Article abstract
Nature Immunology 9, 1028 - 1036 (2008)
Published online: 10 August 2008 | doi:10.1038/ni.1644
The kinases MSK1 and MSK2 act as negative regulators of Toll-like receptor signaling
Olga Ananieva1, Joanne Darragh1, Claus Johansen2, Julia M Carr1, Joanne McIlrath1, Jin Mo Park3, Andrew Wingate1, Claire E Monk1, Rachel Toth1, Susana G Santos1, Lars Iversen2 & J Simon C Arthur1
Abstract
The kinases MSK1 and MSK2 are activated 'downstream' of the p38 and Erk1/2 mitogen-activated protein kinases. Here we found that MSK1 and MSK2 were needed to limit the production of proinflammatory cytokines in response to stimulation of primary macrophages with lipopolysaccharide. By inducing transcription of the mitogen-activated protein kinase phosphatase DUSP1 and the anti-inflammatory cytokine interleukin 10, MSK1 and MSK2 exerted many negative feedback mechanisms. Deficiency in MSK1 and MSK2 prevented the binding of phosphorylated transcription factors CREB and ATF1 to the promoters of the genes encoding interleukin 10 and DUSP1. Mice doubly deficient in MSK1 and MSK2 were hypersensitive to lipopolysaccharide-induced endotoxic shock and showed prolonged inflammation in a model of toxic contact eczema induced by phorbol 12-myristate 13-acetate. Our results establish MSK1 and MSK2 as key components of negative feedback mechanisms needed to limit Toll-like receptor–driven inflammation.
- Medical Research Council Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
- Department of Dermatology, Aarhus University Hospital, DK-8000 Aarhus C, Denmark.
- Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Correspondence to: J Simon C Arthur1 e-mail: j.s.c.arthur@dundee.ac.uk
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