Inhibition of GTPase Rac1 in endothelium by 6-mercaptopurine results in immunosuppression in nonimmune cells: New target for an old drug

Goran Marinković, Jeffrey Kroon, Mark Hoogenboezem, Kees A. Hoeben, Matthijs S. Ruiter, Kondababu Kurakula, Iker Otermin Rubio, Mariska Vos, Carlie J M De Vries, Jaap D. Van Buul, Vivian De Waard

Research output: Contribution to journalArticle

Abstract

Azathioprine and its metabolite 6-mercaptopurine (6-MP) are well established immunosuppressive drugs. Common understanding of their immunosuppressive properties is largely limited to immune cells. However, in this study, the mechanism underlying the protective role of 6-MP in endothelial cell activation is investigated. Because 6-MP and its derivative 6-thioguanosine-59-triphosphate (6-T-GTP) were shown to block activation of GTPase Rac1 in T lymphocytes, we focused on Rac1-mediated processes in endothelial cells. Indeed, 6-MP and 6-T-GTP decreased Rac1 activation in endothelial cells. As a result, the compounds inhibited TNF-a-induced downstream signaling via JNK and reduced activation of transcription factors c-Jun, activating transcription factor-2 and, in addition, NF κ-light-chain- enhancer of activated B cells (NF-κB), which led to decreased transcription of proinflammatory cytokines. Moreover, 6-MP and 6-T-GTP selectively decreased TNF-α-induced VCAM-1 but not ICAM-1 protein levels. Rac1-mediated generation of cell membrane protrusions, which form docking structures to capture leukocytes, also was reduced by 6-MP/6-T-GTP. Consequently, leukocyte transmigration was inhibited after 6-MP/6-T-GTP treatment. These data underscore the anti-inflammatory effect of 6-MP and 6-T-GTP on endothelial cells by blocking Rac1 activation. Our data provide mechanistic insight that supports development of novel Rac1-specific therapeutic approaches against chronic inflammatory diseases. The Journal of Immunology, 2014, 192: 4370-4378.

Original languageEnglish
Pages (from-to)4370-4378
Number of pages9
JournalJournal of Immunology
Volume192
Issue number9
DOIs
Publication statusPublished - May 1 2014

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6-Mercaptopurine
GTP Phosphohydrolases
Immunosuppression
Endothelium
Pharmaceutical Preparations
Endothelial Cells
Immunosuppressive Agents
Leukocytes
Cell Surface Extensions
Activating Transcription Factor 2
Vascular Cell Adhesion Molecule-1
Azathioprine
Intercellular Adhesion Molecule-1
Allergy and Immunology
6-thioguanosine
triphosphoric acid
B-Lymphocytes
Chronic Disease
Anti-Inflammatory Agents
Transcription Factors

ASJC Scopus subject areas

  • Immunology

Cite this

Marinković, G., Kroon, J., Hoogenboezem, M., Hoeben, K. A., Ruiter, M. S., Kurakula, K., ... De Waard, V. (2014). Inhibition of GTPase Rac1 in endothelium by 6-mercaptopurine results in immunosuppression in nonimmune cells: New target for an old drug. Journal of Immunology, 192(9), 4370-4378. https://doi.org/10.4049/jimmunol.1302527

Inhibition of GTPase Rac1 in endothelium by 6-mercaptopurine results in immunosuppression in nonimmune cells : New target for an old drug. / Marinković, Goran; Kroon, Jeffrey; Hoogenboezem, Mark; Hoeben, Kees A.; Ruiter, Matthijs S.; Kurakula, Kondababu; Rubio, Iker Otermin; Vos, Mariska; De Vries, Carlie J M; Van Buul, Jaap D.; De Waard, Vivian.

In: Journal of Immunology, Vol. 192, No. 9, 01.05.2014, p. 4370-4378.

Research output: Contribution to journalArticle

Marinković, G, Kroon, J, Hoogenboezem, M, Hoeben, KA, Ruiter, MS, Kurakula, K, Rubio, IO, Vos, M, De Vries, CJM, Van Buul, JD & De Waard, V 2014, 'Inhibition of GTPase Rac1 in endothelium by 6-mercaptopurine results in immunosuppression in nonimmune cells: New target for an old drug', Journal of Immunology, vol. 192, no. 9, pp. 4370-4378. https://doi.org/10.4049/jimmunol.1302527
Marinković, Goran ; Kroon, Jeffrey ; Hoogenboezem, Mark ; Hoeben, Kees A. ; Ruiter, Matthijs S. ; Kurakula, Kondababu ; Rubio, Iker Otermin ; Vos, Mariska ; De Vries, Carlie J M ; Van Buul, Jaap D. ; De Waard, Vivian. / Inhibition of GTPase Rac1 in endothelium by 6-mercaptopurine results in immunosuppression in nonimmune cells : New target for an old drug. In: Journal of Immunology. 2014 ; Vol. 192, No. 9. pp. 4370-4378.
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