Abstract
Glucocorticoids (GCs) potently inhibit pro-inflammatory responses and are widely used for the treatment of inflammatory diseases, such as allergies, autoimmune disorders, and asthma. Dual-specificity phosphatase 1 (DUSP1), also known as mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1), exerts its effects by dephosphorylation of MAPKs, i.e., extracellular-signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK). Endogenous DUSP1 expression is tightly regulated at multiple levels, involving both transcriptional and post-transcriptional mechanisms. DUSP1 has emerged as a central mediator in the resolution of inflammation, and upregulation of DUSP1 by GCs has been suggested to be a key mechanism of GC actions. In this review, we discuss the impact of DUSP1 on the efficacy of GC-mediated suppression of inflammation and address the underlying mechanisms.
Highlights
Glucocorticoids (GCs) are steroid hormones with immunosuppressive activity that are used to treat a wide variety of inflammatory conditions, including rheumatoid arthritis, pulmonary diseases, and acute inflammation caused by microbial infection
The reduction of tumor necrosis factor (TNF)-α-induced mortality caused by pretreatment with dexamethasone was dependent on the presence of Dual-specificity phosphatase 1 (DUSP1): whereas wildtype mice were entirely protected by dexamethasone administration, Dusp1−/− animals did not benefit from the GC treatment [1]
DUSP1 was strongly downregulated in synovial biopsies from patients with rheumatoid arthritis and osteoarthritis (GEO datasets GDS5401 and GDS5403; Figure 2A), suggesting that DUSP1 deficiency may contribute to disease progression
Summary
Glucocorticoids (GCs) are steroid hormones with immunosuppressive activity that are used to treat a wide variety of inflammatory conditions, including rheumatoid arthritis, pulmonary diseases, and acute inflammation caused by microbial infection. MAPKs are a family of protein kinases that respond to a wide variety of extracellular stimuli They are activated by phosphorylation of tyrosine and threonine residues within their active domains and are inactivated by dephosphorylation of either residue [2,3,4]. TTP-mediated Dusp mRNA decay has been suggested to be a feedback mechanism in inflammatory responses by which TTP limits its own activity: reduced DUSP1 expression enhances p38 MAPK phosphorylation, thereby promoting TTP inactivation [26]. Oxidation of Cys258 within the active site inactivates DUSP1 and leads to its rapid degradation by the proteasome. In this manner, DUSP1 oxidation prolongs MAPK activation, resulting in enhanced inflammatory responses [32,33,34]. ROLE OF DUSP1 IN INFLAMMATORY DISEASES AND ITS INFLUENCE ON GC TREATMENT EFFICACY
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