Mohede I C, Van Ark I, Brons F M, Van Oosterhout A J, Nijkamp F P
Department of Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, The Netherlands.
Int J Immunopharmacol. 1996 Mar;18(3):193-201. doi: 10.1016/0192-0561(96)00008-2.
T-lymphocytes play an important role in allergic asthma. In the present study, the effect of beta(2)-adrenoceptor agonists was examined on proliferation, interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) production by human peripheral blood mononuclear cells (PBMC). The proliferation after 24 h phytohaemagglutinin (PHA) activation was significantly inhibited at high concentrations of salmeterol, isoprenaline and salbutamol (> or = 10(-6) M). A U-shaped concentration response curve was observed for the effect of all agonists on IL-4 production 24 h after PHA activation. Maximal inhibition occurred at 10(-9) M and amounted to 71% (P < 0.02), 38% (P < 0.01) and 49% (P < 0.01) for salmeterol, isoprenaline and salbutamol, respectively. In contrast, no significant effect of salmeterol (10(-11)-10(-5) M) on IL-4 production could be detected after 96 h. A biphasic concentration response curve was observed for the inhibitory activity of all beta-adrenoceptor agonists on IFN-gamma production by PBMC 24 h after PHA activation. The first phase reached a plateau at 10(-9) M and the inhibition amounted to 50% (P < 0.05), 33% (P < 0.01) and 44% (P < 0.05) for salmeterol, isoprenaline and salbutamol, respectively. At higher concentrations of the three beta-adrenoceptor agonists the inhibition was increased up to 80% (P < 0.05), 60% (P < 0.05) and 58% (P < 0.01), respectively. Similar to the results obtained after 24 h, IFN-gamma production after 96 h was biphasically inhibited by salmeterol, and this inhibition (60%) was significantly at 10(-5) M. Together, the present data provide clear evidence for concentration-dependent effects of beta-adrenoceptor agonists on the IL-4 and IFN-gamma production by human PBMC. These results suggest that beta-agonists, at low concentrations, predominantly inhibit IL-4 production and may therefore act as anti-inflammatory drugs in allergic asthma.
T淋巴细胞在过敏性哮喘中起重要作用。在本研究中，检测了β₂-肾上腺素能受体激动剂对人外周血单个核细胞（PBMC）增殖、白细胞介素-4（IL-4）和干扰素-γ（IFN-γ）产生的影响。高浓度（≥10⁻⁶M）的沙美特罗、异丙肾上腺素和沙丁胺醇显著抑制了植物血凝素（PHA）激活24小时后的增殖。PHA激活24小时后，观察到所有激动剂对IL-4产生的浓度-反应曲线呈U形。最大抑制作用出现在10⁻⁹M，沙美特罗、异丙肾上腺素和沙丁胺醇的抑制率分别为71%（P<0.02）、38%（P<0.01）和49%（P<0.01）。相比之下，96小时后未检测到沙美特罗（10⁻¹¹-10⁻⁵M）对IL-4产生有显著影响。PHA激活24小时后，观察到所有β-肾上腺素能受体激动剂对PBMC产生IFN-γ的抑制活性呈双相浓度-反应曲线。第一阶段在10⁻⁹M达到平台期，沙美特罗、异丙肾上腺素和沙丁胺醇的抑制率分别为50%（P<0.05）、33%（P<0.01）和44%（P<0.05）。在三种β-肾上腺素能受体激动剂的较高浓度下，抑制作用分别增加至80%（P<0.05）、60%（P<0.05）和58%（P<0.01）。与24小时后获得的结果相似，96小时后沙美特罗对IFN-γ产生呈双相抑制，在10⁻⁵M时这种抑制作用（60%）显著。总之，本数据为β-肾上腺素能受体激动剂对人PBMC产生IL-4和IFN-γ的浓度依赖性作用提供了明确证据。这些结果表明，低浓度的β-激动剂主要抑制IL-4的产生，因此可能在过敏性哮喘中作为抗炎药物发挥作用。
