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Detection of the mechanism of immunotoxicity of cyclosporine A in murine in vitro and in vivo models

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Author: Schmeits, P.C.J. · Schaap, M.M. · Luijten, M. · Someren, E. van · Boorsma, A. · Loveren, H. van · Peijnenburg, A.A.C.M. · Hendriksen, P.J.M.
Type:article
Date:2015
Source:Archives of Toxicology, 12, 89, 2325-2337
Identifier: 530275
doi: doi:10.1007/s00204-014-1365-9
Keywords: Biology · C57BL/6 · CTLL-2 · Cyclosporine A · Interspecies comparison · Splenocytes · Interleukin 2 · Messenger RNA · Transcription factor Nrf2 · Animal cell · Animal experiment · Cell cycle regulation · Controlled study · Cytotoxic T lymphocyte · Down regulation · Endoplasmic reticulum stress · HepG2 cell line · Human · Human cell · Immune response · Immunotoxicity · In vitro study · In vivo study · Jurkat cell line · Male · Mouse · Nonhuman · Dpleen cell · T lymphocyte activation · Thymoma cell line · Transcriptomics · Unfolded protein response · Upregulation · Biomedical Innovation · Healthy Living · Life · RAPID - Risk Analysis for Products in Development · ELSS - Earth, Life and Social Sciences

Abstract

Transcriptomics in combination with in vitro cell systems is a powerful approach to unravel modes of action of toxicants. An important question is to which extent the modes of action as revealed by transcriptomics depend on cell type, species and study type (in vitro or in vivo). To acquire more insight into this, we assessed the transcriptomic effects of the immunosuppressive drug cyclosporine A (CsA) upon 6 h of exposure of the mouse cytotoxic T cell line CTLL-2, the thymoma EL-4 and primary splenocytes and compared these to the effects in spleens of mice orally treated with CsA for 7 days. EL-4 and CTLL-2 cells showed the highest similarities in response. CsA affected many genes in primary splenocytes that were not affected in EL-4 or CTLL-2. Pathway analysis demonstrated that CsA upregulated the unfolded protein response, endoplasmic reticulum stress and NRF2 activation in EL-4 cells, CTLL-2 cells and primary mouse splenocytes but not in mouse spleen in vivo. As expected, CsA downregulated cell cycle and immune response in splenocytes in vitro, spleens in vivo as well as CTLL-2 in vitro. Genes up- and downregulated in human Jurkat, HepG2 and renal proximal tubular cells were similarly affected in CTLL-2, EL-4 and primary splenocytes in vitro. In conclusion, of the models tested in this study, the known mechanism of immunotoxicity of CsA is best represented in the mouse cytotoxic T cell line CTLL-2. This is likely due to the fact that this cell line is cultured in the presence of a T cell activation stimulant (IL-2) making it more suitable to detect inhibitory effects on T cell activation. © 2014, Springer-Verlag Berlin Heidelberg. Chemicals/CAS: cyclosporin A, 59865-13-3, 63798-73-2; interleukin 2, 85898-30-2 Manufacturers: Sigma, Netherlands