title: TLR7/8 ligand, R-848, inhibits IgE synthesis by acting directly on B lymphocytes.
abstract: TLRs are involved in the regulation of immune responses. R-848, a TLR7/8 ligand, has potent anti-viral and anti-tumour properties and has been used as a new immune response modifier for enhancing Th1 immune response. In this study, we found that R-848 significantly inhibited IgE synthesis from murine B cells at the single cell levels by anti-CD40 plus IL-4-stimulated splenocytes, in which R-848 acted on the early stage of B cell differentiation to modulate IgE synthesis. This inhibitory effect of R-848 on IgE synthesis was not isotype specific as it also inhibited IgG1 synthesis. Moreover, R-848 had no significant effect on the production of IgG2a by anti-CD40 plus IL-4-stimulated splenocytes. Further studies showed that R-848 markedly promoted murine B cell activation induced by anti-CD40 plus IL-4 by up-regulating the expression of B cell activation markers CD25, CD69 and co-stimulatory molecule CD80. In contrast, R-848 inhibited the proliferation and division of murine B cells in anti-CD40 plus IL-4-stimulated splenocytes. R-848 promoted the production of IFN-gamma and IL-12 that were partially responsible for its inhibitory effect on IgE production by anti-CD40 plus IL-4 because the addition of anti-IFN-gamma or anti-IL-12 mAbs to the cultures could significantly restore IgE production by splenocytes. Importantly, R-848 had a direct effect on purified B cells to inhibit IgE production induced by anti-CD40 plus IL-4. Taken together, these results demonstrate that R-848 markedly inhibits IgE synthesis, and suggest that R-848 could be used to treat allergic diseases.
authors.affiliation: Department of Immunology, State Ministry of Education Key Laboratory of Tropical Diseases Control Research, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China.
authors.forename: E
authors.initials: E
authors.lastname: Shen
authors.forename: L
authors.initials: L
authors.lastname: Lu
authors.forename: C
authors.initials: C
authors.lastname: Wu
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D019013:CD40 Antigens / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006967:Hypersensitivity / Q000188:drug therapy; D007093:Imidazoles / Q000378:metabolism* / Q000494:pharmacology*; D007073:Immunoglobulin E / Q000096:biosynthesis*; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D013154:Spleen / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D051200:Toll-Like Receptor 8 / Q000378:metabolism*
chemical_list: D019013:CD40 Antigens; D007093:Imidazoles; D008024:Ligands; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D018664:Interleukin-12; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma; C402365:resiquimod