1. The present study was designed to clarify whether brain pericytes and pericyte-derived transforming growth factor-β1 (TGF-β1) participate in cyclosporin A (CsA)-induced dysfunction of the blood-brain barrier (BBB).
2. The presence of brain pericytes markedly aggravated CsA-increased permeability of MBEC4 cells to sodium fluorescein and accumulation of rhodamine 123 in MBEC4 cells.
3. Exposure to CsA significantly decreased the levels of TGF-β1 mRNA in brain pericytes in pericyte co-cultures. Treatment with TGF-β1 dose-dependently inhibited CsA-induced hyperpermeability and P-glycoprotein dysfunction of MBEC4 cells in pericyte co-cultures.
4. These findings suggest that an inhibition of brain pericyte-derived TGF-β1 contributes to the occurrence of CsA-induced dysfunction of the BBB.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
REFERENCES
Antonelli-Orlidge, A., Saunders, K. B., Smith, S. R., and D’Amore, P. A. (1989). An activated form of transforming growth factor beta is produced by co-cultures of endothelial cells and pericytes. Proc. Natl. Acad. Sci. U.S.A. 86:4544–4548.
Bradford, M. M. (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72:248–254.
Dehouck, M.P., Jolliet-Riant, P., Bree, F., Fruchart, J. C., Cecchelli, R., and Tillement, J. P. (1992). Drug transfer across the blood-brain barrier: Correlation between in vitro and in vivo models. J. Neurochem. 58:1790–1797.
Dohgu, S., Yamauchi, A., Nakagawa, S., Takata, F., Kai, M., Egawa, T., Naito, M., Tsuruo, T., Sawada, Y., Niwa, M., and Kataoka, Y. (2004a). Nitric oxide mediates cyclosporine-induced impairment of the blood-brain barrier in co-cultures of mouse brain endothelial cells and rat astrocytes. Eur. J. Pharmacol. 505:51–59.
Dohgu, S., Yamauchi, A., Takata, F., Naito, M., Tsuruo, T., Higuchi, S., Sawada, Y., and Kataoka, Y. (2004b). Transforming growth factor-beta1 upregulates the tight junction and P-glycoprotein of brain microvascular endothelial cells. Cell. Mol. Neurobiol. 24:491–497.
Dohgu, S., Takata, F., Yamauchi, A., Nakagawa, S., Egawa, T., Naito, M., Tsuruo, T., Sawada, Y., Niwa, M., and Kataoka, Y. (2005). Brain pericytes contribute to the induction and up-regulation of blood-brain barrier functions through transforming growth factor-beta production. Brain Res. 1038:208–215.
Eickelberg, O., Pansky, A., Koehler, E., Bihl, M., Tamm, M., Hildebrand, P., Perruchoud, A. P., Kashgarian, M., and Roth, M. (2001). Molecular mechanisms of TGF-(beta) antagonism by interferon (gamma) and cyclosporine A in lung fibroblasts. FASEB J. 15:797–806.
Fontaine, M., Elmquist, W. F., and Miller, D. W. (1996). Use of rhodamine 123 to examine the functional activity of P-glycoprotein in primary cultured brain microvessel endothelial cell monolayers. Life Sci. 59:1521–1531.
Gijtenbeek, J. M., Van Den Bent, M. J., and Vecht, C. J. (1999). Cyclosporine neurotoxicity. J. Neurol. 246:339–346.
Hori, S., Ohtsuki, S., Hosoya, K., Nakashima, E., and Terasaki, T. (2004). A pericyte-derived angiopoietin-1 multimeric complex induces occludin gene expression in brain capillary endothelial cells through Tie-2 activation in vitro. J. Neurochem. 89:503–513.
Kahan, B. D. (1989). Cyclosporine. N. Engl. J. Med. 321:1725–1738.
Kim, S. J., Angel, P., Lafyatis, R., Hattori, K., Kim, K. Y., Sporn, M. B., Karin, M., and Roberts, A. B. (1990). Autoinduction of transforming growth factor beta 1 is mediated by the AP-1 complex. Mol. Cell. Biol. 10:1492–1497.
Kochi, S., Takanaga, H., Matsuo, H., Naito, M., Tsuruo, T., and Sawada, Y. (1999). Effect of cyclosporin A or tacrolimus on the function of blood-brain barrier cells. Eur. J. Pharmacol. 372:287–295.
Kochi, S., Takanaga, H., Matsuo, H., Ohtani, H., Naito, M., Tsuruo, T., and Sawada, Y. (2000). Induction of apoptosis in mouse brain capillary endothelial cells by cyclosporin A and tacrolimus. Life Sci. 66:2255–2260.
Lai, C. H., and Kuo, K. H. (2005). The critical component to establish in vitro BBB model: Pericyte. Brain Res. Brain Res. Rev. 50:258–265.
Machida, H., Ogawa, K., Funaba, M., Mizutani, T., and Tsujimoto, M. (2000). mRNA expression of type I and type II receptors for activin, transforming growth factor-beta, and bone morphogenetic protein in the murine erythroleukemic cell line, F5–5.fl. Eur. J. Endocrinol. 143:705–710.
Pardridge, W. M. (1999). Blood-brain barrier biology and methodology. J Neurovirol. 5:556–569.
Pfeuffer, I., Klein-Hessling, S., Heinfling, A., Chuvpilo, S., Escher, C., Brabletz, T., Hentsch, B., Schwarzenbach, H., Matthias, P., and Serfling, E. (1994). Octamer factors exert a dual effect on the IL-2 and IL-4 promoters. J. Immunol. 153:5572–5585.
Pirsch, J. D., Miller, J., Deierhoi, M. H., Vincenti, F., and Filo, R. S. (1997). A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group. Transplantation 63:977–983.
Ramsauer, M., Krause, D., and Dermietzel, R. (2002). Angiogenesis of the blood-brain barrier in vitro and the function of cerebral pericytes. FASEB J. 16:1274–1276.
Schinkel, A. H. (1999). P-Glycoprotein, a gatekeeper in the blood-brain barrier. Adv. Drug Deliv. Rev. 36:179–194.
Shuto, H., Kataoka, Y., Kanaya, A., Matsunaga, K., Sueyasu, M., and Oishi, R. (1998). Enhancement of serotonergic neural activity contributes to cyclosporine-induced tremors in mice. Eur. J. Pharmacol. 341:33–37.
Shuto, H., Kataoka, Y., Fujisaki, K., Nakao, T., Sueyasu, M., Miura, I., Watanabe, Y., Fujiwara, M., and Oishi, R. (1999). Inhibition of GABA system involved in cyclosporine-induced convulsions. Life Sci. 65:879–887.
Smith, R. S., Jr., Agata, J., Xia, C. F., Chao, L., and Chao, J. (2005). Human endothelial nitric oxide synthase gene delivery protects against cardiac remodeling and reduces oxidative stress after myocardial infarction. Life Sci. 76:2457–2471.
Tatsuta, T., Naito, M., Oh-hara, T., Sugawara, I., and Tsuruo, T. (1992). Functional involvement of P-glycoprotein in blood-brain barrier. J. Biol. Chem. 267:20383–20391.
The U.S. Multicenter FK506 Liver Study Group. (1994). A comparison of tacrolimus (FK 506) and cyclosporine for immunosuppression in liver transplantation. N. Engl. J. Med. 331:1110–1115.
Thomas, W. E. (1999). Brain macrophages: On the role of pericytes and perivascular cells. Brain Res. Brain Res. Rev. 31:42–57.
Tsuboi, A., Muramatsu, M., Tsutsumi, A., Arai, K., and Arai, N. (1994). Calcineurin activates transcription from the GM-CSF promoter in synergy with either protein kinase C or NF-kappa B/AP-1 in T cells. Biochem. Biophys. Res. Commun. 199:1064–1072.
Untergasser, G., Gander, R., Lilg, C., Lepperdinger, G., Plas, E., and Berger, P. (2005). Profiling molecular targets of TGF-b1 in prostate fibroblast-to-myofibroblast transdifferentiation. Mech. Ageing Dev. 126:59–69.
ACKNOWLEDGMENTS
This work was supported, in part, by Grants-in-Aid for Scientific Research ((B) 17390159) from JSPS, Japan and by a Grant-in-Aid for Exploratory Research (17659160) from MEXT, Japan. The authors thank Dr. Mária A. Deli (Institute of Biophysics, Biological Research Centre of the Hungarian Academy of Sciences) for pertinent comments on the manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Takata, F., Dohgu, S., Yamauchi, A. et al. Inhibition of Transforming Growth Factor-β Production in Brain Pericytes Contributes to Cyclosporin A-Induced Dysfunction of the Blood-Brain Barrier. Cell Mol Neurobiol 27, 317–328 (2007). https://doi.org/10.1007/s10571-006-9125-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10571-006-9125-x