Involvement of NF-kappaB in TGF-beta-mediated suppression of IL-4 signaling.
Control of immune response requires the coordinated integration of both stimulatory and inhibitory factors. Therefore, the cross-talk of different signaling pathways is critical in providing an integrated cellular response to multiple external signals. Both interleukin-4 (IL-4) and transforming growth factor (TGF-beta) are pleiotropic cytokines and play critical roles in controlling immune responses. For example, IL-4 mediates important pro-inflammatory functions in asthma including induction of the IgE isotype switch and expression of vascular cell adhesion molecules. Whereas, TGF-beta is secreted from B, T, and dendritic cells as well as macrophages, and negatively regulates their proliferation, differentiation, and activation by other cytokines. In this study, we examined the effect of TGF-beta on IL-4 signaling using B cells as well as embryonic kidney cells. TGF-beta inhibited IL-4-induced IgG1 production and gene expression of germline epsilon transcripts in B cells. In embryonic kidney cells, TGF-beta signals suppressed IL-4-induced transcription, when we monitored using germline epsilon promoter DNA. Furthermore, activation of NF-kappaB resulted in a resistance to TGF-beta-mediated suppression of IL-4 signaling. These results indicate that TGF-beta-mediated regulation of IL-4 signaling may act by targeting NF-kappaB signaling.
Yamamoto
Tetsuya
T
Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-Ku Kita 12 Nishi 6, Sapporo 060-0812, Japan.
Imoto
Seiyu
S
Sekine
Yuichi
Y
Sugiyama
Kenji
K
Akimoto
Toshihiko
T
Muraguchi
Atsushi
A
Matsuda
Tadashi
T
D000818:Animals; D015152:Blotting, Northern; D002448:Cell Adhesion; D002460:Cell Line; D003713:Dendritic Cells; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015151:Immunoblotting; D007249:Inflammation; D015847:Interleukin-4 / Q000378:metabolism*; D007668:Kidney / Q000196:embryology; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D050800:STAT6 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D016328:NF-kappa B; D012333:RNA, Messenger; D011994:Recombinant Proteins; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D015847:Interleukin-4; D008156:Luciferases