Requirement for dual signals by anti-CD40 and IL-4 for the induction of nuclear factor-kappa B, IL-6, and IgE in human B lymphocytes.
Stimulation of human peripheral B cells via the CD40 receptor and IL-4R together lead to IgE synthesis and secretion, but the intracellular signaling mechanisms by which these signals lead to IgE production are unclear. Roles for the transcription factor NF-kappa B and IL-6 have been postulated in the induction of IgE synthesis by IL-4/CD40. We found that neither anti-CD40 Ab nor IL-4 alone was able to induce significant proliferation of human B cells. However, the combination of anti-CD40 and IL-4 was a potent inducer of B cell proliferation in addition to IgE production from purified human B cells. Furthermore, IL-4 and anti-CD40 synergized for the production of IL-6. While neither IL-4 alone nor anti-CD40 alone was able to induce significant NF-kappa B DNA binding activity, the combination of IL-4 and anti-CD40 induced a strong activation of NF-kappa B, a transcription factor that regulates IL-6 production. These data indicate that both IL-4 and anti-CD40 are required to induce NF-kappa B activation and IL-6 transcription and production, and implicate these events in a signaling pathway augmenting IgE production in human B lymphocytes.
Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA.
J D
JD
Jeppson
H R
HR
Patel
N
N
Sakata
J
J
Domenico
N
N
Terada
E W
EW
Gelfand
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D001667:Binding, Competitive; D019013:CD40 Antigens / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004338:Drug Combinations; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000502:physiology*; D015850:Interleukin-6 / Q000096:biosynthesis*; D016328:NF-kappa B / Q000096:biosynthesis* / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D018808:Transcription Factor AP-1 / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D004268:DNA-Binding Proteins; D004338:Drug Combinations; D015850:Interleukin-6; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D015847:Interleukin-4; D007073:Immunoglobulin E