Dual specificity phosphatase 1 knockout mice show enhanced susceptibility to anaphylaxis but are sensitive to glucocorticoids

JV Maier, S Brema, J Tuckermann… - Molecular …, 2007 - academic.oup.com
JV Maier, S Brema, J Tuckermann, U Herzer, M Klein, M Stassen, A Moorthy, ACB Cato
Molecular Endocrinology, 2007academic.oup.com
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 …
Abstract
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, TNFα) 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.
Oxford University Press