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Glucocorticoid-mediated inhibition of Lck modulates the pattern of T cell receptor-induced calcium signals by down-regulating inositol 1,4,5-trisphosphate receptors

Harr, Michael W.; Rong, Yiping; Bootman, Martin D.; Roderick, H. Llewelyn and Distelhorst, Clark W. (2009). Glucocorticoid-mediated inhibition of Lck modulates the pattern of T cell receptor-induced calcium signals by down-regulating inositol 1,4,5-trisphosphate receptors. The Journal of Biological Chemistry, 284(46) pp. 31860–31871.

DOI (Digital Object Identifier) Link: http://dx.doi.org/10.1074/jbc.M109.005579
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Abstract

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 (IP(3))-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 IP(3) receptor. In addition, low concentrations of dexamethasone were sufficient to inhibit calcium oscillations and interleukin-2 mRNA after weak TCR stimulation. Together, these findings indicate that by inhibiting Lck and subsequently down-regulating IP(3) receptors, glucocorticoids suppress immune responses by weakening the strength of the TCR signal.

Item Type: Journal Article
Copyright Holders: 2009 The American Society for Biochemistry and Molecular Biology, Inc.
ISSN: 1083-351X
Academic Unit/Department: Science > Life, Health and Chemical Sciences
Interdisciplinary Research Centre: Biomedical Research Network (BRN)
Item ID: 34848
Depositing User: Martin Bootman
Date Deposited: 25 Oct 2012 09:53
Last Modified: 07 Mar 2014 15:03
URI: http://oro.open.ac.uk/id/eprint/34848
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