Molecular mechanisms of B lymphocyte activation by the immune response modifier R-848

The imidazoquinoline R-848, originally identified as a highly effective ant iviral agent, has recently been shown to be capable of potent B lymphocyte activation. The B cell-activating properties of R-848 are strikingly simila r to the effects of the CD40 ligand CD154, The present study demonstrates t hat this similarity extends to the intracellular signaling pathways trigger ed by the compound, although both overlapping and distinct mechanisms of si gnaling were seen. Like CD40 ligation, R-848 stimulated activation of the s tress-activated protein kinases c-Jun kinase and p38 and activated the NF-k appaB family of transcription factors. Both R-848 and CD40-mediated B cell differentiation were dependent upon NF-kappaB activation, although the rela tive importance of individual NF-kappaB family members appeared to differ b etween R-848- and CD40-mediated signals, Both signals were partially depend ent upon induction of TNF-alpha and IL-6, and the cytoplasmic adaptor molec ule TNF receptor-associated factor 2 is involved in both R-848- and CD40-me diated differentiation.