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

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 lupus-prone 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.
AuthorsJeffrey J Bednarski, Costas A Lyssiotis, Rebecca Roush, Anthony E Boitano, Gary D Glick, Anthony W Opipari Jr
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 279 Issue 28 Pg. 29615-21 (Jul 09 2004) ISSN: 0021-9258 [Print] United States
PMID15123639 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Chelating Agents
  • Fluorescent Dyes
  • Receptors, Antigen, B-Cell
  • Superoxides
  • Benzodiazepines
  • Egtazic Acid
  • 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid
  • Bz-423
  • Calcium
Topics
  • Animals
  • Apoptosis (physiology)
  • B-Lymphocytes (cytology, drug effects, immunology)
  • Benzodiazepines (chemistry, pharmacology, therapeutic use)
  • Calcium (metabolism)
  • Calcium Signaling (physiology)
  • Cells, Cultured
  • Chelating Agents (metabolism)
  • Disease Models, Animal
  • Egtazic Acid (analogs & derivatives, metabolism)
  • Female
  • Fluorescent Dyes (metabolism)
  • Germinal Center (cytology)
  • Humans
  • Lupus Erythematosus, Systemic (drug therapy)
  • Lymphocyte Activation (physiology)
  • Mice
  • Mice, Inbred BALB C
  • Molecular Structure
  • Receptors, Antigen, B-Cell (metabolism)
  • Superoxides (metabolism)

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