Research ArticleImmunology

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

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Science Signaling  17 Aug 2010:
Vol. 3, Issue 135, pp. ra61
DOI: 10.1126/scisignal.2000934

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Feeding a Response

Decreased immune response under conditions of poor nutrient status is of clinical importance. Arginine is an amino acid that serves as the substrate for the production of the antimicrobial compound nitric oxide (NO) in activated macrophages. NO production is an important part of the innate immune response; thus, the availability of arginine is critical for host resistance to infection (see the Perspective by Morris). Mieulet et al. investigated the relationship between nutrient status and immune response in mice and found that starved mice produced less tumor necrosis factor–α (TNF-α) than did their fed counterparts in response to bacterial lipopolysaccharide (LPS). Experiments with starved macrophages in culture showed that decreased TNF-α production resulted from defective activation of the kinases extracellular signal–regulated kinase 1 (ERK1) and ERK2, and the TNF-α response was rescued by supplementation of culture medium with arginine. Decreased arginine concentrations triggered the dephosphorylation and inactivation of the kinase TPL-2, which is required for ERK activation. Finally, administration of arginine to starved mice rescued their defective response to LPS. Together, these data suggest that arginine can function as a regulatory molecule, as well as a substrate, in the innate immune response and should stimulate interest in the effects of arginine and other nutrients on immune responses in humans.