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J. Biol. Chem., Vol. 276, Issue 17, 14100-14109, April 27, 2001
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From the Canadian Institutes of Health Research Group in
Periodontal Physiology, Faculty of Dentistry, University of
Toronto, Toronto, Ontario M5S 3E2, Canada
The immunosuppressant cyclosporin A (CsA)
markedly inhibits collagen degradation by an intracellular phagocytic
pathway in fibroblasts, an effect that can lead to massive gingival
overgrowth. We used a collagen bead model of collagen phagocytosis to
determine whether CsA inhibits internalization by blocking efflux of
calcium from endoplasmic reticulum (ER) and mitochondrial calcium
stores. CsA caused dose-dependent inhibition of
phagocytosis of collagen-coated (but not bovine serum albumin-coated)
beads. Chelation of intracellular Ca2+ with BAPTA/AM
or inhibition of Ca2+-ATPase of ER stores with thapsigargin
reduced collagen bead phagocytosis. Measurement of intracellular
calcium by ratio fluorometry showed increases in response to
collagen-coated beads. Preincubation with CsA or thapsigargin caused a
>3-fold decrease in intracellular calcium elevations in response to
stimulation with collagen beads. Direct measurements of
Ca2+ in mitochondrial and ER stores showed that CsA only
slightly inhibited collagen bead-induced discharge of calcium from
mitochondria, but almost completely blocked discharge from ER stores.
We reduced the numbers of mitochondria with chronic ethidium bromide
treatment to test for the importance of ER/mitochondrial interactions.
In these cells, CsA delayed collagen bead-induced calcium discharge from mitochondria. Collectively, these data indicate that CsA inhibits
collagen phagocytosis by blocking calcium release from ER stores and
may perturb functional interactions between the ER and mitochondria
that regulate calcium stores.
Mechanism of Cyclosporin-induced Inhibition of Intracellular
Collagen Degradation*
*
This work was supported by Canadian Institutes of Health
Research operating and group grants (to C. A. G. M.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: University of Toronto,
Fitzgerald Bldg., Rm. 244, 150 College St., Toronto, Ontario M5S 3E2,
Canada. Tel.: 416-978-1258; Fax: 416-978-5956; E-mail: christopher.mcculloch@utoronto.ca.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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