Glucocorticoids inhibit the proinflammatory activities of transcription factors such as AP‐1 and NF‐κB as well as that of diverse cellular signaling molecules. One of these signaling molecules is the extracellular signal‐regulated kinase (Erk‐1/2) that controls the release of allergic mediators and the induction of proinflammatory cytokine gene expression in mast cells. The mechanism of inhibition of Erk‐1/2 activity by glucocorticoids is unknown. Here we report a novel dual action of glucocorticoids for this inhibition. Glucocorticoids increase the expression of the MAP kinase phosphatase‐1 (MKP‐1) gene at the promoter level, and attenuate proteasomal degradation of MKP‐1, which we report to be triggered by activation of mast cells. Both induction of MKP‐1 expression and inhibition of its degradation are necessary for glucocorticoid‐mediated inhibition of Erk‐1/2 activation. In NIH‐3T3 fibroblasts, although glucocorticoids up‐regulate the MKP‐1 level, they do not attenuate the proteasomal degradation of this protein and consequently they are unable to inhibit Erk‐1/2 activity. These results identify MKP‐1 as essential for glucocorticoid‐mediated control of Erk‐1/2 activation and unravel a novel regulatory mechanism for this anti‐inflammatory drug.

Sequences located upstream of the transcription initiation site of the Xenopus vitellogenin A2 (vit A2) gene contain a hormone dependent enhancer that confers estrogen control to the heterologous thymidine kinase (tk) promoter. As a minimal functional estrogen responsive element (ERE), we have defined the 13 bp palindrome GGTCACAGTGACC. This ERE binds estrogen receptor preferentially in vitro. Although the ERE shares some structural features with the glucocorticoid responsive element (GRE) it is distinct from this element since it neither binds glucocorticoid receptor in vitro nor does it confer glucocorticoid inducibility to a fusion gene. Point mutations within the ERE decrease its affinity for the estrogen receptor and result in a complete loss of estrogen inducibility.

Activation of the mitogen-activated protein kinase (MAPK) cascade after Toll-like receptor stimulation enables innate immune cells to rapidly activate cytokine gene expression. A balanced response to signals of infectious danger requires that cellular activation is transient. Here, we identify the MAPK phosphatase dual specificity phosphatase 1 (DUSP1) as an essential endogenous regulator of the inflammatory response to lipopolysaccharide (LPS). DUSP1-deficient (DUSP1^−/−) bone marrow–derived macrophages showed selectively prolonged activation of p38 MAPK and increased cytokine production. Intraperitoneal challenge of DUSP1^−/− mice with LPS caused increased lethality and overshooting production of interleukin (IL)-6 and tumor necrosis factor α. Transcriptional profiling revealed that DUSP1 controls a significant fraction of LPS-induced genes, which includes IL-6 and IL-10 as well as the chemokines CCL3, CCL4, and CXCL2. In contrast, the expression of the important mediators of endotoxin lethality, interferon γ and IL-12, was not significantly altered by the absence of DUSP1. These data together demonstrate a specific regulatory role of DUSP1 in controlling a subset of LPS-induced genes that determines the outcome of endotoxin shock.