Involvement of TNF Receptor-Associated Factor 6 in IL-25 Receptor Signaling

J Immunol. 2006 Jan 15;176(2):1013-8. doi: 10.4049/jimmunol.176.2.1013.


IL-25 (IL-17E) induces IL-4, IL-5, and IL-13 production from an unidentified non-T/non-B cell population and subsequently induces Th2-type immune responses such as IgE production and eosinophilic airway inflammation. IL-25R is a single transmembrane protein with homology to IL-17R, but the IL-25R signaling pathways have not been fully understood. In this study, we investigated the signaling pathway under IL-25R, especially the possible involvement of TNFR-associated factor (TRAF)6 in this pathway. We found that IL-25R cross-linking induced NF-kappaB activation as well as ERK, JNK, and p38 activation. We also found that IL-25R-mediated NF-kappaB activation was inhibited by the expression of dominant negative TRAF6 but not of dominant negative TRAF2. Furthermore, IL-25R-mediated NF-kappaB activation, but not MAPK activation, was diminished in TRAF6-deficient murine embryonic fibroblast. In addition, coimmunoprecipitation assay revealed that TRAF6, but not TRAF2, associated with IL-25R even in the absence of ligand binding. Finally, we found that IL-25R-mediated gene expression of IL-6, TGF-beta, G-CSF, and thymus and activation-regulated chemokine was diminished in TRAF6-deficient murine embryonic fibroblast. Taken together, these results indicate that TRAF6 plays a critical role in IL-25R-mediated NF-kappaB activation and gene expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Biological Assay
  • Cell Line
  • Chemokines / genetics
  • Cross-Linking Reagents
  • Cytokines / genetics
  • Gene Expression
  • Interleukins / analysis
  • Interleukins / metabolism*
  • MAP Kinase Signaling System
  • Mice
  • NF-kappa B / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Interleukin / metabolism*
  • Receptors, Interleukin-17
  • Signal Transduction
  • TNF Receptor-Associated Factor 2 / deficiency
  • TNF Receptor-Associated Factor 2 / genetics
  • TNF Receptor-Associated Factor 2 / metabolism
  • TNF Receptor-Associated Factor 6 / deficiency
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / metabolism*


  • Chemokines
  • Cross-Linking Reagents
  • Cytokines
  • Il17rb protein, mouse
  • Interleukins
  • Mydgf protein, mouse
  • NF-kappa B
  • RNA, Messenger
  • Receptors, Interleukin
  • Receptors, Interleukin-17
  • TNF Receptor-Associated Factor 2
  • TNF Receptor-Associated Factor 6