Suppression of human CD4+ T cell activation by 3,4-dimethoxycinnamonyl-anthranilic acid (tranilast) is mediated by CXCL9 and CXCL10
3,4-dimethoxycinnamonyl-anthranilic acid (tranilast) is an orally available anti-allergic drug with structural and functional homologies to immunosuppressive catabolites of the essential amino acid tryptophan and broad anti-inflammatory properties. It has recently been shown to be effective in anima...
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| Main Authors: | , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
[15 September 2011]
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| In: |
Biochemical pharmacology
Year: 2011, Volume: 82, Issue: 6, Pages: 632-641 |
| ISSN: | 1873-2968 |
| DOI: | 10.1016/j.bcp.2011.06.013 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.bcp.2011.06.013 Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0006295211003789 
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| Author Notes: | Anne Hertenstein, Theresa Schumacher, Ulrike Litzenburger, Christiane A. Opitz, Christine S. Falk, Tito Serafini, Wolfgang Wick, Michael Platten |
| Summary: | 3,4-dimethoxycinnamonyl-anthranilic acid (tranilast) is an orally available anti-allergic drug with structural and functional homologies to immunosuppressive catabolites of the essential amino acid tryptophan and broad anti-inflammatory properties. It has recently been shown to be effective in animal models of multiple sclerosis and rheumatoid arthritis, two autoimmune diseases that are mediated by auto-aggressive Th1-polarized CD4+ T lymphocytes. Here we demonstrate potent suppressive effects of tranilast on the function of naïve human CD4+ T cells. Tranilast inhibited inhibits activation and proliferation of purified CD4+ T cells stimulated through the T cell receptor with an EC50 of less than 10μM, a concentration that is well below plasma levels achieved after oral administration of approved doses of 200-600mg in humans. The antiproliferative effects were less potent on naïve CD8+ T cells. Suppression of CD4+ and CD8+ T cell proliferation was associated with an inhibition of T cell activation. Cytokine analyses of naïve CD4+ T cells revealed that tranilast interferes with the production of cyto- and chemokines driven by signal transducer and activator of transcription 1 (STAT1), notably chemokine (C-X-C motif) ligands (CXCL) 9 and 10. Tranilast limited STAT1 phosphorylation in activated T cells and supplementation of CXCL9 or CXCL10 reversed the anti-proliferative effects of tranilast. These data imply CXCL9 and CXCL10 as novel therapeutic targets of tranilast in Th1-mediated autoimmune diseases and identify phospho-STAT1 and its target chemokines CXCL9 and CXCL10 as potential markers for monitoring the bioactivity of tranilast in humans. |
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| Item Description: | Gesehen am 05.10.2022 |
| Physical Description: | Online Resource |
| ISSN: | 1873-2968 |
| DOI: | 10.1016/j.bcp.2011.06.013 |