title: Inhibition of CXCL12-mediated chemotaxis of Jurkat cells by direct immunotoxicants.
abstract: Directional migration of cells to specific locations is required in tissue development, wound healing, and immune responses. Immune cell migration plays a crucial role in both innate and adaptive immunity. Chemokines are small pro-inflammatory chemoattractants that control the migration of leukocytes. In addition, they are also involved in other immune processes such as lymphocyte development and immune pathology. In a previous toxicogenomics study using the Jurkat T cell line, we have shown that the model immunotoxicant TBTO inhibited chemotaxis toward the chemokine CXCL12. In the present work, we aimed at assessing a novel approach to detecting chemicals that affect the process of cell migration. For this, we first evaluated the effects of 31 chemicals on mRNA expression of genes that are known to be related to cell migration. With this analysis, seven immunotoxicants were identified as potential chemotaxis modulators, of which five (CoCl2 80 µM, MeHg 1 µM, ochratoxin A 10 µM, S9-treated ochratoxin A 10 µM, and TBTO 100 nM) were confirmed as chemotaxis inhibitor in an in vitro trans-well chemotaxis assay using the chemokine CXCL12. The transcriptome data of the five compounds together with previously obtained protein phosphorylation profiles for two out of five compounds (i.e., ochratoxin A and TBTO) revealed that the mechanisms behind the chemotaxis inhibition are different for these immunotoxicants. Moreover, the mTOR inhibitor rapamycin had no effect on the chemotaxis of Jurkat cells, indicating that the mTOR pathway is not involved in CXCL12-mediated chemotaxis of Jurkat cells, which is opposite to the findings on human primary T cells (Munk et al. in PLoS One 6(9):e24667, 2011). Thus, the results obtained from the chemotaxis assay conducted with Jurkat cells might not fully represent the results obtained with human primary T cells. Despite this difference, the present study indicated that some compounds may exert their immunotoxic effects through inhibition of CXCL12-mediated chemotaxis.
authors: RIKILT-Institute of Food Safety, Wageningen University and Research Centre, P.O. Box 230, 6700 AE, Wageningen, The Netherlands.|Department of Toxicogenomics, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.|Netherlands Toxicogenomics Centre, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
authors: Jia
authors: J
authors: Shao
authors: RIKILT-Institute of Food Safety, Wageningen University and Research Centre, P.O. Box 230, 6700 AE, Wageningen, The Netherlands.
authors: Inge
authors: I
authors: Stout
authors: RIKILT-Institute of Food Safety, Wageningen University and Research Centre, P.O. Box 230, 6700 AE, Wageningen, The Netherlands.|Netherlands Toxicogenomics Centre, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
authors: Oscar L
authors: OL
authors: Volger
authors: RIKILT-Institute of Food Safety, Wageningen University and Research Centre, P.O. Box 230, 6700 AE, Wageningen, The Netherlands.|Netherlands Toxicogenomics Centre, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
authors: Peter J M
authors: PJ
authors: Hendriksen
authors: National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA, Bilthoven, The Netherlands.|Department of Toxicogenomics, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.|Netherlands Toxicogenomics Centre, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
authors: Henk
authors: H
authors: van Loveren
authors: RIKILT-Institute of Food Safety, Wageningen University and Research Centre, P.O. Box 230, 6700 AE, Wageningen, The Netherlands. ad.peijnenburg@wur.nl.|Netherlands Toxicogenomics Centre, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands. ad.peijnenburg@wur.nl.
authors: Ad A C M
authors: AA
authors: Peijnenburg
mesh_terms: D002464:Cell Migration Inhibition / Q000187:drug effects* / Q000235:genetics; D054377:Chemokine CXCL12 / Q000276:immunology / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000633:toxicity*; D019169:Jurkat Cells; D012333:RNA, Messenger / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D059467:Transcriptome / Q000187:drug effects; D014220:Trialkyltin Compounds / Q000633:toxicity*
chemical_list: D054377:Chemokine CXCL12; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D014220:Trialkyltin Compounds; C005961:bis(tri-n-butyltin)oxide
keywords: CXCL12; Chemotaxis; Direct immunotoxicity; Jurkat