CD40-mediated p38 mitogen-activated protein kinase activation is required for immunoglobulin class switch recombination to IgE.
BACKGROUND
Signaling through CD40 activates multiple kinases and signal pathways that drive diverse CD40-mediated biologic functions. The specific pathways activated by CD40 signaling involving CD40-dependent Ig class switch recombination (CSR) have not been defined.


OBJECTIVE
We sought to dissect CD40-activated signaling required for CD40-mediated Ig CSR by using the specific signal pathway inhibitors, with the emphasis on CD40-activated p38 mitogen-activated protein kinase (p38 MAPK) signaling in CD40-mediated CSR to IgE.


METHODS
Human B cells were costimulated with IL-4 plus anti-CD40 in the presence or absence of specific signal pathway inhibitors. Ig production, kinase phosphorylation, IgH epsilon germline transcripts and Smu-Sepsilon recombination were examined, and their relationships were analyzed.


RESULTS
CD40-dependent IgE induction was inhibited by the specific p38 MAPK inhibitor SB203580 but not by the extracellular signal-regulated protein kinase-specific inhibitor PD98059 or the phosphatidylinositol 3-kinase-specific inhibitor LY294002. CD40 activation of p38 MAPK correlated with CD40-dependent IgE production, and IgE suppression by SB203580 correlated with the inhibition of CD40-activated p38 MAPK phosphorylation. Suppression of IgE production by SB203580 was not due to inhibition of cell proliferation because SB203580 did not suppress IL-4 plus alpha-CD40-induced cell proliferation. SB203580, but neither PD98059 nor LY294002, inhibited CD40-dependent Smu-Sepsilon recombination, as determined by using a digestion circularization PCR assay. The inhibitory effects of SB203580 on IgE production and Smu-Sepsilon recombination were directly related to its ability to suppress production of Ig epsilon germline transcripts.


CONCLUSIONS
These results demonstrate that p38 MAPK is required for CD40-mediated class switching to IgE.
Hart and Louis Laboratory, Division of Clinical Immunology, Department of Medicine, UCLA School of Medicine, 90095, USA.
Ke
K
Zhang
Ling
L
Zhang
Daocheng
D
Zhu
David
D
Bae
Andre
A
Nel
Andrew
A
Saxon
D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D019013:CD40 Antigens / Q000502:physiology*; D002478:Cells, Cultured; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D017578:Immunoglobulin Class Switching; D007073:Immunoglobulin E / Q000096:biosynthesis / Q000235:genetics*; D007148:Immunoglobulin mu-Chains / Q000235:genetics; D015847:Interleukin-4 / Q000037:antagonists & inhibitors; D008213:Lymphocyte Activation; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016133:Polymerase Chain Reaction / Q000379:methods; D011401:Promoter Regions, Genetic; D011725:Pyridines / Q000494:pharmacology; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases
D019013:CD40 Antigens; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007148:Immunoglobulin mu-Chains; D011725:Pyridines; D015847:Interleukin-4; D007073:Immunoglobulin E; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580