Mozo L, Gayo A, Suárez A, Rivas D, Zamorano J, Gutiérrez C
Department of Immunology, Hospital Central de Asturias, Centro Universitario, Oviedo.
J Allergy Clin Immunol. 1998 Dec;102(6 Pt 1):968-76. doi: 10.1016/s0091-6749(98)70335-5.
A high level of expression of IL-4Ralpha chain on the surface of lymphocytes has been described in certain allergic and inflammatory autoimmune diseases. Progression of these diseases are usually controlled by steroid treatment. One mechanism by which these drugs exert their antiinflammatory and immunosuppressive effects is by widely repressing or enhancing the production of cytokines and their receptors.
The effect of glucocorticoids on IL-4Ralpha chain expression has not been previously studied, and this is the aim of the present report. For this purpose, human lymphocytes were induced to express IL-4Ralpha chain by means of protein kinase C (PKC) activation with phorbol myristate acetate (PMA) or by triggering the Janus kinase-Stat pathway with IL-4 in the presence or absence of pharmacologic doses of dexamethasone.
IL-4Ralpha cell surface expression was studied by flow cytofluorometry. The levels and stability of mRNA were assessed by Northern blot analysis. The effect of dexamethasone on the IL-4Ralpha rate of transcription was determined by nuclear run-on experiments.
Dexamethasone significantly downregulated PMA-induced IL-4Ralpha mRNA and protein levels in total peripheral blood mononuclear cells and in isolated T cells. The mechanism involved a posttranscriptional regulation of IL-4Ralpha expression because dexamethasone decreased the PMA-induced IL-4Ralpha mRNA half-life. However, we found that PMA did not influence the transcription rate of IL-4Ralpha gene, irrespective of the presence or absence of dexamethasone. This immunosuppressor also diminished the IL-4-induced IL-4Ralpha expression on the surface of isolated T and B lymphocytes but, interestingly, without modifying mRNA levels that indicates that dexamethasone downregulated IL-4-dependent IL-4Ralpha expression by acting at a translational or posttranslational level. In fact, we observed that the drug did not affect IL-4-induced IL-4Ralpha gene transcription rate nor did it shorten mRNA half-life. The effect of dexamethasone on the IL-4Ralpha was steroid specific because it was totally reversed by the glucocorticoid receptor antagonist RU486.
Our results support that dexamethasone may influence the course of allergic and inflammatory diseases by downregulating the expression of IL-4Ralpha.
在某些过敏性和炎性自身免疫性疾病中，淋巴细胞表面白细胞介素-4受体α链（IL-4Rα）呈高水平表达。这些疾病的进展通常通过类固醇治疗来控制。这些药物发挥抗炎和免疫抑制作用的一种机制是广泛抑制或增强细胞因子及其受体的产生。
糖皮质激素对IL-4Rα链表达的影响此前尚未研究，本报告旨在对此进行研究。为此，在有或没有药理剂量地塞米松的情况下，通过用佛波醇肉豆蔻酸酯乙酸酯（PMA）激活蛋白激酶C（PKC）或用IL-4触发Janus激酶-信号转导子和转录激活子（JAK-STAT）途径，诱导人淋巴细胞表达IL-4Rα链。
通过流式细胞荧光术研究IL-4Rα细胞表面表达。通过Northern印迹分析评估mRNA的水平和稳定性。用地塞米松对IL-4Rα转录速率的影响通过核转录实验来确定。
地塞米松显著下调外周血单个核细胞和分离的T细胞中PMA诱导的IL-4Rα mRNA和蛋白水平。其机制涉及IL-4Rα表达的转录后调控，因为地塞米松缩短了PMA诱导的IL-4Rα mRNA半衰期。然而，我们发现PMA不影响IL-4Rα基因的转录速率，无论是否存在地塞米松。这种免疫抑制剂也减少了IL-4诱导的分离的T和B淋巴细胞表面的IL-4Rα表达，但有趣的是，并未改变mRNA水平，这表明地塞米松通过在翻译或翻译后水平起作用下调IL-4依赖性IL-4Rα表达。事实上，我们观察到该药物不影响IL-4诱导的IL-4Rα基因转录速率，也不缩短mRNA半衰期。地塞米松对IL-IRα的作用具有类固醇特异性，因为糖皮质激素受体拮抗剂RU486可完全逆转该作用。
我们的结果支持地塞米松可能通过下调IL-4Rα的表达来影响过敏性和炎性疾病的进程。
