Research ArticleImmunology

The TNF Family Member 4-1BBL Sustains Inflammation by Interacting with TLR Signaling Components During Late-Phase Activation

Science Signaling  01 Oct 2013:
Vol. 6, Issue 295, pp. ra87
DOI: 10.1126/scisignal.2004431

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Targeting the Late Phase

The microbial product lipopolysaccharide (LPS) stimulates Toll-like receptor 4 (TLR4) on the surface of macrophages, which results in the production of proinflammatory cytokines, including tumor necrosis factor–α (TNF-α). Activation of macrophages by LPS occurs in two phases, early and late, and the late phase is responsible for sustained TNF-α production, which can be detrimental. Noting that the TNF superfamily member 4-1BB ligand (4-1BBL) is present on the cell surface, where its interaction with TLR4 is required to mediate the late-phase response, Ma et al. found that the 4-1BBL cytoplasmic and transmembrane domains interacted with TLR4 and participated in the formation of a receptor signaling complex containing the adaptor protein TIRAP that was required for sustained TNF-α production. Treatment of mice with a TIRAP inhibitor peptide reduced TNF-α production and protected the mice from LPS-induced sepsis. Together, these findings suggest that targeting the TIRAP–4-1BBL interaction may provide an anti-inflammatory therapy by preventing the sustained production of TNF-α.