TRAF6 is a critical signal transducer in IL-33 signaling pathway.
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-kappaB (NF-kappaB) 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-kappaB 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-kappaB activation. Thus, these data demonstrate that TRAF6 plays a pivotal role in IL-33 signaling pathway through its ubiquitin ligase activity.
Funakoshi-Tago
Megumi
M
Department of Biochemistry, Kyoritsu University of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
Tago
Kenji
K
Hayakawa
Morisada
M
Tominaga
Shin-Ichi
S
Ohshio
Tomoyuki
T
Sonoda
Yoshiko
Y
Kasahara
Tadashi
T
D000818:Animals; D043422:Carboxypeptidases A / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D000067596:Interleukin-33; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D048029:TNF Receptor-Associated Factor 6 / Q000172:deficiency / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C506535:Il33 protein, mouse; D000067596:Interleukin-33; D015850:Interleukin-6; D007378:Interleukins; D050505:Mutant Proteins; D048029:TNF Receptor-Associated Factor 6; D044767:Ubiquitin-Protein Ligases; D043422:Carboxypeptidases A; C503326:Cpa3 protein, mouse