Cited by 249Immune Response and InflammationEstrogen and related hormone effectsNF-κB Signaling Pathways

Macrophage glucocorticoid receptors regulate Toll-like receptor 4-mediated inflammatory responses by selective inhibition of p38 MAP kinase

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Bhattacharyya, Sandip, Brown, Diane E., Brewer, Judson A., Vogt, Sherri K., Muglia, Louis J.·2007·Blood

Abstract

To explore the role of glucocorticoids in regulation of kinase pathways during innate immune responses, we generated mice with conditional deletion of glucocorticoid receptor (GR) in macrophages (MGRKO). Activation of toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS) caused greater mortality and cytokine production in MGRKO mice than in controls. Ex vivo, treatment with dexamethasone (Dex) markedly inhibited LPS-mediated induction of inflammatory genes in control but not GR-deficient macrophages. We show that Dex inhibits p38 MAPK, but not PI3K/Akt, ERK, or JNK, in control macrophages. Associated with p38 inhibition, Dex induced MAP kinase phosphatase-1 (MKP-1) in control, but not MGRKO, macrophages. Consistent with the ex vivo studies, treatment with a p38 MAPK-specific inhibitor resulted in rescue of MGRKO mice from LPS-induced lethality. Taken together, we identify p38 MAPK and its downstream targets as essential for GR-mediated immunosuppression in macrophages.

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Crossref · 10.1182/blood-2006-10-048215

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Authors
Bhattacharyya, S., Brown, D. E., Brewer, J. A., Vogt, S. K., & Muglia, L. J.
Affiliations
  • Departments of Pediatrics
  • Washington University in St. Louis (US)
Venue
Blood
Published
2007-01-25
Volume
109
Issue
10
Pages
4313-4319
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
OpenAlex
W2104547539
Cited by
249
References
58
Citations by year
2026: 7 · 2025: 11 · 2024: 9 · 2023: 15 · 2022: 13 · 2021: 11 · 2020: 20 · 2019: 15 · 2018: 10 · 2017: 23 · 2016: 6 · 2015: 15 · 2014: 12 · 2013: 12 · 2012: 11
FWCI
5.70
Type
journal article
Language
en
Open access
Locations
  • Blood (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Allergy and Infectious Diseases (AI50655, R01AI050655, R21AI050655)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
Keywords
glucocorticoid receptor, macrophages, TLR4, p38 MAPK, dexamethasone, lipopolysaccharide, MKP-1, immunosuppression, innate immunity, inflammatory cytokines, conditional knockout mice, PI3K/Akt, ERK, JNK
MeSH terms
Animals, Dexamethasone, Enzyme Inhibitors, Inflammation, Lipopolysaccharides, Macrophages, Mice, Inbred C57BL, Models, Biological, Phosphoprotein Phosphatases, Receptors, Glucocorticoid, Cytokines, Protein Tyrosine Phosphatases, Immediate-Early Proteins, Mice, Knockout, Cell Cycle Proteins, Inflammation Mediators, p38 Mitogen-Activated Protein Kinases, Toll-Like Receptor 4, Mice, Dual Specificity Phosphatase 1, Protein Phosphatase 1

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