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Sci. Signal., 17 August 2010
Vol. 3, Issue 135, p. ra61
[DOI: 10.1126/scisignal.2000934]


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

Virginie Mieulet1,2, Lijun Yan1*, Caroline Choisy3, Katherine Sully1, Julia Procter2, Andreas Kouroumalis4, Steve Krywawych5, Mario Pende6, Steven C. Ley4, Christophe Moinard3, and Richard F. Lamb1{dagger}

1 Department of Oncology, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta, Canada T6G 1Z2.
2 Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
3 Laboratoire de Biologie de la Nutrition, EA 2498, Université Paris Descartes, Faculté de Pharmacie, Avenue de l’Observatoire 75270, Paris Cedex 06, France.
4 Division of Immune Cell Biology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
5 Department of Chemical Pathology, Great Ormond Street Hospital for Sick Children, London WC1N 3JH, UK.
6 INSERM U845, Medical School, Paris Descartes University, 156 Rue de Vaugirard, 75015 Paris, France.

* Present address: Center for Life Sciences and Environmental Sciences, Harbin University of Commerce, 1 Xue-Hai Street, Songbei District, Harbin 150028, China.

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.

{dagger} To whom correspondence should be addressed. E-mail: rflamb{at}

Citation: V. Mieulet, L. Yan, C. Choisy, K. Sully, J. Procter, A. Kouroumalis, S. Krywawych, M. Pende, S. C. Ley, C. Moinard, R. F. Lamb, TPL-2–Mediated Activation of MAPK Downstream of TLR4 Signaling Is Coupled to Arginine Availability. Sci. Signal. 3, ra61 (2010).

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