TRIF signaling is essential for TLR4-driven IgE class switching
Department of Medicine, Division of Infectious Diseases and Immunology
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
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-beta (TRIF)-related adaptor molecule (TRAM), which recruits TRIF. Following stimulation with LPS plus IL-4, Tram(-/-) and Trif(-/-) B cells completely failed to express Cepsilon germline transcripts (GLT) and secrete IgE. In contrast, Myd88(-/-) B cells had normal expression of Cepsilon GLT but reduced IgE secretion in response to LPS plus IL-4. Following LPS plus IL-4 stimulation, Cgamma1 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-kappaB p65 nuclear translocation beyond 3 h and had reduced binding of p65 to the Iepsilon promoter. Addition of the NF-kappaB inhibitor, JSH-23, to wild-type B cells 15 h after LPS plus IL-4 stimulation selectively blocked Cepsilon GLT expression and IgE secretion but had little effect on Cgamma1 GLT expression and IgG secretion. These results indicate that sustained activation of NF-kappaB driven by TRIF is essential for LPS plus IL-4-driven activation of the Cepsilon locus and class switching to IgE.
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Citation: J Immunol. 2014 Mar 15;192(6):2651-8. doi: 10.4049/jimmunol.1300909. Epub 2014 Feb 14.Link to article on publisher's site
Janssen, Erin; Ozcan, Esra; Liadaki, Kyriaki; Jabara, Haifa H.; Manis, John; Ullas, Sumana; Akira, Shizuo; Fitzgerald, Katherine A.; Golenbock, Douglas T.; and Geha, Raif S., "TRIF signaling is essential for TLR4-driven IgE class switching" (2014). Infectious Diseases and Immunology Publications and Presentations. 179.