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Cited by 430Protein Tyrosine PhosphatasesCytokine Signaling Pathways and InteractionsProtein Kinase Regulation and GTPase Signaling

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Antiinflammatory effects of dexamethasone are partly dependent on induction of dual specificity phosphatase 1

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Abraham, Sonya M., Lawrence, Toby, Kleiman, Anna, Warden, Paul, Medghalchi, Mino, Tuckermann, Jan, Saklatvala, Jeremy, Clark, Andrew R.·2006·The Journal of Experimental Medicine
DOI 10.1084/jem.20060336PMC PMC2118371
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Abstract

Glucocorticoids (GCs), which are used in the treatment of immune-mediated inflammatory diseases, inhibit the expression of many inflammatory mediators. They can also induce the expression of dual specificity phosphatase 1 (DUSP1; otherwise known as mitogen-activated protein kinase [MAPK] phosphatase 1), which dephosphorylates and inactivates MAPKs. We investigated the role of DUSP1 in the antiinflammatory action of the GC dexamethasone (Dex). Dex-mediated inhibition of c-Jun N-terminal kinase and p38 MAPK was abrogated in DUSP1-/- mouse macrophages. Dex-mediated suppression of several proinflammatory genes (including tumor necrosis factor, cyclooxygenase 2, and interleukin 1alpha and 1beta) was impaired in DUSP1-/- mouse macrophages, whereas other proinflammatory genes were inhibited by Dex in a DUSP1-independent manner. In vivo antiinflammatory effects of Dex on zymosan-induced inflammation were impaired in DUSP1-/- mice. Therefore, the expression of DUSP1 is required for the inhibition of proinflammatory signaling pathways by Dex in mouse macrophages. Furthermore, DUSP1 contributes to the antiinflammatory effects of Dex in vitro and in vivo.

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Figure 1. Altered JNK and p38 MAPK signaling in DUSP1−/− BMMs. (A) 106 DUSP1+/+ or DUSP1−/− BMMs were pretreated with vehicle or 100 nM Dex for 4 h and stimulated with LPS for the indicated times. Lysates were blotted for DUSP1 or tubulin-α (top) and total or phosphorylated MAPKs (bottom). Two exposures of the same DUSP1 Western blot are shown to illustrate differences in basal and LPS-induced DUSP1 protein expression. (B) DUSP1+/+ or DUSP1−/− BMMs were pretreated with 1 nM to 1 μM Dex for 4 h and stimulated with LPS for 4 h. In two separate representative experiments, lysates were sequentially blotted for DUSP1 and tubulin-α (top) or for phosphorylated and total MAPKs (bottom). (C) Wild-type and GRdim BMMs were pretreated with 1 nM to 1 μM Dex for 4 h and stimulated with LPS for 4 h. Lysates were blotted for DUSP1 or actin.
Figure 1. Altered JNK and p38 MAPK signaling in DUSP1−/− BMMs. (A) 106 DUSP1+/+ or DUSP1−/− BMMs were pretreated with vehicle or 100 nM Dex for 4 h and stimulated with LPS for the indicated times. Lysates were blotted for DUSP1 or tubulin-α (top) and total or phosphorylated MAPKs (bottom). Two exposures of the same DUSP1 Western blot are shown to illustrate differences in basal and LPS-induced DUSP1 protein expression. (B) DUSP1+/+ or DUSP1−/− BMMs were pretreated with 1 nM to 1 μM Dex for 4 h and stimulated with LPS for 4 h. In two separate representative experiments, lysates were sequentially blotted for DUSP1 and tubulin-α (top) or for phosphorylated and total MAPKs (bottom). (C) Wild-type and GRdim BMMs were pretreated with 1 nM to 1 μM Dex for 4 h and stimulated with LPS for 4 h. Lysates were blotted for DUSP1 or actin.CC BY-NC-SA · PubMed Central
Figure 2. Antiinflammatory actions of Dex are impaired in DUSP1−/− BMMs. (A) 106 DUSP1+/+ or DUSP1−/− BMMs were pretreated with 1 nM to 1 μM Dex for 4 h and stimulated with LPS for 4 h. Cytokines in supernatants were quantified by ELISA. Graphs indicate means ± SEM (error bars) from at least three independent experiments. Cell lysates were blotted for COX-2, IL-1β, iNOS, and ERK proteins. (B) Cells were treated as in A, and the expression of various mRNAs was examined by RPA. P, undigested probe (10% of input). (C) 106 DUSP1+/+ or DUSP1−/− BMMs were pretreated with 100 nM Dex and/or 10 μM SB202190 and stimulated with LPS for 4 h. Lysates were blotted for Cox-2, IL-1β, or ERK proteins (top), or the expression of various mRNAs was examined by RPA (bottom).
Figure 2. Antiinflammatory actions of Dex are impaired in DUSP1−/− BMMs. (A) 106 DUSP1+/+ or DUSP1−/− BMMs were pretreated with 1 nM to 1 μM Dex for 4 h and stimulated with LPS for 4 h. Cytokines in supernatants were quantified by ELISA. Graphs indicate means ± SEM (error bars) from at least three independent experiments. Cell lysates were blotted for COX-2, IL-1β, iNOS, and ERK proteins. (B) Cells were treated as in A, and the expression of various mRNAs was examined by RPA. P, undigested probe (10% of input). (C) 106 DUSP1+/+ or DUSP1−/− BMMs were pretreated with 100 nM Dex and/or 10 μM SB202190 and stimulated with LPS for 4 h. Lysates were blotted for Cox-2, IL-1β, or ERK proteins (top), or the expression of various mRNAs was examined by RPA (bottom).CC BY-NC-SA · PubMed Central
Figure 3. Dose-dependent suppression of various inflammatory mediator mRNAs by Dex in DUSP1+/+ and DUSP1−/− BMMs. BMMs were treated as in Fig. 2 B. mRNAs were quantified using qPCR (CSF2, TNF, CXCL1, and COX-2) or RPA. mRNA levels were normalized against GAPDH and expressed as percentages of the level in cells treated with LPS alone. Graphs show mean values ± SEM (error bars) from three to six independent experiments. 100% values are identified by heavy tick marks on the y axes.
Figure 3. Dose-dependent suppression of various inflammatory mediator mRNAs by Dex in DUSP1+/+ and DUSP1−/− BMMs. BMMs were treated as in Fig. 2 B. mRNAs were quantified using qPCR (CSF2, TNF, CXCL1, and COX-2) or RPA. mRNA levels were normalized against GAPDH and expressed as percentages of the level in cells treated with LPS alone. Graphs show mean values ± SEM (error bars) from three to six independent experiments. 100% values are identified by heavy tick marks on the y axes.CC BY-NC-SA · PubMed Central
Figure 4. Impaired antiinflammatory action of Dex in DUSP1−/− mice. Dorsal air pouches were created in DUSP1+/+ and DUSP1−/− mice. Mice were orally dosed with 1 mg/kg Dex or vehicle. After 1 h, zymosan was injected into the air pouches. After a further 4 h, mice were killed, and leukocyte numbers and cytokine concentrations in exudates were quantified. Horizontal bars above graphs represent statistical analysis of differences between control and Dex-treated animals (Student's t test).
Figure 4. Impaired antiinflammatory action of Dex in DUSP1−/− mice. Dorsal air pouches were created in DUSP1+/+ and DUSP1−/− mice. Mice were orally dosed with 1 mg/kg Dex or vehicle. After 1 h, zymosan was injected into the air pouches. After a further 4 h, mice were killed, and leukocyte numbers and cytokine concentrations in exudates were quantified. Horizontal bars above graphs represent statistical analysis of differences between control and Dex-treated animals (Student's t test).CC BY-NC-SA · PubMed Central

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Research works printed but not linked: 3

  1. 2005, Curr. Opin. Investig. Drugs., 6, 503
  2. 1996, Oncogene., 13, 925
  3. 2002, FASEB J., 16, 1832

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Metadata

Authors
Abraham, S. M., Lawrence, T., Kleiman, A., Warden, P., Medghalchi, M., Tuckermann, J., Saklatvala, J., & Clark, A. R.
Affiliations
  • Imperial College London (GB)
  • Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE)
ORCID
Venue
The Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2006-07-31
Volume
203
Issue
8
Pages
1883-1889
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.20060336
PMC
PMC2118371
OpenAlex
W2159379486
Cited by
430
References
29
Citations by year
2026: 9 · 2025: 16 · 2024: 12 · 2023: 22 · 2022: 12 · 2021: 19 · 2020: 12 · 2019: 17 · 2018: 13 · 2017: 21 · 2016: 23 · 2015: 24 · 2014: 33 · 2013: 27 · 2012: 28
FWCI
11.27
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
Funders
Wellcome Trust
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
  • Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
dexamethasone, glucocorticoids, MKP-1, MAPK phosphatase, macrophages, c-Jun N-terminal kinase, p38 MAPK, pro-inflammatory gene expression, TNF-α, cyclooxygenase-2, interleukin-1, zymosan-induced inflammation, MAPK dephosphorylation
MeSH terms
Animals, Anti-Inflammatory Agents, Bone Marrow, Dexamethasone, Dose-Response Relationship, Drug, Enzyme Induction, Gene Expression Regulation, Glucocorticoids, Inflammation, Macrophages, Phosphoprotein Phosphatases, RNA, Messenger, Signal Transduction, Protein Tyrosine Phosphatases, Immediate-Early Proteins, Cell Cycle Proteins, JNK Mitogen-Activated Protein Kinases, p38 Mitogen-Activated Protein Kinases, Mice, Dual Specificity Phosphatase 1, Protein Phosphatase 1

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