Hu Aihua, Fatma Sumbul, Cao Jing, Grunstein Judith S, Nino Gustavo, Grumbach Yael, Grunstein Michael M
University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Am J Physiol Lung Cell Mol Physiol. 2009 May;296(5):L790-803. doi: 10.1152/ajplung.90572.2008. Epub 2009 Feb 27.
The anti-inflammatory actions of endogenous glucocorticoids (GCs) are regulated by the activities of the GC-activating and -inactivating enzymes, 11beta-hydroxysteroid dehydrogenase (11beta-HSD)-1 and 11beta-HSD2, respectively, that catalyze the interconversion of the inert GC, cortisone, and its bioactive derivative, cortisol. Proinflammatory cytokines regulate 11beta-HSD1 expression in various cell types and thereby modulate the bioavailability of cortisol to the glucocorticoid receptor (GR). Since endogenous GCs reportedly attenuate the airway asthmatic response to allergen exposure, we investigated whether airway smooth muscle (ASM) exhibits cytokine-induced changes in 11beta-HSD1 expression that enable the ASM to regulate its own bioavailability of GC and, accordingly, the protective effect of GR signaling on airway function under proasthmatic conditions. Human ASM cells exposed to the primary proasthmatic T helper type 2 (Th2) cytokine, IL-13, exhibited upregulated expression of 11beta-HSD1, an effect that was attributed to activation of the transcription factor, AP-1, coupled to MAPK signaling via the ERK1/2 and JNK pathways. The induction of 11beta-HSD1 expression and its oxoreductase activity by IL-13 (also IL-4) served to amplify the conversion of cortisone to cortisol by the cytokine-exposed ASM and, hence, heighten GR-mediated transcriptional activation. Extended studies demonstrated that this amplified 11beta-HSD1-dependent GC activation enabled physiologically relevant concentrations of cortisone to exert enhanced protection of ASM tissues from the proasthmatic effects of IL-13 on ASM constrictor and relaxation responsiveness. Collectively, these novel findings identify a Th2 cytokine-driven homeostatic feedback mechanism in ASM that enhances its responsiveness to endogenous GCs by upregulating 11beta-HSD1 activity, thereby curtailing the adverse effects of the proasthmatic cytokine on airway function.
内源性糖皮质激素（GCs）的抗炎作用分别由GC激活酶和失活酶11β-羟基类固醇脱氢酶（11β-HSD）-1和11β-HSD2的活性调节，这两种酶催化惰性GC可的松及其生物活性衍生物皮质醇的相互转化。促炎细胞因子调节多种细胞类型中11β-HSD1的表达，从而调节皮质醇对糖皮质激素受体（GR）的生物利用度。由于据报道内源性GCs可减轻气道对过敏原暴露的哮喘反应，我们研究了气道平滑肌（ASM）是否表现出细胞因子诱导的11β-HSD1表达变化，从而使ASM能够调节自身GC的生物利用度，并相应地调节GR信号在哮喘前期条件下对气道功能的保护作用。暴露于主要的哮喘前期2型辅助性T细胞（Th2）细胞因子白细胞介素-13（IL-13）的人ASM细胞表现出11β-HSD1表达上调，这一效应归因于转录因子AP-1的激活，AP-1通过细胞外信号调节激酶1/2（ERK1/2）和应激活化蛋白激酶（JNK）途径与丝裂原活化蛋白激酶（MAPK）信号传导相关联。IL-13（以及IL-4）对11β-HSD1表达及其氧化还原酶活性的诱导作用，促使暴露于细胞因子的ASM将可的松转化为皮质醇的过程增强，从而增强GR介导的转录激活。进一步的研究表明，这种增强的依赖11β-HSD1的GC激活作用使生理相关浓度的可的松能够增强对ASM组织的保护，使其免受IL-13对ASM收缩和舒张反应性的哮喘前期影响。总的来说，这些新发现确定了ASM中一种由Th2细胞因子驱动的稳态反馈机制，该机制通过上调11β-HSD1活性增强其对内源性GCs的反应性，从而减少哮喘前期细胞因子对气道功能的不利影响。
