CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes

The Journal of Clinical Investigation
Imke TiedeMarkus F Neurath


Azathioprine and its metabolite 6-mercaptopurine (6-MP) are immunosuppressive drugs that are used in organ transplantation and autoimmune and chronic inflammatory diseases such as Crohn disease. However, their molecular mechanism of action is unknown. In the present study, we have identified a unique and unexpected role for azathioprine and its metabolites in the control of T cell apoptosis by modulation of Rac1 activation upon CD28 costimulation. We found that azathioprine and its metabolites induced apoptosis of T cells from patients with Crohn disease and control patients. Apoptosis induction required costimulation with CD28 and was mediated by specific blockade of Rac1 activation through binding of azathioprine-generated 6-thioguanine triphosphate (6-Thio-GTP) to Rac1 instead of GTP. The activation of Rac1 target genes such as mitogen-activated protein kinase kinase (MEK), NF-kappaB, and bcl-x(L) was suppressed by azathioprine, leading to a mitochondrial pathway of apoptosis. Azathioprine thus converts a costimulatory signal into an apoptotic signal by modulating Rac1 activity. These findings explain the immunosuppressive effects of azathioprine and suggest that 6-Thio-GTP derivates may be useful as potent immunosuppressive...Continue Reading


Jan 1, 1975·Arthritis and Rheumatism·E GinzlerD Kaplan
Jan 1, 1992·European Journal of Clinical Pharmacology·L Lennard
Sep 26, 1991·The New England Journal of Medicine·D K Podolsky
May 1, 1980·The New England Journal of Medicine·D H PresentB S Pasternack
Dec 1, 1981·Annals of the Rheumatic Diseases·M De Silva, B L Hazleman
Oct 1, 1995·Gastroenterology·C O ElsonR H Riddell
Jul 15, 1995·Annals of Internal Medicine·D C PearsonL R Sutherland
Oct 1, 1995·Current Opinion in Immunology·L H BoiseC B Thompson
Jun 22, 1999·Current Opinion in Immunology·C ScaffidiM E Peter
Aug 24, 1999·Molecular and Cellular Biology·T Joneson, D Bar-Sagi
Jan 13, 2000·Scandinavian Journal of Immunology·T T MacDonaldS L Pender
Aug 5, 2000·The Journal of Immunology : Official Journal of the American Association of Immunologists·A KhoshnanA E Nel
Mar 23, 2001·Nature Immunology·M GomezD A Cantrell
Oct 6, 2000·Science·A R SimonK L Guan
Nov 9, 2000·The Journal of Immunology : Official Journal of the American Association of Immunologists·S JodoS T Ju
Jan 26, 2002·Lancet·Fergus Shanahan
Jun 4, 2002·Nature Medicine·Markus F NeurathLaurie H Glimcher

❮ Previous
Next ❯


Mar 26, 2011·Inflammatory Bowel Diseases·Iris DotanLloyd Mayer
Jan 15, 2008·European Journal of Clinical Pharmacology·Shirley Kow Yin KhamAllen Eng Juh Yeoh
May 29, 2008·European Journal of Clinical Pharmacology·Srikumar SahasranamanSandip Roy
Jun 2, 2006·Springer Seminars in Immunopathology·Mary K Crow
Feb 8, 2011·Seminars in Immunopathology·Melissa R Keller, William J Burlingham
Oct 2, 2004·International Journal of Colorectal Disease·Martin H Holtmann, Markus F Neurath
Mar 28, 2009·Journal of Neurology·Andrew ChanNicolas von Ahsen
Sep 17, 2010·Clinical and Experimental Medicine·Silvana GuerrieroRosanna Dammacco
Oct 9, 2007·Apoptosis : an International Journal on Programmed Cell Death·Christian LiedtkeChristian Trautwein
Aug 24, 2006·Digestive Diseases and Sciences·Martin H HoltmannMarkus F Neurath
Nov 30, 2005·Current Gastroenterology Reports·Simon Travis
May 20, 2004·Current Treatment Options in Gastroenterology·Maria T. Abreu
Jun 12, 2013·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Roslyn KempMichael Schultz
Dec 3, 2010·Journal of Crohn's & Colitis·A DignassUNKNOWN European Crohn's and Colitis Organisation (ECCO)
Dec 3, 2010·Journal of Crohn's & Colitis·Anne Thai, Thomas Prindiville
Dec 3, 2010·Journal of Crohn's & Colitis·O PozlerP Krásničanová
May 18, 2011·Journal of Crohn's & Colitis·Andreas StallmachTony Bruns
Jul 14, 2004·Digestive and Liver Disease : Official Journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver·S RossettiA Palmo
Jun 21, 2005·Journal of Hepatology·Julia SeidererThomas Ochsenkühn
Apr 15, 2005·Mutation Research·Thierry DervieuxBruce Neri
Sep 9, 2004·Clinical Gastroenterology and Hepatology : the Official Clinical Practice Journal of the American Gastroenterological Association·Marla C Dubinsky
Sep 3, 2010·ACS Chemical Biology·Bifeng YuanYinsheng Wang
Jan 24, 2013·Translational Psychiatry·L ManterolaJ L Zugaza
Apr 16, 2010·The New England Journal of Medicine·Jean Frédéric ColombelUNKNOWN SONIC Study Group
Dec 24, 2004·The New England Journal of Medicine·Philip F Halloran
Jan 13, 2004·Proceedings of the National Academy of Sciences of the United States of America·E KakkisM Passage
Oct 19, 2012·The Journal of Biological Chemistry·Changjun YouYinsheng Wang
Aug 1, 2012·Human Molecular Genetics·Gabriele StoccoWilliam E Evans
Jul 30, 2008·Journal of Gastroenterology and Hepatology·Akira AndohYoshihide Fujiyama
Oct 14, 2009·Journal of Gastroenterology and Hepatology·Michael C Grimm
Oct 1, 2010·Journal of Gastroenterology and Hepatology·Peter R Gibson, Richard B Gearry
Jun 30, 2012·Journal of Gastroenterology and Hepatology·Rebecca L Roberts, Murray L Barclay
Oct 14, 2004·Gut·M P Peppelenbosch, S J H van Deventer
Aug 13, 2004·Gut·M J CarterUNKNOWN IBD Section, British Society of Gastroenterology
Feb 17, 2006·Gut·S P L TravisUNKNOWN European Crohn's and Colitis Organisation
Sep 13, 2003·Gut·M H Holtmann, M F Neurath
Feb 2, 2011·Molecular Cancer Therapeutics·Sally A CoulthardLinda A Hogarth

❮ Previous
Next ❯

Methods Mentioned

transmission electron microscopy
Protein Assay

Related Concepts

Related Feeds

Autoimmune Diseases

Autoimmune diseases occur as a result of an attack by the immune system on the body’s own tissues resulting in damage and dysfunction. There are different types of autoimmune diseases, in which there is a complex and unknown interaction between genetics and the environment. Discover the latest research on autoimmune diseases here.

BCL-2 Family Proteins

BLC-2 family proteins are a group that share the same homologous BH domain. They play many different roles including pro-survival signals, mitochondria-mediated apoptosis and removal or damaged cells. They are often regulated by phosphorylation, affecting their catalytic activity. Here is the latest research on BCL-2 family proteins.


Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis