The TLR4 ligand LPS causes mouse B cells to undergo IgE and IgG1 isotype switching in the presence of IL-4. TLR4 activates two signaling pathways mediated by the adaptor molecules MyD88 and Toll/IL-IR domain-containing adapter-inducing IFN-β (TRIF)–related adaptor molecule (TRAM), which recruits TRIF. Following stimulation with LPS plus IL-4, Tram−/− and Trif−/− B cells completely failed to express Cε germline transcripts (GLT) and secrete IgE. In contrast, Myd88−/− B cells had normal expression of Cε GLT but reduced IgE secretion in response to LPS plus IL-4. Following LPS plus IL-4 stimulation, Cγ1 GLT expression was modestly reduced in Tram−/− and Trif−/− B cells, whereas Aicda expression and IgG1 secretion were reduced in Tram−/−, Trif−/−, and Myd88−/− B cells. B cells from all strains secreted normal amounts of IgE and IgG1 in response to anti-CD40 plus IL-4. Following stimulation with LPS plus IL-4, Trif−/− B cells failed to sustain NF-κB p65 nuclear translocation beyond 3 h and had reduced binding of p65 to the Iε promoter. Addition of the NF-κB inhibitor, JSH-23, to wild-type B cells 15 h after LPS plus IL-4 stimulation selectively blocked Cε GLT expression and IgE secretion but had little effect on Cγ1 GLT expression and IgG secretion. These results indicate that sustained activation of NF-κB driven by TRIF is essential for LPS plus IL-4–driven activation of the Cε locus and class switching to IgE.
CITATION STYLE
Janssen, E., Ozcan, E., Liadaki, K., Jabara, H. H., Manis, J., Ullas, S., … Geha, R. S. (2014). TRIF Signaling Is Essential for TLR4-Driven IgE Class Switching. The Journal of Immunology, 192(6), 2651–2658. https://doi.org/10.4049/jimmunol.1300909
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