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TPL-2-Mediated Activation of MAPK Downstream of TLR4 Signaling Is Coupled to Arginine Availability

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Date
2010-08-17
ICR Author
Procter, Julia
Author
Mieulet, V
Yan, L
Choisy, C
Sully, K
Procter, J
Kouroumalis, A
Krywawych, S
Pende, M
Ley, SC
Moinard, C
Lamb, RF
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Type
Journal Article
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Abstract
The innate immune response is influenced by the nutrient status of the host. Mitogen-activated protein kinases (MAPKs), such as extracellular signal-regulated kinase 1 (ERK1) and ERK2, are activated after the stimulation of macrophages with bacterial lipopolysaccharide (LPS) and are necessary for the optimal production of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha). We uncovered a role for the extracellular nutrient arginine in the activation of ERK1/2 in LPS-stimulated macrophages. Arginine facilitated the activation of MAPKs by preventing the dephosphorylation and inactivation of the MAPK kinase kinase tumor-promoting locus 2 (TPL-2). Starvation of mice decreased the concentration of arginine in the plasma and impaired the activation of ERK1/2 by LPS. Supplementation of starved mice with arginine promoted the subsequent activation of ERK1/2 and the production of TNF-alpha in response to LPS. Thus, arginine is critical for two aspects of the innate immune response in macrophages: It is the precursor used in the generation of the antimicrobial mediator nitric oxide, and it facilitates MAPK activation and consequently cytokine production.
URI
https://repository.icr.ac.uk/handle/internal/2365
DOI
https://doi.org/10.1126/scisignal.2000934
Collections
  • Breast Cancer Research
Research team
Target Validation and DNA Damage Response
Language
eng
License start date
2010-08-17
Citation
SCIENCE SIGNALING, 2010, 3
Publisher
AMER ASSOC ADVANCEMENT SCIENCE

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