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

• Published in: Biochemical pharmacology Vol. 82; no. 6; pp. 632 - 641
• Main Authors: Hertenstein, Anne, Schumacher, Theresa, Litzenburger, Ulrike, Opitz, Christiane A., Falk, Christine S., Serafini, Tito, Wick, Wolfgang, Platten, Michael
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 15.09.2011; Elsevier
• Subjects: animal models; Anti-allergic drug; anti-inflammatory activity; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Biomarkers - metabolism; Blotting, Western; CD4-positive T-lymphocytes; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD8-positive T-lymphocytes; Cell Culture Techniques; cell proliferation; Cell Proliferation - drug effects; Chemokine CXCL10 - immunology; Chemokine CXCL10 - metabolism; Chemokine CXCL9 - immunology; Chemokine CXCL9 - metabolism; chemokines; Diseases of the osteoarticular system; Dose-Response Relationship, Drug; drugs; essential amino acids; Flow Cytometry; Humans; Inflammatory joint diseases; Jurkat Cells; Life Sciences; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Medical sciences; metabolites; monitoring; Multiple sclerosis; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Neurology; oral administration; ortho-Aminobenzoates - pharmacology; Pharmaceutical sciences; Pharmacology; Pharmacology. Drug treatments; phosphorylation; Reverse Transcriptase Polymerase Chain Reaction; Rheumatoid arthritis; sclerosis; STAT1 Transcription Factor - metabolism; T cell; transcription factors; tryptophan; Tryptophan catabolism; Anti-allergic drug; Multiple sclerosis; Tryptophan catabolism; Rheumatoid arthritis; T cell; CD4 T lymphocyte; CXCL10 chemokine; Diseases of the osteoarticular system; Autoimmune disease; Inflammatory joint disease; Antihistaminic; Antiallergic; Inflammatory disease; T-Lymphocyte; Antagonist; CXC chemokine; Human; Drug; Immunopathology; Nervous system diseases; Tryptophan; Chronic; Tranilast; CXCL9 chemokine; Aminoacid; Central nervous system disease; Catabolism; H1 Histamine receptor; Anthranilic acid; Life Sciences
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2011.06.013

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.