Involvement of NF- [formula omitted]B in TGF- [formula omitted]-mediated suppression of IL-4 signaling

Abstract

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-β) 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-β 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-β on IL-4 signaling using B cells as well as embryonic kidney cells. TGF-β inhibited IL-4-induced IgG1 production and gene expression of germline ε transcripts in B cells. In embryonic kidney cells, TGF-β signals suppressed IL-4-induced transcription, when we monitored using germline ε promoter DNA. Furthermore, activation of NF-κB resulted in a resistance to TGF-β-mediated suppression of IL-4 signaling. These results indicate that TGF-β-mediated regulation of IL-4 signaling may act by targeting NF-κB signaling.