Glucocorticoid-mediated Inhibition of Lck Modulates the Pattern of T Cell Receptor-induced Calcium Signals by Down-regulating Inositol 1,4,5-Trisphosphate Receptors

被引：42

作者：

Harr, Michael W. ^{[1
]}

Rong, Yiping ^{[2
]}

Bootman, Martin D. ^{[5
]}

Roderick, H. Llewelyn ^{[5
,6
]}

Distelhorst, Clark W. ^{[1
,2
,3
,4
]}

机构：

[1] Case Western Reserve Univ, Dept Med, Div Hematol & Oncol, Cleveland, OH 44106 USA

[2] Case Western Reserve Univ, Dept Pharmacol, Cleveland, OH 44106 USA

[3] Case Western Reserve Univ, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA

[4] Univ Hosp Cleveland, Cleveland, OH 44106 USA

[5] Babraham Inst, Lab Mol & Cellular Signalling, Cambridge CB22 3AT, England

[6] Univ Cambridge, Dept Pharmacol, Cambridge CB2 1PD, England

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2009年 / 284卷 / 46期

基金：

英国生物技术与生命科学研究理事会;

关键词：

PROTEIN SECONDARY STRUCTURE; KAPPA-B ACTIVITY; TYROSINE PHOSPHORYLATION; NEGATIVE REGULATION; GENE-EXPRESSION; LYMPHOMA-CELLS; NUCLEAR FACTOR; ACTIVATION; KINASE; TRANSCRIPTION;

D O I：

10.1074/jbc.M109.005579

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Glucocorticoids are potent immunosuppressive agents that block upstream signaling events required for T cell receptor (TCR) activation. However, the mechanism by which glucocorticoids inhibit downstream responses, such as inositol 1,4,5-trisphosphate (IP3)-induced calcium signals, is not completely understood. Here we demonstrate that low concentrations of dexamethasone rapidly convert transient calcium elevations to oscillations after strong TCR stimulation. Dexamethasone converted the pattern of calcium signaling by inhibiting the Src family kinase Lck, which was shown to interact with and positively regulate Type I IP3 receptor. In addition, low concentrations of dexamethasone were sufficient to inhibit calcium oscillations and interleukin-2mRNA after weak TCR stimulation. Together, these findings indicate that by inhibiting Lck and subsequently down-regulating IP3 receptors, glucocorticoids suppress immune responses by weakening the strength of the TCR signal.

引用

页码：31860 / 31871

页数：12

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