Maier Jana V, Brema Susanne, Tuckermann Jan, Herzer Ute, Klein Matthias, Stassen Michael, Moorthy Anbalagan, Cato Andrew C B
Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, P.O. Box 3640, D-76021 Karlsruhe, Germany.
Mol Endocrinol. 2007 Nov;21(11):2663-71. doi: 10.1210/me.2007-0067. Epub 2007 Jul 17.
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.
双特异性磷酸酶DUSP1（也称为丝裂原活化磷酸酶1或MKP-1）使丝裂原活化蛋白激酶（MAPKs）去磷酸化，尤其是p38，并对先天免疫起负调节作用。最近的研究表明，糖皮质激素（GCs）可使DUSP1基因转录上调，且在DUSP1基因敲除小鼠中，GCs的抗炎作用受损。在此我们发现，在DUSP1基因敲除小鼠的骨髓来源肥大细胞（BMMCs）中，GC介导的对由IgE受体交联激活的ERK-1和ERK-2的去磷酸化作用未受影响。磷酸化的p38 MAPK的去磷酸化作用受损，但仅在GC处理的早期阶段。来自DUSP1基因敲除小鼠的BMMCs中，促炎细胞因子和趋化因子基因表达（CCL2、IL-6、TNFα）仍受GCs下调，这表明在这些小鼠中存在GC作用的补偿机制。在DUSP1+/+和DUSP1-/- BMMCs中，GC均上调了几种磷酸酶基因（DUSP2、DUSP4、DUSP9和富含PEST结构域的酪氨酸磷酸酶）的表达。DUSP1基因敲除小鼠表现出肥大细胞脱颗粒增强，且对过敏反应高度敏感，但这些效应仍受GCs下调。GCs还抑制了DUSP1基因敲除小鼠中的其他炎症反应，如二硝基氟苯诱导的接触性超敏反应和脂多糖诱导的死亡。因此，GC介导的抗炎作用在很大程度上不依赖于DUSP1。
