15-Deoxy-Δ12,14-prostaglandin J2 Regulates Endogenous Cot MAPK Kinase Kinase 1 Activity Induced by Lipopolysaccharide*
- Matilde Caivano‡§,
- Cristina Rodriguez§¶,
- Philip Cohen‡ and
- Susana Alemany, Supported by a short-term fellowship from the European Molecular Biology Organization.¶∥
- ¶Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Facultad Medicina Universidad Autónoma de Madrid, Arturo Duperier 4, 28029 Madrid, Spain and the ‡Medical Research Council Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee DD15EH, United Kingdom
- ∥ To whom correspondence should be addressed. E-mail: salemany{at}iib.uam.es.
Abstract
Cot is a MAPK kinase kinase that has been implicated in cellular activation and proliferation. Here, we show that the addition of lipopolysaccharide (LPS) to RAW264 macrophages induces a 10-fold increase of endogenous Cot activity, measured as MAPK kinase kinase 1 activity. Taxol, but not phorbol 12-myristate 13-acetate (PMA), induces a similar activation of Cot. A tyrosine kinase activity is involved in Cot activation by LPS. 15-Deoxy-Δ12,14-prostaglandin J2, but not rosiglitazone, blocks Cot activation by LPS. Furthermore, 15-deoxy-Δ12,14-prostaglandin J2 also inhibited the LPS-induced Cot in vitro. However, 15-deoxy-Δ12,14-prostaglandin J2 does not inhibit MAPK kinase 1 or ERK1/ERK2 activation/phosphorylation induced by PMA and mediated by c-Raf. Considering these data, we propose that the inhibition of LPS-induced Cot activation is one mechanism by which 15-deoxy-Δ12,14-prostaglandin J2 acts as an anti-inflammatory.
Footnotes
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↵1 The abbreviations used are: LPS, lipopolysaccharide; ERK, extracellular signal-regulated kinase; FBS, fetal bovine serum; Gö6850, bisindolylmaleimide I; Herb A, herbimycin A; 15d-PGJ2, 15-deoxy-Δ12,14-prostaglandin J2; PGE2, prostaglandin E2; MAPK, mitogen-activated protein kinase; MKK1, MAPK kinase 1; MKKK, MAPK kinase kinase; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; PMA, phorbol 12-myristate 13-acetate; PPAR-γ, peroxisome proliferator-activated receptor-γ; TNF-α, tumor necrosis factor α.
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↵2 M. Caivano, C. Rodriguez, P. Cohen, and S. Alemany, unpublished results.
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↵* This work was supported by grants from the Association for International Cancer Research, Fundació “La Caixa,” and BMC (to S. A.) and from the United Kingdom Medical Research Council and Royal Society (to P. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵§ These authors contributed equally to this work.
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- Received June 20, 2003.
- Revision received October 2, 2003.
- The American Society for Biochemistry and Molecular Biology, Inc.
