TRAF6 is a critical signal transducer in IL-33 signaling pathway

Megumi Funakoshi-Tago, Kenji Tago, Morisada Hayakawa, Shin ichi Tominaga, Tomoyuki Ohshio, Yoshiko Sonoda, Tadashi Kasahara

Research output: Contribution to journalArticlepeer-review

115 Citations (Scopus)


IL-33 has been shown to induce Th2 responses by signaling through the IL-1 receptor-related protein, ST2L. However, the signal transduction pathways activated by the ST2L have not been characterized. Here, we found that IL-33-induced monocyte chemoattractant protein (MCP)-1, MCP-3 and IL-6 expression was significantly inhibited in TNF receptor-associated Factor 6 (TRAF6)-deficient MEFs. IL-33 rapidly induced the formation of ST2L complex containing IL-1 receptor-associated kinase (IRAK), however, lack of TRAF6 abolished the recruitment of IRAK to ST2L. Consequently, p38, JNK and Nuclear factor-κB (NF-κB) activation induced by IL-33 was completely inhibited in TRAF6-deficient MEFs. On the other hand, IL-33-induced ERK activation was observed regardless of the presence of TRAF6. The introduction of TRAF6 restored the efficient activation of p38, JNK and NF-κB in TRAF6 deficient MEFs, resulting in the induction of MCP-1, MCP-3 and IL-6 expression. Moreover, IL-33 augmented autoubiquitination of TRAF6 and the reconstitution of TRAF6 mutant (C70A) that is defective in its ubiquitin ligase activity failed to restore IL-33-induced p38, JNK and NF-κB activation. Thus, these data demonstrate that TRAF6 plays a pivotal role in IL-33 signaling pathway through its ubiquitin ligase activity.

Original languageEnglish
Pages (from-to)1679-1686
Number of pages8
JournalCellular Signalling
Issue number9
Publication statusPublished - 2008 Sept 1


  • IL-33
  • JNK
  • NF-κB
  • ST2L
  • TRAF6
  • p38

ASJC Scopus subject areas

  • Cell Biology


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