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-γ 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-γ 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. © 2008 The Authors.