MODULATION OF IL-4 INDUCED GERMLINE EPSILON-RNA SYNTHESIS IN HUMAN B-CELLS BY TUMOR-NECROSIS-FACTOR-ALPHA, ANTI-CD40 MONOCLONAL-ANTIBODIES OR TRANSFORMING GROWTH-FACTOR-BETA CORRELATES WITH LEVELS OF IGE PRODUCTION

To determine the role of germline-epsilon transcription in IgE synthesis, the effects of cytokines on germline-epsilon RNA synthesis in IL-4 dependent epsilon-switching in B cells was investigated. Induction of germline-epsilon transcription in highly purified B cells seems to be a specific property of IL-4, since none of the other cytokines tested [IL-1-alpha,beta, IL-2, IL-3, IL-5, IL-6, IL-7, IL-9, IL-10, G-CSF, GM-CSF, M-CSF, IFN-gamma, IFN-alpha, tumor necrosis factor (TNF)-alpha, and transforming growth factor (TGF)-beta] were effective. TGF-beta, IFN-gamma, and IFN-alpha inhibit IL-4 dependent IgE synthesis, but only TGF-beta blocked germline-epsilon RNA synthesis in purified B cells, indicating that this may be the mechanism by which TGF-beta inhibits IgE synthesis, and that IFN-gamma and IFN-alpha act on other stages of the regulatory process resulting in IgE production. IL-5, IL-6, and TNF-alpha enhance IL-4 dependent IgE synthesis, but only TNF-alpha enhanced IL-4 induced germline-epsilon 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-epsilon transcription. These data, together with the observation that epsilon-switching in cultures initiated with single sIgM+, sIgE- B cells in all instances was preceded by germline-epsilon RNA synthesis, indicate that there is a strong relationship between germline-epsilon transcription and IgE synthesis.