RESUMEN
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.
Asunto(s)
Ciclosporina/toxicidad , Inmunosupresores/toxicidad , Linfocitos T Citotóxicos/efectos de los fármacos , Animales , Línea Celular , Línea Celular Tumoral , Regulación hacia Abajo/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Perfilación de la Expresión Génica/métodos , Células Hep G2 , Humanos , Células Jurkat , Masculino , Ratones , Ratones Endogámicos C57BL , Desplegamiento Proteico/efectos de los fármacos , Bazo/citología , Bazo/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Timoma/inmunología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Treatment with coumarin derivatives is highly individualised due to high intra- and inter-individual variation in dose response and risks of severe bleeding or thromboembolic complications. Treatment focuses on reaching and maintaining a stable target international normalised ratio (INR). However, unexpected INRs that are not explained by noncompliance or vitamin K intake may occur. Here we describe seven cases of unexpected INRs, and provide clues that clarify the underlying mechanism.