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 journalArticlepeer-review

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

ASJC Scopus subject areas

  • Immunology

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