Elliott L H, Levay A K, Sparks B, Miller M, Roszman T L
Department of Microbiology and Immunology, College of Medicine, University of Kentucky, Lexington, 40536-0084, USA.
Cell Immunol. 1996 Apr 10;169(1):117-24. doi: 10.1006/cimm.1996.0099.
One possible explanation for the link between stress and increased incidence of infection can be attributed to concomitant increases in levels of glucocorticoids (GS) and prostaglandin E2 (PGE2), both of which possess potent immunoregulatory activities. We have previously demonstrated that concentrations of PGE2 and the synthetic glucocorticoid, dexamethasone (DEX), which individually do not inhibit human T-cell responsiveness to anti-CD3 monoclonal antibody (mAb), act synergistically to inhibit IL-2 secretion and subsequent T-cell proliferation. In the present paper, we demonstrate that treatment of anti-CD3 mAb-stimulated T-cells with low (10(-8) and 10(-9) M) concentrations of DEX and PGE2 results in the inhibition of steady-state levels of IL-2 mRNA. Initial studies to elucidate the biochemical mechanisms involved indicate that the inhibitory effects of DEX and PGE2 cannot be correlated with increased levels of intracellular cAMP or the induction of apoptosis. However, the data indicate that DEX and PGE2 when added together interrupt anti-CD3 mAb-induced tyrosine phosphorylation of substrate proteins. Furthermore, the synergistic effect of DEX and PGE2 is mimicked by agonists for the cAMP-independent EP3 subtype of the PGE2 receptor. These data suggest that DEX and PGE2 elicit cAMP-independent signaling pathways which interact to inhibit the T-cell receptor-linked signal transduction cascade in anti-CD3 mAb-stimulated T-cells.
压力与感染发病率增加之间的联系，一种可能的解释是糖皮质激素（GS）和前列腺素E2（PGE2）水平同时升高，这两者都具有强大的免疫调节活性。我们之前已经证明，PGE2和合成糖皮质激素地塞米松（DEX）的浓度，单独使用时并不抑制人类T细胞对抗CD3单克隆抗体（mAb）的反应性，但它们共同作用时会协同抑制白细胞介素-2（IL-2）的分泌以及随后的T细胞增殖。在本文中，我们证明用低浓度（10^(-8)和10^(-9) M）的DEX和PGE2处理抗CD3 mAb刺激的T细胞，会导致IL-2 mRNA稳态水平受到抑制。为阐明其中涉及的生化机制而进行的初步研究表明，DEX和PGE2的抑制作用与细胞内cAMP水平升高或细胞凋亡的诱导无关。然而，数据表明，DEX和PGE2一起添加时会中断抗CD3 mAb诱导的底物蛋白酪氨酸磷酸化。此外，PGE2受体的cAMP非依赖性EP3亚型的激动剂可模拟DEX和PGE2的协同作用。这些数据表明，DEX和PGE2引发了cAMP非依赖性信号通路，它们相互作用以抑制抗CD3 mAb刺激的T细胞中与T细胞受体相关的信号转导级联反应。
