title: TRIF signaling is essential for TLR4-driven IgE class switching.
abstract: 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.
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, MA 02115;
authors.forename: Erin
authors.initials: E
authors.lastname: Janssen
authors.forename: Esra
authors.initials: E
authors.lastname: Ozcan
authors.forename: Kyriaki
authors.initials: K
authors.lastname: Liadaki
authors.forename: Haifa H
authors.initials: HH
authors.lastname: Jabara
authors.forename: John
authors.initials: J
authors.lastname: Manis
authors.forename: Sumana
authors.initials: S
authors.lastname: Ullas
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Golenbock
authors.forename: Raif S
authors.initials: RS
authors.lastname: Geha
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D003564:Cytidine Deaminase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015151:Immunoblotting; D017578:Immunoglobulin Class Switching / Q000187:drug effects / Q000276:immunology*; D007073:Immunoglobulin E / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007139:Immunoglobulin epsilon-Chains / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007142:Immunoglobulin gamma-Chains / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010655:Phenylenediamines / Q000276:immunology / Q000494:pharmacology; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000276:immunology* / Q000378:metabolism; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D003564:Cytidine Deaminase; D007073:Immunoglobulin E; D007074:Immunoglobulin G; D007139:Immunoglobulin epsilon-Chains; D007142:Immunoglobulin gamma-Chains; D015847:Interleukin-4; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D010655:Phenylenediamines; D018123:Receptors, Interleukin; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; D000098830:AICDA (Activation-Induced Cytidine Deaminase); C549066:4-methyl-N1-(3-phenylpropyl)benzene-1,2-diamine; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C476416:Ticam2 protein, mouse; C493487:Tlr4 protein, mouse