Title
Detection of the mechanism of immunotoxicity of cyclosporine A in murine in vitro and in vivo models
Author
Schmeits, P.C.J.
Schaap, M.M.
Luijten, M.
van Someren, E.
Boorsma, A.
van Loveren, H.
Peijnenburg, A.A.C.M.
Hendriksen, P.J.M.
Publication year
2015
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
Subject
Life
RAPID - Risk Analysis for Products in Development
ELSS - Earth, Life and Social Sciences
Biomedical Innovation
Biology
Healthy Living
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
To reference this document use:
http://resolver.tudelft.nl/uuid:d5268521-be0c-474c-b932-3c9c77e83509
DOI
https://doi.org/10.1007/s00204-014-1365-9
TNO identifier
530275
ISSN
0340-5761
Source
Archives of Toxicology, 89 (12), 2325-2337
Document type
article