Yamamoto Tetsuya, Imoto Seiyu, Sekine Yuichi, Sugiyama Kenji, Akimoto Toshihiko, Muraguchi Atsushi, Matsuda Tadashi
Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-Ku Kita 12 Nishi 6, Sapporo 060-0812, Japan.
Biochem Biophys Res Commun. 2004 Jan 16;313(3):627-34. doi: 10.1016/j.bbrc.2003.11.163.
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.
免疫反应的调控需要刺激因子和抑制因子的协同整合。因此，不同信号通路之间的相互作用对于细胞对多种外部信号产生整合反应至关重要。白细胞介素-4（IL-4）和转化生长因子（TGF-β）都是多效性细胞因子，在免疫反应调控中发挥关键作用。例如，IL-4在哮喘中介导重要的促炎功能，包括诱导IgE同种型转换和血管细胞黏附分子的表达。而TGF-β由B细胞、T细胞、树突状细胞以及巨噬细胞分泌，并通过其他细胞因子对它们的增殖、分化和激活起负调控作用。在本研究中，我们使用B细胞和胚胎肾细胞检测了TGF-β对IL-4信号传导的影响。TGF-β抑制B细胞中IL-4诱导的IgG1产生和种系ε转录本的基因表达。在胚胎肾细胞中，当我们使用种系ε启动子DNA进行监测时，TGF-β信号抑制了IL-4诱导的转录。此外，NF-κB的激活导致对TGF-β介导的IL-4信号抑制产生抗性。这些结果表明，TGF-β介导的IL-4信号调控可能通过靶向NF-κB信号传导来发挥作用。
