PMID- 30710049
OWN - NLM
STAT- MEDLINE
DCOM- 20200110
LR  - 20200315
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 202
IP  - 6
DP  - 2019 Mar 15
TI  - MEK2 Negatively Regulates Lipopolysaccharide-Mediated IL-1beta Production through 
      HIF-1alpha Expression.
PG  - 1815-1825
LID - 10.4049/jimmunol.1801477 [doi]
AB  - LPS-activated macrophages require metabolic reprogramming and glucose uptake 
      mediated by hypoxia-inducible factor (HIF)-1 alpha and glucose transporter 1 (Glut1) 
      expression for proinflammatory cytokine production, especially IL-1beta. This 
      process is tightly regulated through activation of MAPK kinases, including the 
      MEK/ERK pathway as well as several transcription factors including HIF-1alpha. 
      Although MAPK kinase (MEK) 2 deficiency had no significant effect on NO, TNF-alpha, 
      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-1alpha 
      and Glut1 levels, and substantially increased IL-1beta as well as IL-6 production in 
      response to LPS stimulation. Knockdown of HIF-1alpha expression via short 
      interference RNA decreased the level of HIF-1alpha expression in MEK2-deficient BMDMs 
      and decreased IL-1beta 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-1beta production. Finally, we investigated the role of Mek1 and Mek2 
      double and triple mutation on ERK phosphorylation, HIF-1alpha expression, and IL-1beta 
      production. We found that MEK2 is the major kinase, which inversely 
      proportionally regulates HIF-1alpha and IL-1beta expression independent of ERK 
      activation. Our findings demonstrate a novel regulatory function for MEK2 in 
      response to TLR4 activation in IL-1beta production through modulating HIF-1alpha 
      expression.
CI  - Copyright (c) 2019 by The American Association of Immunologists, Inc.
FAU - Talwar, Harvinder
AU  - Talwar H
AD  - Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, 
      Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI 
      48201.
FAU - Bouhamdan, Mohamad
AU  - Bouhamdan M
AD  - Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, 
      Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI 
      48201.
FAU - Bauerfeld, Christian
AU  - Bauerfeld C
AD  - Division of Critical Care, Department of Pediatrics, Wayne State University 
      School of Medicine and Detroit Medical Center, Detroit, MI 48201.
FAU - Talreja, Jaya
AU  - Talreja J
AD  - Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, 
      Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI 
      48201.
FAU - Aoidi, Rifdat
AU  - Aoidi R
AD  - The Francis Crick Institute, London NW1 1AT, United Kingdom.
FAU - Houde, Nicolas
AU  - Houde N
AD  - Centre de Recherche sur le Cancer de l'Universite Laval, L'Hotel-Dieu de Quebec, 
      Quebec City, Quebec, Canada; and.
FAU - Charron, Jean
AU  - Charron J
AUID- ORCID: 0000-0002-5133-0056
AD  - Centre de Recherche sur le Cancer de l'Universite Laval, L'Hotel-Dieu de Quebec, 
      Quebec City, Quebec, Canada; and.
FAU - Samavati, Lobelia
AU  - Samavati L
AUID- ORCID: 0000-0002-3327-2585
AD  - Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, 
      Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI 
      48201; ay6003@wayne.edu.
AD  - Center for Molecular Medicine and Genetics, Wayne State University School of 
      Medicine, Detroit, MI 48201.
LA  - eng
GR  - R01 HL113508/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190201
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Hif1a protein, mouse)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Lipopolysaccharides)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 2)
RN  - EC 2.7.12.2 (Map2k2 protein, mouse)
SB  - IM
MH  - Animals
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/immunology/*metabolism
MH  - Inflammation/chemically induced/immunology/*metabolism
MH  - Interleukin-1beta/immunology/*metabolism
MH  - Lipopolysaccharides/toxicity
MH  - MAP Kinase Kinase 2/immunology/*metabolism
MH  - Macrophages/immunology/*metabolism
MH  - Mice
MH  - Mice, Mutant Strains
MH  - RAW 264.7 Cells
PMC - PMC6401293
MID - NIHMS1519161
EDAT- 2019/02/03 06:00
MHDA- 2020/01/11 06:00
PMCR- 2020/03/15
CRDT- 2019/02/03 06:00
PHST- 2018/11/09 00:00 [received]
PHST- 2019/01/15 00:00 [accepted]
PHST- 2019/02/03 06:00 [pubmed]
PHST- 2020/01/11 06:00 [medline]
PHST- 2019/02/03 06:00 [entrez]
PHST- 2020/03/15 00:00 [pmc-release]
AID - jimmunol.1801477 [pii]
AID - 10.4049/jimmunol.1801477 [doi]
PST - ppublish
SO  - J Immunol. 2019 Mar 15;202(6):1815-1825. doi: 10.4049/jimmunol.1801477. Epub 2019 
      Feb 1.