TPL-2-mediated activation of MAPK downstream of TLR4 signaling is coupled to arginine availability.
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.
Mieulet
Virginie
V
Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada.
Yan
Lijun
L
Choisy
Caroline
C
Sully
Katherine
K
Procter
Julia
J
Kouroumalis
Andreas
A
Krywawych
Steve
S
Pende
Mario
M
Ley
Steven C
SC
Moinard
Christophe
C
Lamb
Richard F
RF
D000596:Amino Acids / Q000097:blood; D000818:Animals; D001120:Arginine / Q000378:metabolism* / Q000494:pharmacology; D015153:Blotting, Western; D002852:Chromatography, Ion Exchange; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology*; D007113:Immunity, Innate / Q000502:physiology*; D007150:Immunohistochemistry; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000596:Amino Acids; D008070:Lipopolysaccharides; D011518:Proto-Oncogene Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D001120:Arginine; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse