Research ArticleImmunology

Switching of the Relative Dominance Between Feedback Mechanisms in Lipopolysaccharide-Induced NF-κB Signaling

Science Signaling  14 Jan 2014:
Vol. 7, Issue 308, pp. ra6
DOI: 10.1126/scisignal.2004764

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Rewiring NF-κB Signaling

The bacterial product lipopolysaccharide (LPS) stimulates nuclear factor κB (NF-κB) signaling, which results in the production of proinflammatory cytokines, such as tumor necrosis factor–α (TNF-α), as part of the immune response. NF-κB target genes also include those encoding proteins that inhibit NF-κB signaling through negative feedback loops. By simultaneously studying the dynamics of the nuclear translocation of the NF-κB subunit RelA and the activity of a Tnf-driven reporter in a mouse macrophage cell line, Sung et al. found that the gene encoding RelA was also a target of NF-κB. Synthesis of RelA occurred only at higher concentrations of LPS and constituted a positive feedback loop that dominated over existing negative feedback mechanisms. Genes expressed in response to a high concentration of LPS were enriched for those involved in innate immune responses. Together, these data suggest that the RelA-mediated positive feedback loop enables macrophages to mount an effective immune response only above a critical concentration of LPS.