title: Methotrexate and its therapeutic antagonists caffeine and theophylline, target a motogenic T-cell mechanism driven by thrombospondin-1 (TSP-1).
abstract: Methotrexate (MTX) is a widely used treatment for inflammatory diseases such as rheumatoid arthritis and psoriasis, based on the concept that it is immunosuppressive. Its mechanism of action, however, remains unclear, although it is thought to depend on adenosine. Caffeine and theophylline, which have several targets including adenosine receptors, have been shown to suppress the beneficial clinical effects of MTX. Here we show that MTX and caffeine and theophylline differentially affect a motogenic T-cell mechanism driven by endogenous thrombospondin-1 (TSP-1) and its receptor, low density lipoprotein receptor-related protein 1 (LRP1). MTX stimulated TSP-1 expression and the motogenic TSP-1/TSP-1 receptor mechanism in primary human T cells, hence mimicking IL-2 and CXCL12, which similar to MTX, dampen inflammatory disease. SiRNA-mediated gene silencing of TSP-1 and LRP1 inhibited this stimulatory effect. Caffeine and theophylline inhibited the TSP-1/TSP-1 receptor mechanism by inhibiting LRP1 expression. These results indicate that the effect of MTX on T cells is immunoregulatory rather than immunosuppressive, and suggest a pathway dependent on TSP-1/TSP-1 receptor interactions for the regulation of immune responses.
authors.affiliation: Department of Medicine, Division of Dermatology, Karolinska Institute at Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Toomas
authors.initials: T
authors.lastname: Talme
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Immunology, Karolinska Institute at Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Bergdahl
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Immunology, Karolinska Institute at Karolinska University Hospital, Stockholm, Sweden.|Department of Laboratory Medicine, Division of Therapeutic Immunology, Karolinska Institute at Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Karl-Gösta
authors.initials: KG
authors.lastname: Sundqvist
mesh_terms: D002110:Caffeine / Q000494:pharmacology*; D016207:Cytokines / Q000494:pharmacology; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008727:Methotrexate / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008934:Mitogens / Q000276:immunology; D034741:RNA, Small Interfering; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000502:physiology*; D013806:Theophylline / Q000494:pharmacology*; D019700:Thrombospondin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008934:Mitogens; D034741:RNA, Small Interfering; D019700:Thrombospondin 1; D002110:Caffeine; D013806:Theophylline; D008727:Methotrexate
keywords: Cytokines; Lipoprotein receptor related protein1; Lymphocytes; Methotrexate; Thrombospondin-1