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TPL-2-mediated activation of MAPK downstream of TLR4 signaling is coupled to arginine availability.

Authors
  • Mieulet, Virginie
  • Yan, Lijun
  • Choisy, Caroline
  • Sully, Katherine
  • Procter, Julia
  • Kouroumalis, Andreas
  • Krywawych, Steve
  • Mario Pende
  • Ley, Steven C
  • Moinard, Christophe
  • Lamb, Richard F
Type
Published Article
Journal
Science Signaling
Publisher
American Association for the Advancement of Science (AAAS)
Publication Date
Jun 04, 2010
Volume
3
Issue
135
Identifiers
DOI: 10.1126/scisignal.2000934
PMID: 20716763
Source
USPC - SET - SVS
License
White

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.

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