MEK2 Negatively Regulates Lipopolysaccharide-Mediated IL-1β Production through HIF-1α Expression.
Journal
Journal of immunology (Baltimore, Md. : 1950)
ISSN: 1550-6606
Titre abrégé: J Immunol
Pays: United States
ID NLM: 2985117R
Informations de publication
Date de publication:
15 03 2019
15 03 2019
Historique:
received:
09
11
2018
accepted:
15
01
2019
pubmed:
3
2
2019
medline:
11
1
2020
entrez:
3
2
2019
Statut:
ppublish
Résumé
LPS-activated macrophages require metabolic reprogramming and glucose uptake mediated by hypoxia-inducible factor (HIF)-1 α and glucose transporter 1 (Glut1) expression for proinflammatory cytokine production, especially IL-1β. This process is tightly regulated through activation of MAPK kinases, including the MEK/ERK pathway as well as several transcription factors including HIF-1α. Although MAPK kinase (MEK) 2 deficiency had no significant effect on NO, TNF-α, or IL-12 production in response to LPS challenge, MEK2-deficient murine bone marrow-derived macrophages (BMDMs) exhibited lower IL-10 production. Importantly, MEK2-deficient BMDMs exhibited a preserved ERK1/2 phosphorylation, higher HIF-1α and Glut1 levels, and substantially increased IL-1β as well as IL-6 production in response to LPS stimulation. Knockdown of HIF-1α expression via short interference RNA decreased the level of HIF-1α expression in MEK2-deficient BMDMs and decreased IL-1β production in response to LPS treatment. Furthermore, we performed gain of function experiments by overexpressing MEK2 protein in RAW264.7 cells. LPS stimulation of MEK2 overexpressed in RAW264.7 cells led to a marked decreased IL-1β production. Finally, we investigated the role of
Identifiants
pubmed: 30710049
pii: jimmunol.1801477
doi: 10.4049/jimmunol.1801477
pmc: PMC6401293
mid: NIHMS1519161
doi:
Substances chimiques
Hif1a protein, mouse
0
Hypoxia-Inducible Factor 1, alpha Subunit
0
Interleukin-1beta
0
Lipopolysaccharides
0
MAP Kinase Kinase 2
EC 2.7.12.2
Map2k2 protein, mouse
EC 2.7.12.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1815-1825Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL113508
Pays : United States
Informations de copyright
Copyright © 2019 by The American Association of Immunologists, Inc.
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