoprenaline-mediated response following a desensitizing treatment except for position 46G>A (Gly16Arg). Analyses at the haplotype level indicated that there was no influence of haplotype on beta (2)-adrenoceptor-mediated responses in mast cells.
These data indicate that certain polymorphisms in ADRB2 influence beta(2)-adrenoceptor-mediated responses in human lung mast cells.
先前的研究表明，人类肺肥大细胞中β₂ - 肾上腺素能受体介导的反应具有高度变异性。本研究的目的是确定β₂ - 肾上腺素能受体基因（ADRB2）的多态性是否影响（a）β₂ - 肾上腺素能受体介导的抑制作用以及（b）人类肺肥大细胞中β₂ - 肾上腺素能受体介导反应的脱敏作用的这种变异性。
从人肺组织中分离肥大细胞。测定β - 肾上腺素能受体激动剂异丙肾上腺素（10⁻¹⁰ - 10⁻⁵ M）对肥大细胞中IgE介导的组胺释放的抑制作用（n = 92）。此外，在肥大细胞与异丙肾上腺素（10⁻⁶ M）长期（24小时）孵育的脱敏处理后，评估异丙肾上腺素的抑制作用（n = 65）。通过对先前报道为多态性的ADRB2启动子和编码区的11个位点进行基因分型，确定多态性对这些功能反应的潜在影响。
除了491C>T（Thr164Ile）位点外，ADRB2的任何多态性位点对异丙肾上腺素抑制肥大细胞组胺释放的效力均无影响。除了46G>A（Gly16Arg）位点外，ADRB2的任何多态性位点对脱敏处理后异丙肾上腺素介导反应的脱敏程度均无影响。单倍型水平分析表明，单倍型对肥大细胞中β₂ - 肾上腺素能受体介导的反应无影响。
这些数据表明，ADRB2中的某些多态性影响人类肺肥大细胞中β₂ - 肾上腺素能受体介导的反应。
