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Molecular Mechanisms of B Lymphocyte Activation by the Immune Response Modifier R-848¹

Gail A. Bishop^2,*,,,, Yina Hsing, Bruce S. Hostager^*, Sangita V. Jalukar^*, Luis M. Ramirez and Mark A. Tomai^¶

Departments of ^* Microbiology and Internal Medicine, Graduate Program in Immunology, and Veterans Administration Medical Center, Iowa City, IA 52242; and ^¶ Department of Pharmacology, 3M Pharmaceuticals, St. Paul, MN 55144

The imidazoquinoline R-848, originally identified as a highly effective antiviral agent, has recently been shown to be capable of potent B lymphocyte activation. The B cell-activating properties of R-848 are strikingly similar to the effects of the CD40 ligand CD154. The present study demonstrates that this similarity extends to the intracellular signaling pathways triggered by the compound, although both overlapping and distinct mechanisms of signaling were seen. Like CD40 ligation, R-848 stimulated activation of the stress-activated protein kinases c-Jun kinase and p38 and activated the NF-B family of transcription factors. Both R-848- and CD40-mediated B cell differentiation were dependent upon NF-B activation, although the relative importance of individual NF-B family members appeared to differ between R-848- and CD40-mediated signals. Both signals were partially dependent upon induction of TNF- and IL-6, and the cytoplasmic adaptor molecule TNF receptor-associated factor 2 is involved in both R-848- and CD40-mediated differentiation.

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