Leung D Y, Martin R J, Szefler S J, Sher E R, Ying S, Kay A B, Hamid Q
Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado 80206.
J Exp Med. 1995 Jan 1;181(1):33-40. doi: 10.1084/jem.181.1.33.
In steroid-resistant (SR) asthma, there is a lack of clinical responsiveness to oral prednisone. Previous studies indicate that this may be explained by the effect of the combination of interleukin 2 (IL-2) and IL-4 on glucocorticoid receptor binding affinity. By contrast, steroid-sensitive (SS) asthmatics respond well to glucocorticoids, and this is accompanied by a decrease in the numbers of bronchoalveolar lavage (BAL) messenger RNA+ (mRNA+) cells expressing IL-4 and IL-5, and an increase in interferon gamma (IFN-gamma) transcripts. In the present study, we hypothesized that SR asthma is associated with alterations in T helper types 1/2 (Th2/Th1)-type cytokine gene expression. BAL was performed in six SR asthmatics and six SS asthmatics, before and after a 1-wk course of 40 mg daily prednisone. mRNA+ cells for IL-2, IL-4, IL-5, and IFN-gamma was measured by in situ hybridization using 35S-labeled RNA probes. Before prednisone therapy, there were significantly greater numbers of BAL cells (per 1,000) expressing IL-2 mRNA (p < 0.01) and IL-4 mRNA (p < 0.05) in SR asthmatics as compared with SS asthmatics, but no differences between the two groups in the numbers of BAL cells expressing IFN-gamma or IL-5 mRNA expression were observed. After a 1-wk course of prednisone, IL-2 expression was not altered in either group. However, SS asthmatics had a significant decrease in the numbers of BAL cells expressing mRNA for IL-4 (p < 0.01) and IL-5 (p < 0.001), and a rise in the numbers of IFN-gamma mRNA+ cells (p < 0.01). In contrast, after prednisone treatment, SR asthmatics had no significant change in either the number of BAL cells expressing mRNA for IL-4 or IL-5. Of note, there was an unexpected decrease in the numbers of IFN-gamma mRNA+ cells (p = 0.05). Our current findings indicate that SR asthma is associated with a dysregulation of the expression of the genes encoding for Th2/Th1 cytokines in airway cells and is compatible with the concept that a combination of IL-2 and IL-4 induce glucocorticoid (GR) binding affinity and T cell responsiveness to glucocorticoids.
在激素抵抗型（SR）哮喘中，口服泼尼松缺乏临床反应性。先前的研究表明，这可能是由白细胞介素2（IL-2）和IL-4的组合对糖皮质激素受体结合亲和力的影响所致。相比之下，激素敏感型（SS）哮喘患者对糖皮质激素反应良好，同时支气管肺泡灌洗（BAL）中表达IL-4和IL-5的信使RNA+（mRNA+）细胞数量减少，而干扰素γ（IFN-γ）转录本增加。在本研究中，我们假设SR哮喘与1型/2型辅助性T细胞（Th2/Th1）型细胞因子基因表达的改变有关。在6例SR哮喘患者和6例SS哮喘患者中，于每日40mg泼尼松治疗1周疗程前后进行BAL。使用35S标记的RNA探针通过原位杂交测量IL-2、IL-4、IL-5和IFN-γ的mRNA+细胞。在泼尼松治疗前，与SS哮喘患者相比，SR哮喘患者中表达IL-2 mRNA（p<0.01）和IL-4 mRNA（p<0.05）的BAL细胞数量（每1000个）显著更多，但两组在表达IFN-γ或IL-5 mRNA的BAL细胞数量上未观察到差异。经过1周的泼尼松疗程后，两组中IL-2的表达均未改变。然而，SS哮喘患者中表达IL-4 mRNA（p<0.01）和IL-5 mRNA（p<0.001）的BAL细胞数量显著减少，而IFN-γ mRNA+细胞数量增加（p<0.01）。相比之下，泼尼松治疗后，SR哮喘患者中表达IL-4或IL-5 mRNA的BAL细胞数量均无显著变化。值得注意的是，IFN-γ mRNA+细胞数量意外减少（p=0.05）。我们目前的研究结果表明，SR哮喘与气道细胞中Th2/Th1细胞因子编码基因表达失调有关，并且与IL-2和IL-4的组合诱导糖皮质激素（GR）结合亲和力以及T细胞对糖皮质激素反应性的概念相符。
