Modulation of IL-4 induced germline ε RNA synthesis in human B cells by tumor necrosis factor-α, anti-CD40 monoclonal antibodies or transforming growth factor-β correlates with levels of IgE production
To determine the role of germline ∈ transcription in IgE synthesis, the effects of cytokines on germline ∈ RNA synthesis in IL-4 dependent ∈ switching in B cells was investigated. Induction of germline ∈ transcription in highly purified B cells seems to be a specific property of IL-4, since none of the other cytokines tested [IL-1α, β, IL-2, IL-3, IL-5, IL-6, IL-7, IL-9, IL-10, G-CSF, GM-CSF, M-CSF, IFN-γ, IFN-α, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β] were effective. TGF-β, IFN-γ, and IFN-α inhibit IL-4 dependent IgE synthesis, but only TGF-β blocked germline ∈ RNA synthesis in purified B cells, indicating that this may be the mechanism by which TGF-β inhibits IgE synthesis, and that IFN-γ and IFN-α act on other stages of the regulatory process resulting In IgE production. IL-5, IL-6, and TNF-α enhance IL-4 dependent IgE synthesis, but only TNF-α enhanced IL-4 induced germline ∈ RNA synthesis. Finally, anti-CD40 mAbs and the non-IL-4 producing CD4+ T cell clone A3, which in the presence of IL-4 induce IgE synthesis by purified B cells, both strongly enhanced germline ∈ transcription. These data, together with the observation that ∈ switching in cultures initiated with single slgM+, slgE− B cells in all instances was preceded by germline ∈ RNA synthesis, indicate that there is a strong relationship between germline ∈ transcription and IgE synthesis.