TY - JOUR
T1 - MEK2 negatively regulates lipopolysaccharide-mediated IL-1β production through HIF-1α expression
AU - Talwar, Harvinder
AU - Bouhamdan, Mohamad
AU - Bauerfeld, Christian
AU - Talreja, Jaya
AU - Aoidi, Rifdat
AU - Houde, Nicolas
AU - Charron, Jean
AU - Samavati, Lobelia
N1 - Funding Information:
This work was supported by National Heart, Lung, and Blood Institute Grant R01HL113508 (to L.S.) as well as the Department of Medicine and the Center for Molecular Medicine and Genetics of Wayne State University School of Medicine (to L.S.).
Publisher Copyright:
© 2019 by The American Association of Immunologists, Inc.
PY - 2019
Y1 - 2019
N2 - LPS-activated macrophages require metabolic reprogramming and glucose uptake mediated by hypoxia-inducible factor (HIF)-1 a 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-a, 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 Mek1 and Mek2 double and triple mutation on ERK phosphorylation, HIF-1α expression, and IL-1β production. We found that MEK2 is the major kinase, which inversely proportionally regulates HIF-1α and IL-1β expression independent of ERK activation. Our findings demonstrate a novel regulatory function forMEK2 in response to TLR4 activation in IL-1β production through modulating HIF-1α expression.
AB - LPS-activated macrophages require metabolic reprogramming and glucose uptake mediated by hypoxia-inducible factor (HIF)-1 a 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-a, 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 Mek1 and Mek2 double and triple mutation on ERK phosphorylation, HIF-1α expression, and IL-1β production. We found that MEK2 is the major kinase, which inversely proportionally regulates HIF-1α and IL-1β expression independent of ERK activation. Our findings demonstrate a novel regulatory function forMEK2 in response to TLR4 activation in IL-1β production through modulating HIF-1α expression.
UR - http://www.scopus.com/inward/record.url?scp=85062397734&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1801477
DO - 10.4049/jimmunol.1801477
M3 - Article
C2 - 30710049
AN - SCOPUS:85062397734
VL - 202
SP - 1815
EP - 1825
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 6
ER -