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Dual Specificity Phosphatase 1 Knockout Mice Show Enhanced Susceptibility to Anaphylaxis but Are Sensitive to Glucocorticoids

Forschungszentrum Karlsruhe (J.V.M., S.B., U.H., A.M., A.C.B.C.), Institute of Toxicology and Genetics, D-76021 Karlsruhe, Germany; Molecular Biology of Tissue Specific Hormone Action (J.T.), Leibniz Institute for Age Research-Fritz-Lipmann-Institute e.V., D-07745 Jena, Germany; and Institute of Immunology (M.K., M.S.), Johannes Gutenberg University, Hochhaus am Augustusplatz, D-55131 Mainz, Germany

Address all correspondence and requests for reprints to: Andrew C. B. Cato, Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, P.O. Box 3640, D-76021 Karlsruhe, Germany. E-mail: andrew.cato{at}itg.fzk.de.

Dual specificity phosphatase DUSP1 (otherwise known as mitogen-activated phosphatase 1 or MKP-1) dephosphorylates MAPKs, particularly p38, and negatively regulates innate immunity. Recent studies have shown that the DUSP1 gene is transcriptionally up-regulated by glucocorticoids (GCs) and that the antiinflammatory action of GCs is impaired in DUSP1–/– mice. Here we show that GC-mediated dephosphorylation of ERK-1 and ERK-2 activated by IgE receptor cross-linking is unimpaired in bone marrow-derived mast cells (BMMCs) of DUSP1–/– mice. Dephosphorylation of phospho-p38 MAPK is impaired but only at early times of GC treatment. Proinflammatory cytokine and chemokine gene expression (CCL2, IL-6, TNF) is still down-regulated by GCs in BMMCs from DUSP1–/– mice, suggesting a compensatory mechanism for the GC action in these mice. In both DUSP1+/+ and DUSP1–/– BMMCs, GC up-regulated the expression of several phosphatase genes (DUSP2, DUSP4, DUSP9, and PEST domain-enriched tyrosine phosphatase). DUSP1–/– mice show enhanced mast cell degranulation and are highly susceptible to anaphylaxis, but these effects are still down-regulated by GCs. GCs also repressed other inflammatory responses such as dinitrofluorobenzene-induced contact hypersensitivity and lipopolysaccharide-induced mortality in DUSP1–/– mice. Thus GC-mediated antiinflammatory action is largely independent of DUSP1.

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