title: CD40-mediated tumor necrosis factor receptor-associated factor 3 signaling upregulates IL-4-induced germline Cepsilon transcription in a human B cell line.
abstract: Induction of germline C epsilon transcription in B cells by IL-4, which is a critical initiating step for IgE class switching, is enhanced by CD40 engagement. Although signaling by CD40 is initiated by the binding of tumor necrosis factor receptor-associated factor (TRAF) family members to its cytoplasmic domain, whether those TRAF family proteins mediate enhancement of germline Cepsilon transcription is not evident. We report here that CD40-induced TRAF3-dependent activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase 1 (MEK1) is involved in the upregulation of IL-4-driven germline C epsilon transcription in a human Burkitt's lymphoma B cell line, DG75. Among the six known TRAF proteins, TRAF2, 3, 5, and 6 associated with CD40 in an unstimulated state, and the levels of these four proteins were unaffected by anti-CD40 stimulation. Antisense oligodeoxynucleotide (ODN) for TRAF3 inhibited CD40-induced activation of MEK1-ERK pathway by decreasing expression of TRAF3 protein, but antisense ODNs for TRAF2, 5, and 6 were ineffective. Furthermore, CD40-mediated enhancement of IL-4-driven germline C epsilon transcription was inhibited by antisense ODN for TRAF3 and by a MEK1 inhibitor, PD98059. These results suggest that in DG75 cells, TRAF3-induced MEK1 activation may be involved in CD40-mediated upregulation of IL-4-driven germline C epsilon transcription.
authors.affiliation: Clinical Research Center, National Sagamihara Hospital, 18-1 Sakuradai, Sagamihara 228-8522, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Basaki
authors.forename: Koichi
authors.initials: K
authors.lastname: Ikizawa
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kajiwara
authors.forename: Yukiyoshi
authors.initials: Y
authors.lastname: Yanagihara
mesh_terms: D002051:Burkitt Lymphoma / Q000503:physiopathology*; D019013:CD40 Antigens / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005854:Germ Cells; D006801:Humans; D007139:Immunoglobulin epsilon-Chains / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism* / Q000494:pharmacology; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011506:Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D048015:TNF Receptor-Associated Factor 5; D048029:TNF Receptor-Associated Factor 6; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D019013:CD40 Antigens; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007139:Immunoglobulin epsilon-Chains; D016376:Oligonucleotides, Antisense; D011506:Proteins; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D048015:TNF Receptor-Associated Factor 5; D048029:TNF Receptor-Associated Factor 6; D015847:Interleukin-4; D017346:Protein Serine-Threonine Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one