Tsitoura Daphne C, Rothman Paul B
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10034, USA.
J Clin Invest. 2004 Feb;113(4):619-27. doi: 10.1172/JCI18975.
Glucocorticoids have potent immunosuppressive properties, but their effects are often modulated by the conditions prevailing in the local immune milieu. In this study we determined whether the action of glucocorticoids is influenced by the degree of signaling during T cell activation. We found that dexamethasone (Dex) effectively suppressed T cell receptor-induced (TCR-induced) proliferation of naive CD4+ T cells, through a mechanism involving downregulation of c-Fos expression and inhibition of activator protein-1 (AP-1), nuclear factor of activated T cells (NF-AT), and NF-kappaB transcriptional activity. However, enhancement of TCR signaling by CD28- or IL-2-mediated costimulation abrogated the suppressive effect of Dex on c-Fos expression and AP-1 function and restored cellular proliferation. The amount of signaling through the MAPK pathway was critical in determining the effect of Dex on T cell activation. In particular, costimulatory signaling via MAPK kinase (MEK) and extracellular signal-regulated kinase (ERK) was essential for the development of T cell resistance to Dex. Selective blockade of MEK/ERK signal transduction abolished the costimulation-induced resistance. In contrast, transmission of IL-2 signals via STAT5 and CD28 signals via NF-kappaB remained inhibited by Dex. These results imply that the immune system, by regulating the degree of local costimulation through MEK/ERK, can modify the effect of glucocorticoids on T cells. Moreover, these findings suggest that MAPK inhibitors may offer a therapeutic solution for glucocorticoid resistance.
糖皮质激素具有强大的免疫抑制特性，但其作用常受局部免疫环境中普遍存在的条件所调节。在本研究中，我们确定了糖皮质激素的作用是否受T细胞活化过程中信号传导程度的影响。我们发现，地塞米松（Dex）通过一种涉及下调c-Fos表达以及抑制活化蛋白-1（AP-1）、活化T细胞核因子（NF-AT）和核因子κB（NF-κB）转录活性的机制，有效抑制了幼稚CD4+ T细胞的T细胞受体诱导（TCR诱导）的增殖。然而，CD28或IL-2介导的共刺激增强TCR信号传导，消除了Dex对c-Fos表达和AP-1功能的抑制作用，并恢复了细胞增殖。通过丝裂原活化蛋白激酶（MAPK）途径的信号传导量在决定Dex对T细胞活化的作用方面至关重要。特别是，经由MAPK激酶（MEK）和细胞外信号调节激酶（ERK）的共刺激信号对于T细胞对Dex产生抗性的发展至关重要。选择性阻断MEK/ERK信号转导消除了共刺激诱导的抗性。相反，经由信号转导和转录激活因子5（STAT5）的IL-2信号传导以及经由NF-κB的CD28信号传导仍受Dex抑制。这些结果表明，免疫系统可通过调节经由MEK/ERK的局部共刺激程度来改变糖皮质激素对T细胞的作用。此外，这些发现表明MAPK抑制剂可能为糖皮质激素抵抗提供一种治疗解决方案。
