Involvement of TNF receptor-associated factor 6 in IL-25 receptor signaling.
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.
Maezawa
Yuko
Y
Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Nakajima
Hiroshi
H
Suzuki
Kotaro
K
Tamachi
Tomohiro
T
Ikeda
Kei
K
Inoue
Jun-ichiro
J
Saito
Yasushi
Y
Iwamoto
Itsuo
I
D000818:Animals; D001483:Base Sequence; D001681:Biological Assay; D002460:Cell Line; D018925:Chemokines / Q000235:genetics; D003432:Cross-Linking Reagents; D016207:Cytokines / Q000235:genetics; D015870:Gene Expression; D007378:Interleukins / Q000032:analysis / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism*; D053722:Receptors, Interleukin-17; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D018925:Chemokines; D003432:Cross-Linking Reagents; D016207:Cytokines; C485810:Il17rb protein, mouse; D007378:Interleukins; C442281:Mydgf protein, mouse; D016328:NF-kappa B; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6