The TNF family member 4-1BBL sustains inflammation by interacting with TLR signaling components during late-phase activation

Sci Signal. 2013 Oct 1;6(295):ra87. doi: 10.1126/scisignal.2004431.


Activation of Toll-like receptor (TLR)-dependent signaling leads to the expression of genes encoding proinflammatory factors, such as tumor necrosis factor-α (TNF-α), and this proinflammatory gene expression is sustained for the duration of the inflammatory response. TLR4-mediated inflammation, which occurs in two phases, depends on the TNF family member 4-1BB ligand (4-1BBL) to sustain TNF-α production during late-phase signaling. We showed that Toll-interleukin-1 receptor (TIR) domain-containing adaptor protein (TIRAP) and the kinase IRAK2 interacted with 4-1BBL to mediate late-phase TLR4 signaling. Expression of 4-1bbl depended on early TLR4 signaling that also induced Tnf expression, and 4-1BBL translocated to the plasma membrane, where it interacted with TLR4 to mediate late-phase signaling. TLR4-4-1BBL-mediated signaling depended on TIRAP and IRAK2, as well as a complex consisting of the E3 ubiquitin ligase TRAF6 (TNF receptor-associated factor 6), the kinase TAK1 (transforming growth factor-β-activated kinase 1), and the adaptor protein TAB1 (TAK-binding protein 1). Inhibition of this late-phase pathway reduced the extent of TNF-α production by mouse macrophages exposed to the TLR4 ligand lipopolysaccharide (LPS) and ameliorated LPS-induced sepsis in mice. Together, these data suggest that TIRAP and IRAK2 are critical for the sustained inflammatory response that is mediated by late-phase signaling by the TLR-4-1BBL complex.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-1BB Ligand / genetics
  • 4-1BB Ligand / immunology*
  • Animals
  • HEK293 Cells
  • Humans
  • Inflammation / chemically induced
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / pathology
  • Interleukin-1 Receptor-Associated Kinases / genetics
  • Interleukin-1 Receptor-Associated Kinases / immunology
  • Lipopolysaccharides / toxicity
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / immunology
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / immunology
  • Mice
  • Protein Transport / genetics
  • Protein Transport / immunology
  • Receptors, Interleukin-1 / genetics
  • Receptors, Interleukin-1 / immunology
  • Sepsis / chemically induced
  • Sepsis / genetics
  • Sepsis / immunology
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / immunology
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / immunology*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology


  • 4-1BB Ligand
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Receptors, Interleukin-1
  • TIRAP protein, human
  • TIRAP protein, mouse
  • TLR4 protein, human
  • TNF Receptor-Associated Factor 6
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Interleukin-1 Receptor-Associated Kinases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7