TRIF signaling is essential for TLR4-driven IgE class switching.

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Journal of immunology (Baltimore, Md. : 1950), ISSN: 1550-6606, Vol: 192, Issue: 6, Page: 2651-8

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PMC3952935; 3952935
Janssen, Erin; Ozcan, Esra; Liadaki, Kyriaki; Jabara, Haifa H.; Manis, John; Ullas, Sumana; Akira, Shizuo; Fitzgerald, Katherine A.; Golenbock, Douglas T.; Geha, Raif S.
The American Association of Immunologists
Immunology and Microbiology; Adaptor Proteins, Vesicular Transport; Animals; B-Lymphocytes; Cell Survival; Cytidine Deaminase; Immunoblotting; Immunoglobulin Class Switching; Immunoglobulin E; Immunoglobulin G; Immunoglobulin epsilon-Chains; Immunoglobulin gamma-Chains; Interleukin-4; Lipopolysaccharides; Mice; Mice, 129 Strain; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Myeloid Differentiation Factor 88; Phenylenediamines; Receptors, Interleukin; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Toll-Like Receptor 4; Transcription Factor RelA; Cells; Genetics; Immunity; Immunology and Infectious Disease; Immunology of Infectious Disease; Infectious Disease
article description
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.