The kinases MSK1 and MSK2 act as negative  regulators of Toll-like receptor signaling.
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.
Ananieva
Olga
O
Medical Research Council Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
Darragh
Joanne
J
Johansen
Claus
C
Carr
Julia M
JM
McIlrath
Joanne
J
Park
Jin Mo
JM
Wingate
Andrew
A
Monk
Claire E
CE
Toth
Rachel
R
Santos
Susana G
SG
Iversen
Lars
L
Arthur
J Simon C
JS
D000818:Animals; D008070:Lipopolysaccharides / Q000276:immunology* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000276:immunology / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000172:deficiency* / Q000276:immunology / Q000502:physiology; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000276:immunology / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000187:drug effects / Q000276:immunology*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
D008070:Lipopolysaccharides; D051193:Toll-Like Receptors; D014157:Transcription Factors; C016658:phorbolol myristate acetate; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C485459:Rps6ka4 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate