Dual specificity phosphatase 1 knockout mice show enhanced susceptibility to anaphylaxis but are sensitive to glucocorticoids.
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, TNFalpha) 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.
Maier
Jana V
JV
Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, P.O. Box 3640, D-76021 Karlsruhe, Germany.
Brema
Susanne
S
Tuckermann
Jan
J
Herzer
Ute
U
Klein
Matthias
M
Stassen
Michael
M
Moorthy
Anbalagan
A
Cato
Andrew C B
AC
D000707:Anaphylaxis / Q000235:genetics*; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics* / Q000502:physiology*; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D005938:Glucocorticoids / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018805:Sepsis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016207:Cytokines; D005938:Glucocorticoids; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1