Letter to the Editor

Nanne Bloksma

Department of Pharmacology and Pathophysiology, Utrecht Institute of Parmaceutical Sciences and Faculty of Biology, Utrecht University, P.O. Box 80082, NL-3508 TB Utrecht, The Netherlands

To the Editor:

Ezendam et al. (2004)Go recently reported on effects of the T cell inhibitor, cyclosporin A (CsA), on hexachlorobenzene (HCB)-induced immunopathology in the Brown Norway (BN) rat. CsA treatment significantly prevented HCB-induced immunopathology. It delayed the onset and reduced the severity of macroscopic skin lesions, previously microscopically characterized by perivascular inflammation (Michielsen et al., 1997Go), and prevented the perivascular infiltrates of eosinophils in the lungs. Based on these results, it was concluded that T cells play a prominent role in HCB-induced immunopathology. However, an earlier study into the effects of T cell depletion on HCB-induced immunopathology in congenitally athymic rhnu Wag/Rij rats and BN rats having undergone young adult thymectomy, lethal irradiation, and bone marrow reconstitution, showed no effects on incidence and severity of lung and skin lesions, be it that the latter had a delayed onset (Michielsen et al., 1999Go). Although it is beyond doubt that CsA is a potent inhibitor of T cell activation, it exerts as an inhibitor of calcineurin direct effects on many other cell types than T cells (Matsuda and Koyasu, 2003Go; Su et al., 1995Go). Besides effects on B cells, macrophages, and other types of leukocytes (Hamalainen et al., 2002Go; Kaye et al., 1992Go; Park et al., 1995Go), CsA has diverse effects on vascular endothelium and vascular myocytes (Rodicio, 2000Go). Interestingly, it was recently shown that calcineurin promoted expression of monocyte chemotactic protein-1 by vascular smooth muscle cells and mediated vascular inflammation, and that these effects could be inhibited by CsA (Satonaka et al., 2004Go). As long as involvement of these and other "T cell independent" effects of CsA have not been excluded, effects observed by Ezendam and coworkers do not justify conclusions on the involvement of T cells in the HCB-induced immunopathology.

REFERENCES

Ezendam, J., Hassing, I., Bleumink, R., Vos, J. G., and Pieters, R. (2004). Hexachlorobenzene-induced immunopathology in Brown Norway rats is partly mediated by T cells. Toxicol. Sci. 78, 88–95.[Abstract/Free Full Text]

Hamalainen, M., Lahti, A., and Moilanen, E. (2002). Calcineurin inhibitors, cyclosporin A and tacrolimus inhibit expression of inducible nitric oxide synthase in colon epithelial and macrophage cell lines. Eur. J. Pharmacol. 448, 239–244.[CrossRef][ISI][Medline]

Kaye, R. E., Fruman, D. A., Bierer, B. E., Albers, M. W., Zydowsky, L. D., Ho, S.I., Jin, Y.J., Castells, M.C., Schreiber, S.L., Walsh, C. T., et al. (1992). Effects of cyclosporin A and FK506 on Fc epsilon receptor type I-initiated increases in cytokine mRNA in mouse bone marrow-derived progenitor mast cells: Resistance to FK506 is associated with a deficiency in FK506-binding protein FKBP12. Proc. Natl. Acad. Sci. USA 89, 8542–8546.[Abstract]

Matsuda, S. and Koyasu, S. (2003). Regulation of MAPK signaling pathways through immunophilin-ligand complex. Curr. Top. Med. Chem. 3, 1358–1367.[ISI][Medline]

Michielsen, C. C., Bloksma, N., Klatter, F. A., Rozing, J., Vos, J.G., and van Dijk, J. E. (1999). The role of thymus-dependent T cells in hexachlorobenzene-induced inflammatory skin and lung lesions. Toxicol. Appl. Pharmacol. 161, 180–191.[CrossRef][ISI][Medline]

Michielsen, C. P., Bloksma, N., Ultee, A., van Mil, F., and Vos, J. G. (1997). Hexachlorobenzene-induced immunomodulation and skin and lung lesions: A comparison between Brown Norway, Lewis, and Wistar rats. Toxicol. Appl. Pharmacol. 144, 12–26.[CrossRef][ISI][Medline]

Park, J., Yaseen, N. R., Hogan, P. G., Rao, A., and Sharma, S. (1995). Phosphorylation of the transcription factor NFATp inhibits its DNA binding activity in cyclosporin a-treated human B and T cells. J. Biol. Chem. 270, 20653–20659.[Abstract/Free Full Text]

Rodicio, J. L. (2000). Calcium antagonists and renal protection from cyclosporine nephrotoxicity: Long-term trial in renal transplantation patients. J. Cardiovasc. Pharmacol. 35(Suppl. 1), S7–11. Review.[CrossRef]

Satonaka, H., Suzuki, E., Nishimatsu, H., Oba, S., Takeda, R., Goto, A., Omata, M., Fujita, T., Nagai, R., and Hirata, Y. (2004). Calcineurin promotes the expression of monocyte chemoattractant protein-1 in vascular myocytes and mediates vascular inflammation. Circ. Res. 94, 693–700.[Abstract/Free Full Text]

Su, Q., Zhao, M., Weber, E., Eugster, H.P., and Ryffel, B. (1995). Distribution and activity of calcineurin in rat tissues. Evidence for post-transcriptional regulation of testis-specific calcineurin B. Eur. J. Biochem. 230,469–474.[Abstract]





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