CD40 employs p38 MAP kinase in IgE isotype switching.
IgE switching requires the prior induction of C epsilon germline transcripts which is mediated by the concerted binding of STAT-6 and NF kappa B to the C epsilon promoter. These transcription factors are regulated by IL-4 and CD40, respectively. However the latter can effect other signaling pathways and the present study explores the role of p38 MAPK in induction of C epsilon germline transcripts. CD40 and IL-4, both alone and in synergy, were initially shown to activate the C epsilon promoter in a B cell lymphoma cell line. Under the same conditions CD40 caused activation of p38 MAPK, whereas IL-4 was ineffective. The p38 MAPK inhibitor, SB203580, and a dominant negative form of p38 MAPK decreased the CD40 activation of the C epsilon promoter by reducing the ability of CD40 to increase the transactivation potential of NF kappa B. This study suggests that p38 MAPK is crucially important in mediating CD40 activation of NF kappa B which acts to induce C epsilon germline transcripts, ultimately facilitating IgE switching.
Brady
K
K
Department of Pharmacology, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Foster Avenue, Blackrock, Co. Dublin, Ireland.
Fitzgerald
S
S
Ingvarsson
S
S
Borrebaeck
C A
CA
Moynagh
P N
PN
D019013:CD40 Antigens / Q000378:metabolism*; D002460:Cell Line; D017930:Genes, Reporter; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007073:Immunoglobulin E / Q000235:genetics / Q000378:metabolism*; D007132:Immunoglobulin Isotypes / Q000235:genetics / Q000378:metabolism*; D007134:Immunoglobulin Switch Region; D008156:Luciferases / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D050800:STAT6 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
D019013:CD40 Antigens; D007132:Immunoglobulin Isotypes; D016328:NF-kappa B; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D007073:Immunoglobulin E; D008156:Luciferases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases