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.
Gauchat
J F
JF
DNAX Research Institute, Human Immunology Department, Palo Alto, CA 94304-1104.
Aversa
G
G
Gascan
H
H
de Vries
J E
JE
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D001402:B-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens; D002999:Clone Cells / Q000276:immunology; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis / Q000235:genetics; D007139:Immunoglobulin epsilon-Chains / Q000096:biosynthesis / Q000235:genetics*; D015847:Interleukin-4 / Q000494:pharmacology*; D012313:RNA / Q000096:biosynthesis* / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D019013:CD40 Antigens; D007139:Immunoglobulin epsilon-Chains; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007073:Immunoglobulin E; D012313:RNA