A novel benzodiazepine increases the sensitivity of B cells to receptor stimulation with synergistic effects on calcium signaling and apoptosis

Jeffrey J. Bednarski, Costas A. Lyssiotis, Rebecca Roush, Anthony E. Boitano, Gary D. Glick, Anthony W. Opipari

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Bz-423 is a 1,4-benzodiazepine with selective lymphotoxic properties and potent therapeutic activity against lupus-like disease in autoimmune mice. In NZB/W lupusprone mice, Bz-423 specifically kills germinal center B cells, which are the cells that drive disease both in this model and in human systemic lupus erythematosus. In this report, the mechanistic basis for the selective action of Bz-423 is investigated. We show that Bz-423-induces superoxide as an immediate early response and that this reactive oxygen species is more effective as a second messenger death signal in B cells activated by B cell receptor stimulation compared with resting cells. As a result, low [Bz-423] that are not cytotoxic to non-stimulated cells kill stimulated cells in synergy with anti-immunoglobulin M antibodies. Subsequent experiments demonstrated that Bz-423 extends the rise in intracellular calcium that accompanies anti-immunoglobulin M stimulation, and this effect mediates the synergistic death response. Because B cell hyperactivation and altered calcium signaling is a distinguishing feature of autoreactive lymphocytes in lupus, the mechanism by which Bz-423 induces apoptosis preferentially targets disease-causing cells on the basis of their activation state. Thus, molecules like Bz-423 could form the basis for new and selective anti-lupus agents.

Original languageEnglish
Pages (from-to)29615-29621
Number of pages7
JournalJournal of Biological Chemistry
Volume279
Issue number28
DOIs
StatePublished - Jul 9 2004

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