Versluis Mieke, Postma Dirkje S, Timens Wim, Hylkema Machteld N
Department of Pathology and Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Int Immunopharmacol. 2008 Jun;8(6):866-73. doi: 10.1016/j.intimp.2008.02.001. Epub 2008 Mar 4.
Inhalation of adenosine-5'-monophosphate (AMP) causes bronchoconstriction in asthma but not in healthy subjects. Bronchoconstriction upon AMP inhalation is thought to occur by histamine release and subsequent binding to receptors on airway smooth muscle cells.
To explain enhanced sensitivity to AMP in asthma, mast cell expression of the adenosine A2A and A2B receptors and histamine release were measured after incubation of human mast cell line 1 (HMC-1) cells with AMP and the non-specific adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA) for 1.5 and 6 h. To establish a Thelper-2 environment resembling the asthma phenotype, HMC-1 cells were additionally cultured with IL-4 and IL-13 alone or stimulated with the combination of both cytokines and AMP and NECA. To study effects of prolonged presence of the inflammatory environment, the cells were pre-incubated overnight (18 h) with IL-4 and IL-13 and additionally stimulated with AMP and NECA for 1.5 or 6 h.
AMP and NECA hardly affected adenosine receptor expression but increased IL-8 secretion. Incubation with IL-4 and IL-13 for 6 h increased adenosine A2A receptor expression and histamine secretion, but decreased IL-8 secretion. The combination of IL-4, IL-13, and AMP/NECA for 6 h increased A2B receptor expression and IL-8 secretion. Overnight stimulation with IL-4, IL-13 and subsequent stimulation with AMP/NECA for 1.5 h decreased A2AR expression which was accompanied by increased histamine secretion.
These results suggest a role for decreased A(2A)R expression in enhanced adenosine responsiveness as observed in asthma.
吸入5'-单磷酸腺苷（AMP）可导致哮喘患者支气管收缩，但对健康受试者无此作用。吸入AMP后发生的支气管收缩被认为是通过组胺释放以及随后与气道平滑肌细胞上的受体结合而发生的。
为了解释哮喘患者对AMP敏感性增强的原因，将人肥大细胞系1（HMC-1）细胞与AMP和非特异性腺苷受体激动剂5'-N-乙基羧酰胺腺苷（NECA）孵育1.5小时和6小时后，测量腺苷A2A和A2B受体的肥大细胞表达以及组胺释放。为建立类似于哮喘表型的辅助性T细胞2环境，HMC-1细胞单独用白细胞介素-4（IL-4）和白细胞介素-13培养，或用这两种细胞因子与AMP和NECA的组合刺激。为研究炎症环境长期存在的影响，细胞先用IL-4和IL-13预孵育过夜（18小时），然后再用AMP和NECA额外刺激1.5小时或6小时。
AMP和NECA对腺苷受体表达影响不大，但增加了白细胞介素-8（IL-8）的分泌。用IL-4和IL-13孵育6小时增加了腺苷A2A受体表达和组胺分泌，但减少了IL-8分泌。IL-4、IL-13与AMP/NECA共同作用6小时增加了A2B受体表达和IL-8分泌。用IL-4、IL-13过夜刺激，随后用AMP/NECA刺激1.5小时，降低了A2A受体表达，同时组胺分泌增加。
这些结果表明，如在哮喘中观察到的，A(2A)R表达降低在腺苷反应性增强中起作用。
