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

Tiede, Imke; Fritz, Gerhard; Strand, Susanne; Poppe, Daniela; Dvorsky, Radovan; Strand, Dennis; Lehr, Hans Anton; Wirtz, Stefan; Becker, Christoph; Atreya, Raja; Mudter, Jonas; Hildner, Kai; Bartsch, Brigitte; Holtmann, Martin; Blumberg, Richard; Walczak, Henning; Iven, Heiko; Galle, Peter R.; Ahmadian, Mohammad Reza; Neurath, Markus F.

doi:10.1172/jci16432

Cited by 828Protein Kinase Regulation and GTPase SignalingCell death mechanisms and regulationT-cell and B-cell Immunology

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

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Tiede, Imke, Fritz, Gerhard, Strand, Susanne, Poppe, Daniela, Dvorsky, Radovan, Strand, Dennis, Lehr, Hans Anton, Wirtz, Stefan +12 more·2003·Journal of Clinical Investigation

DOI 10.1172/jci16432PMC PMC152932

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Abstract

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 agents in autoimmune diseases and organ transplantation.

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Treatment with the lymphocyte-modulating agent azathioprine impairs function of molecules that function as immune checkpoints.
“treatment with the lymphocyte-modulating agent Azathioprine results in impaired function of molecules that function as immune checkpoints (131)”
From The Role of Immune and Inflammatory Cells in Idiopathic Pulmonary Fibrosis (2018) · cites this paper as [131]

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Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease
Hugot, J.-P., Chamaillard, M., Zouali, H., Lesage, S., Cézard, J.-P., Belaiche, J., Almer, S., Tysk, C., O'Morain, C. A., Gassull, M., et al. (2001) · Nature · doi:10.1038/35079107 · Cited by 5,591 · see citing works
A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease
Ogura, Y., Bonen, D. K., Inohara, N., Nicolae, D. L., Chen, F. F., Ramos, R., Britton, H., Moran, T., Karaliuskas, R., Duerr, R. H., et al. (2001) · Nature · doi:10.1038/35079114 · Cited by 5,030 · see citing works
A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry
Nicoletti, I., Migliorati, G., Pagliacci, M. C., Grignani, F., & Riccardi, C. (1991) · Journal of Immunological Methods · doi:10.1016/0022-1759(91)90198-o · Cited by 4,580 · see citing works
A Short-Term Study of Chimeric Monoclonal Antibody cA2 to Tumor Necrosis Factor α for Crohn's Disease
Targan, S. R., Hanauer, S. B., van Deventer, S. J. H., Mayer, L., Present, D. H., Braakman, T., DeWoody, K. L., Schaible, T. F., & Rutgeerts, P. J. (1997) · New England Journal of Medicine · doi:10.1056/nejm199710093371502 · Cited by 3,135 · see citing works
Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in Crohn disease and experimental colitis in vivo
Atreya, R., Mudter, J., Finotto, S., Müllberg, J., Jostock, T., Wirtz, S., Schütz, M., Bartsch, B., Holtmann, M., Becker, C., et al. (2000) · Nature Medicine · doi:10.1038/75068 · Cited by 1,293 · see citing works
Self-citation
Inflammatory Bowel Disease
Podolsky, D. K. (1991) · New England Journal of Medicine · doi:10.1056/nejm199109263251306 · Cited by 1,228 · see citing works
Experimental models of inflammatory bowel disease
Elson, C. O., Sartor, R. B., Tennyson, G. S., & Riddell, R. H. (1995) · Gastroenterology · doi:10.1016/0016-5085(95)90599-5 · Cited by 1,212 · see citing works
Reduction in mitochondrial potential constitutes an early irreversible step of programmed lymphocyte death in vivo.
Zamzami, N., Marchetti, P., Castedo, M., Zanin, C., Vayssière, J. L., Petit, P. X., & Kroemer, G. (1995) · The Journal of experimental medicine · doi:10.1084/jem.181.5.1661 · Cited by 1,166 · see citing works
Treatment of Crohn's Disease with 6-Mercaptopurine
Present, D. H., Korelitz, B. I., Wisch, N., Glass, J. L., Sachar, D. B., & Pasternack, B. S. (1980) · New England Journal of Medicine · doi:10.1056/nejm198005013021801 · Cited by 1,024 · see citing works
Azathioprine and 6-Mercaptopurine in Crohn Disease
Pearson, D. C., May, G. R., Fick, G. H., et al. (1995) · Annals of Internal Medicine · doi:10.7326/0003-4819-123-2-199507150-00009 · Cited by 959 · see citing works
MATURE T LYMPHOCYTE APOPTOSIS—Immune Regulation in a Dynamic and Unpredictable Antigenic Environment
Lenardo, M. J., Chan, F. K.-M., Hornung, F., McFarland, H. F., Siegel, R. M., Wang, J., & Zheng, L. (1999) · Annual Review of Immunology · doi:10.1146/annurev.immunol.17.1.221 · Cited by 931 · see citing works
The clinical pharmacology of 6-mercaptopurine
Lennard, L. (1992) · European Journal of Clinical Pharmacology · doi:10.1007/bf02220605 · Cited by 654 · see citing works
Cbl-b regulates the CD28 dependence of T-cell activation
Chiang, Y. J., Kole, H. K., Brown, K. E., Naramura, M., Fukuhara, S., Hu, R.-J., Jang, I. K., Gutkind, J. S., Shevach, E. M., & Gu, H. (2000) · Nature · doi:10.1038/35003235 · Cited by 626 · see citing works
The role of Th1/Th2 polarization in mucosal immunity
Neurath, M. F., Finotto, S., & Glimcher, L. H. (2002) · Nature Medicine · doi:10.1038/nm0602-567 · Cited by 623 · see citing works
Self-citation
ASSOCIATION BETWEEN BIOLOGICAL PROPERTIES OF HUMAN IMMUNODEFICIENCY VIRUS VARIANTS AND RISK FOR AIDS AND AIDS MORTALITY
Tersmette, M. (1989) · The Lancet · doi:10.1016/s0140-6736(89)92628-7 · Cited by 579 · see citing works
A controlled double blind study of azathioprine in the management of Crohn's disease.
Candy, S., Wright, J., Gerber, M., Adams, G., Gerig, M., & Goodman, R. (1995) · Gut · doi:10.1136/gut.37.5.674 · Cited by 567 · see citing works
Crohn's disease
Shanahan, F. (2002) · The Lancet · doi:10.1016/s0140-6736(02)07284-7 · Cited by 478 · see citing works
Long-term follow-up of patients with Crohn's disease treated with azathioprine or 6-mercaptopurine
Bouhnik, Y., Scemama, G., Taï, R., Matuchansky, C., Rambaud, J. C., Lémann, M., Modigliani, R., & Mary, J. (1996) · The Lancet · doi:10.1016/s0140-6736(96)90402-x · Cited by 466 · see citing works
Beneficial effect of azathioprine and prediction of prognosis in primary biliary cirrhosis
Christensen, E., Neuberger, J., Crowe, J., Altman, D. G., Pópper, H., Portmann, B. C., Doniach, D., Ranek, L., Tygstrup, N., & Williams, R. L. (1985) · Gastroenterology · doi:10.1016/0016-5085(85)90213-6 · Cited by 423 · see citing works
A role for TNF-alpha and mucosal T helper-1 cytokines in the pathogenesis of Crohn’s disease
Plevy, S., Landers, C. J., Prehn, J., et al. (1997) · The Journal of Immunology · doi:10.4049/jimmunol.159.12.6276 · Cited by 389 · see citing works
Dominant negative mutation of the hematopoietic-specific Rho GTPase, Rac2, is associated with a human phagocyte immunodeficiency.
Williams, D., Tao, W., Yang, F., Kim, C., Gu, Y., Mansfield, P. J., Levine, J. E., Petryniak, B., Derrow, C. W., Harris, C., et al. (2000) · PubMed · Cited by 334 · see citing works
Interleukin-2- and interferon-gamma-secreting T cells in normal and diseased human intestinal mucosa.
Breese, E. J., Braegger, C., Corrigan, C. J., Walker-Smith, J. A., & MacDonald, T. T. (1993) · PubMed Central · Cited by 327 · see citing works
Lamina propria T cells in Crohn's disease and other gastrointestinal inflammation show defective CD2 pathway-induced apoptosis
Boirivant, M., Marini, M., Felice, G. D., Pronio, A., Montesani, C., Tersigni, R., & Strober, W. (1999) · Gastroenterology · doi:10.1016/s0016-5085(99)70177-0 · Cited by 267 · see citing works
CD28 costimulation prevents cell death during primary T cell activation
Noel, P. J., Boise, L., Green, J. M., & Thompson, C. B. (1996) · The Journal of Immunology · doi:10.4049/jimmunol.157.2.636 · Cited by 260 · see citing works
Healing of severe recurrent ileitis with azathioprine therapy in patients with Crohn's disease
D’Haens, G., Geboes, K., Ponette, E., et al. (1997) · Gastroenterology · doi:10.1016/s0016-5085(97)70027-1 · Cited by 250 · see citing works
Azathioprine for maintenance of remission in Crohn's disease: Benefits outweigh the risk of lymphoma
Lewis, J. D., Schwartz, J. S., & Lichtenstein, G. R. (2000) · Gastroenterology · doi:10.1016/s0016-5085(00)70353-2 · Cited by 243 · see citing works
Lack of effect of intravenous administration on time to respond to azathioprine for steroid-treated Crohn's disease
Sandborn, W. J., Tremaine, W. J., Wolf, D. C., et al. (1999) · Gastroenterology · doi:10.1016/s0016-5085(99)70445-2 · Cited by 240 · see citing works
Treatment of Allergic Airway Inflammation and Hyperresponsiveness by Antisense-Induced Local Blockade of Gata-3 Expression
Finotto, S., Sanctis, G. T. D., Lehr, H. A., Herz, U., Buerke, M., Schipp, M., Bartsch, B., Atreya, R. N., Schmitt, E., Galle, P. R., et al. (2001) · The Journal of Experimental Medicine · doi:10.1084/jem.193.11.1247 · Cited by 234 · see citing works
Self-citation
Regulation of STAT3 by Direct Binding to the Rac1 GTPase
Simon, A. R., Vikis, H. G., Stewart, S., Fanburg, B. L., Cochran, B., & Guan, K. (2000) · Science · doi:10.1126/science.290.5489.144 · Cited by 224 · see citing works
The NF-κB Cascade Is Important in Bcl-xL Expression and for the Anti-Apoptotic Effects of the CD28 Receptor in Primary Human CD4+ Lymphocytes
Khoshnan, A., Tindell, C., Laux, I., Bae, D. J., Bennett, B. L., & Nel, A. E. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.4.1743 · Cited by 221 · see citing works
Azathioprine combined with prednisolone or monotherapy with prednisolone in active Crohn's disease
Ewe, K., Press, A. G., Singe, C. C., et al. (1993) · Gastroenterology · doi:10.1016/0016-5085(93)90709-l · Cited by 218 · see citing works
Cbl-b Is a Negative Regulator of Receptor Clustering and Raft Aggregation in T Cells
Krawczyk, C. M., Bachmaier, K., Sasaki, T., Jones, R. G., Snapper, S. B., Bouchard, D., Kozieradzki, I., Ohashi, P. S., Alt, F. W., & Penninger, J. M. (2000) · Immunity · doi:10.1016/s1074-7613(00)00046-7 · Cited by 216 · see citing works
Apoptosis signaling in lymphocytes
Scaffidi, C., Kirchhofft, S., Krammer, P. H., & Peter, M. E. (1999) · Current Opinion in Immunology · doi:10.1016/s0952-7915(99)80045-4 · Cited by 204 · see citing works
Recent Developments in the Immunology of Inflammatory Bowel Disease
MacDonald, Monteleone, & Pender (2000) · Scandinavian Journal of Immunology · doi:10.1046/j.1365-3083.2000.00658.x · Cited by 197 · see citing works
CD28 costimulation inhibits TCR-induced apoptosis during a primary T cell response
Radvanyi, L. G., Shi, Y., Vaziri, H., Sharma, A. K., Dhala, R., Mills, G. B., & Miller, R. G. (1996) · The Journal of Immunology · doi:10.4049/jimmunol.156.5.1788 · Cited by 194 · see citing works
Role of the guanosine triphosphatase Rac2 in T helper 1 cell differentiation.
Li, B., Yu, H., Zheng, W.-P., Voll, R., Na, S., Roberts, A. W., Williams, D. A., Davis, R., Ghosh, S., & Flavell, R. (2000) · Science · doi:10.1126/science.288.5474.2219 · Cited by 182 · see citing works
Suppression of Ras-Induced Apoptosis by the Rac GTPase
Joneson, T., & Bar‐Sagi, D. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.9.5892 · Cited by 175 · see citing works
Regulation of T-cell apoptosis in inflammatory bowel disease: to die or not to die, that is the mucosal question
Neurath, M. F., Finotto, S., Fuss, I. J., Boirivant, M., Galle, P. R., & Strober, W. (2001) · Trends in Immunology · doi:10.1016/s1471-4906(00)01798-1 · Cited by 174 · see citing works
Self-citation
TGF-β1 down-regulates Th2 development and results in decreased IL-4-induced STAT6 activation and GATA-3 expression
Heath, V. L., Murphy, E. E., Crain, C., Tomlinson, M. G., & O’Garra, A. (2000) · European Journal of Immunology · doi:10.1002/1521-4141(200009)30:9 · Cited by 170 · see citing works
Activation of human B lymphocytes
Fauci, A. S., Whalen, G., & Burch, C. (1980) · Cellular Immunology · doi:10.1016/0008-8749(80)90204-x · Cited by 149 · see citing works
CD28 and apoptosis
Boise, L., Noel, P. J., & Thompson, C. B. (1995) · Current Opinion in Immunology · doi:10.1016/0952-7915(95)80067-0 · Cited by 139 · see citing works
THE TREATMENT OF CHRONIC ULCERATIVE COLITIS WITH 6‐MERCAPTOPURINE
Bean, R. H. D. (1962) · The Medical Journal of Australia · doi:10.5694/j.1326-5377.1962.tb20590.x · Cited by 126 · see citing works
Beneficial effect of azathioprine and prediction of prognosis in primary biliary cirrhosis
Christensen, E., Neuberger, J., Crowe, J., et al. (1985) · Gastroenterology · doi:10.5555/uri:pii:0016508585902136 · Cited by 122 · see citing works
CTLA-4 regulates cell cycle progression during a primary immune response
Greenwald, R. J., Oosterwegel, M. A., van der Woude, D., Kubal, A., Mandelbrot, D. A., Boussiotis, V. A., & Sharpe, A. H. (2002) · European Journal of Immunology · doi:10.1002/1521-4141(200202)32:2 · Cited by 120 · see citing works
Autoimmunity and Apoptosis: The Crohn's Connection
Beutler, B. (2001) · Immunity · doi:10.1016/s1074-7613(01)00176-5 · Cited by 118 · see citing works
CD28 Signaling via VAV/SLP-76 Adaptors
Raab, M., Pfister, S. M., & Rudd, C. E. (2001) · Immunity · doi:10.1016/s1074-7613(01)00248-5 · Cited by 112 · see citing works
Differential regulation of bcl-2 and bcl-x by CD3, CD28, and the IL-2 receptor in cloned CD4+ helper T cells. A model for the long-term survival of memory cells
Mueller, D. L., Seiffert, S., Fang, W., & Behrens, T. W. (1996) · The Journal of Immunology · doi:10.4049/jimmunol.156.5.1764 · Cited by 108 · see citing works
Azathioprine pharmacokinetics after intravenous, oral, delayed release oral and rectal foam administration.
Os, E. C. V., Zins, B., Sandborn, W. J., et al. (1996) · Gut · doi:10.1136/gut.39.1.63 · Cited by 107 · see citing works
Long‐term maintenance therapy with azathioprine in systemic lupus erythematosus
Ginzler, E. M., Sharon, E., Diamond, H. S., & Kaplan, D. S. (1975) · Arthritis & Rheumatism · doi:10.1002/art.1780180106 · Cited by 101 · see citing works
Control of pre-T cell proliferation and differentiation by the GTPase Rac-1
Gomez, M., Tybulewicz, V. L. J., & Cantrell, D. A. (2000) · Nature Immunology · doi:10.1038/79808 · Cited by 90 · see citing works
Activation of p21-CDC42/Rac-Activated Kinases by CD28 Signaling: p21-Activated Kinase (PAK) and MEK Kinase 1 (MEKK1) May Mediate the Interplay Between CD3 and CD28 Signals
Kaga, S., Ragg, S. J., Rogers, K. A., & Ochi, A. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.160.9.4182 · Cited by 77 · see citing works
Quantitation of 6-thioguanine in peripheral blood leukocyte DNA in Crohn's disease patients on maintenance 6-mercaptopurine therapy
Cuffari, C., Seidman, E. G., Latour, S., & Théorêt, Y. (1996) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/y96-056 · Cited by 77 · see citing works
Activities of immunosuppressive agents in vitro. II. Different timing of azathioprine and methotrexate in inhibition and stimulation of mixed lymphocyte reaction.
Bach, M., & Bach, J. (1972) · PubMed · Cited by 51 · see citing works
Reduction of infectious complications following heart transplantation with triple-drug immunotherapy.
Andreone, P. A., OLIVARI, M. T., Elick, B. A., et al. (1987) · PubMed · Cited by 50 · see citing works
Long-term azathioprine in rheumatoid arthritis: a double-blind study.
Silva, M. D., & Hazleman, B. L. (1981) · Annals of the Rheumatic Diseases · doi:10.1136/ard.40.6.560 · Cited by 47 · see citing works
Effects of azathioprine therapy on bone marrow-dependent and thymus-dependent cells in man.
Abdou, N. I., Zweiman, B., & Casella, S. R. (1973) · PubMed · Cited by 46 · see citing works
Mechanism of Activation of an Immunosuppressive Drug: Azathioprine. Quantum Chemical Study on the Reaction of Azathioprine with Cysteine
Hoffmann, M., Rychlewski, J., Chrzanowska, M., et al. (2001) · Journal of the American Chemical Society · doi:10.1021/ja010378c · Cited by 41 · see citing works
Double-masked trial of azathioprine in multiple sclerosis. British and Dutch Multiple Sclerosis Azathioprine Trial Group.
(1988) · PubMed · Cited by 41 · see citing works
Effect of azathioprine and cytosine arabinoside on humoral and cellular immunity in vitro.
Röllinghoff, M., Schrader, J. W., & Wagner, H. (1973) · PubMed · Cited by 39 · see citing works
Leukemia inhibitory factor is a mediator of Escherichia coli lipopolysaccharide-induced acute thymic atrophy
Sempowski, G. D., Rhein, M. E., Scearce, R. M., & Haynes, B. F. (2002) · European Journal of Immunology · doi:10.1002/1521-4141(200211)32:11 · Cited by 38 · see citing works
Activation of human B lymphocytes. XI. Differential effects of azathioprine on B lymphocytes and lymphocyte subpopulations regulating B cell function.
Dimitriu, A., & Fauci, A. S. (1978) · PubMed · Cited by 36 · see citing works
CD95 (Fas) Ligand-Expressing Vesicles Display Antibody-Mediated, FcR-Dependent Enhancement of Cytotoxicity
Jodo, S., Hohlbaum, A. M., Xiao, S., Chan, D. V., Strehlow, D., Sherr, D. H., Marshak‐Rothstein, A., & Ju, S. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.10.5487 · Cited by 34 · see citing works
Activation of Human B Lymphocytes
Dimitriu, A., & Fauci, A. S. (1978) · The Journal of Immunology · doi:10.4049/jimmunol.121.6.2335 · Cited by 30 · see citing works
TEN-YEAR RESULTS OF RENAL TRANSPLANTATION WITH AZATHIOPRINE AND PREDNISOLONE AS ONLY IMMUNOSUPPRESSION
Mcgeown, M., Donaldson, R. A., Kennedy, J. A., et al. (1988) · The Lancet · doi:10.1016/s0140-6736(88)91792-8 · Cited by 28 · see citing works
Methylation of 6-mercaptopurine and 6-thioguanine by thiopurine S -methyltransferase
Kröplin, T., & Iven, H. (2000) · European Journal of Clinical Pharmacology · doi:10.1007/s002280000137 · Cited by 22 · see citing works
Self-citation
DINNER OF THE GENTLEMEN EDUCATED AT ST. BARTHOLOMEW'S HOSPITAL.
(1824) · The Lancet · doi:10.1016/s0140-6736(02)92936-3 · Cited by 7 · see citing works
Activation of the Ras-related GTPase Rap1 by thymocyte TCR engagement and during selection
(2000) · Pure Amsterdam UMC · doi:10.1002/1521-4141(200010)30:10 · Cited by 3 · see citing works

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Authors: Tiede, I., Fritz, G., Strand, S., Poppe, D., Dvorsky, R., Strand, D., Lehr, H. A., Wirtz, S., Becker, C., Atreya, R., Mudter, J., Hildner, K., Bartsch, B., Holtmann, M., Blumberg, R., Walczak, H., Iven, H., Galle, P. R., Ahmadian, M. R., & Neurath, M. F.
Affiliations: Johannes Gutenberg University Mainz (DE)
Brigham and Women's Hospital (US)
German Cancer Research Center (DE)
University of Lübeck (DE)
Max Planck Society (DE)
Corresponding author: Neurath, Markus F.
ORCID: Fritz, Gerhard
Wirtz, Stefan
Becker, Christoph
Atreya, Raja
Hildner, Kai
Holtmann, Martin
Blumberg, Richard
Walczak, Henning
Galle, Peter R.
Ahmadian, Mohammad Reza
Neurath, Markus F.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2003-04-15
Volume: 111
Issue: 8
Pages: 1133-1145
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci16432
PMC: PMC152932
OpenAlex: W2136628679
Cited by: 828
References: 67
Citations by year: 2026: 10 · 2025: 18 · 2024: 25 · 2023: 33 · 2022: 37 · 2021: 31 · 2020: 30 · 2019: 31 · 2018: 31 · 2017: 42 · 2016: 45 · 2015: 37 · 2014: 48 · 2013: 52 · 2012: 45
FWCI: 15.05
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Max Planck Institute for Plasma Physics (submittedVersion)
MPG.PuRe (Max Planck Society) (submittedVersion)
Funders: Deutsche Forschungsgemeinschaft
Bundesministerium für Bildung und Forschung
National Institutes of Health (DK44319, DK53056)
Harvard Digestive Diseases Center, Harvard University
National Institute of Diabetes and Digestive and Kidney Diseases (DK51362, DK 44319, DK53056, R01DK053056, R56DK053056, R37DK044319, R01DK051362, R01DK044319)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords: azathioprine, 6-mercaptopurine, Rac1 activation, CD28 costimulation, CD4+ T cells, T cell apoptosis, immunosuppression, Crohn's disease, mitochondrial apoptosis, MEK, NF-κB, Bcl-xL, GTPase inhibitors
MeSH terms: Adult, Aged, Azathioprine, Cells, Cultured, DNA-Binding Proteins, Humans, Immunosuppressive Agents, Lymphocyte Activation, Middle Aged, Phosphorylation, CD4-Positive T-Lymphocytes, Trans-Activators, Apoptosis, Protein Serine-Threonine Kinases, CD28 Antigens, rac1 GTP-Binding Protein, STAT3 Transcription Factor, I-kappa B Kinase

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

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