Suppression of human CD4+ T cell activation by 3,4-dimethoxycinnamonyl-anthranilic acid (tranilast) is mediated by CXCL9 and CXCL10

Anne Hertenstein (1, 2) , Theresa Schumacher (1) , Ulrike Litzenburger (1, 2) , Christiane A. Opitz (1, 2) , Christine S. Falk (3, 4) , Tito Serafini (5) , Wolfgang Wick (1, 2) , Michael Platten (1, 2)

1 Department of Neurooncology
2 DKFZ - German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg]
3 Universität Heidelberg [Heidelberg] = Heidelberg University
4 Institute for Transplantation Immunology
5 Nuon Therpeutics Inc.

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 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.

Mots clés: Life Sciences

Domaines: Pharmacologie

Anne Hertenstein, Theresa Schumacher, Ulrike Litzenburger, Christiane A. Opitz, Christine S. Falk, et al.. Suppression of human CD4+ T cell activation by 3,4-dimethoxycinnamonyl-anthranilic acid (tranilast) is mediated by CXCL9 and CXCL10. Biochemical Pharmacology, 2011, 82 (6), pp.632. ⟨10.1016/j.bcp.2011.06.013⟩. ⟨hal-00722842⟩