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.
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Authors | Jeffrey J Bednarski, Costas A Lyssiotis, Rebecca Roush, Anthony E Boitano, Gary D Glick, Anthony W Opipari Jr |
Journal | The Journal of biological chemistry
(J Biol Chem)
Vol. 279
Issue 28
Pg. 29615-21
(Jul 09 2004)
ISSN: 0021-9258 [Print] United States |
PMID | 15123639
(Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
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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
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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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