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Molecular and Cellular Biology, November 2002, p. 7802-7811, Vol. 22, No. 22
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.22.7802-7811.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Dexamethasone Causes Sustained Expression of Mitogen-Activated Protein Kinase (MAPK) Phosphatase 1 and Phosphatase-Mediated Inhibition of MAPK p38

Marina Lasa, Sonya M. Abraham, Christine Boucheron, Jeremy Saklatvala, and Andrew R. Clark*

Kennedy Institute of Rheumatology Division, Imperial College Faculty of Medicine, London W6 8LH, United Kingdom

Received 15 February 2002/ Returned for modification 20 March 2002/ Accepted 16 August 2002

The stress-activated protein kinase p38 stabilizes a number of mRNAs encoding inflammatory mediators, such as cyclooxygenase 2 (Cox-2). In HeLa cells the anti-inflammatory glucocorticoid dexamethasone destabilizes Cox-2 mRNA by inhibiting p38 function. Here we demonstrate that this effect is phosphatase dependent. Furthermore, in HeLa cells dexamethasone induced the sustained expression of mitogen-activated protein kinase phosphatase 1 (MKP-1), a potent inhibitor of p38 function. The inhibition of p38 and the induction of MKP-1 by dexamethasone occurred with similar dose dependence and kinetics. No other known p38 phosphatases were induced by dexamethasone, and other cell types which failed to express MKP-1 also failed to inhibit p38 in response to dexamethasone. The proinflammatory cytokine interleukin 1 (IL-1) induced MKP-1 expression in a p38-dependent manner and acted synergistically with dexamethasone to induce MKP-1 expression. In HeLa cells treated with IL-1 or IL-1 and dexamethasone, the dynamics of p38 activation mirrored the expression of MKP-1. These observations suggest that MKP-1 participates in a negative-feedback loop which regulates p38 function and that dexamethasone may inhibit proinflammatory gene expression in part by inducing MKP-1 expression.

* Corresponding author. Mailing address: Kennedy Institute of Rheumatology Division, Imperial College Faculty of Medicine, 1 Aspenlea Rd., Hammersmith, London W6 8LH, United Kingdom. Phone: (44) 20 8383 4430. Fax: (44) 20 8383 4499. E-mail: andy.clark{at}ic.ac.uk.

Molecular and Cellular Biology, November 2002, p. 7802-7811, Vol. 22, No. 22
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.22.7802-7811.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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