Abstract
Low-dose methotrexate (MTX) is an established and highly effective treatment for severe psoriasis and rheumatoid arthritis; however, its mechanism of action remains unclear. We investigated the effects of low-dose MTX on antigen-stimulated peripheral blood mononuclear cells and explored through which cellular pathways these effects are mediated. We show that MTX caused a dose-dependent suppression of T cell activation and adhesion molecule expression, and this was not due to lymphocyte apoptosis. The suppression of intercellular adhesion molecule (ICAM)-1 was adenosine and folate-dependent, while MTX suppression of the skin-homing cutaneous lymphocyte-associated antigen (CLA) was adenosine-independent. The effect of MTX on CLA, but not ICAM-1, required the constant presence of MTX in cultures. Thus, the suppression of T cell activation and T cell adhesion molecule expression, rather than apoptosis, mediated in part by adenosine or polyglutamated MTX or both, are important mechanisms in the anti-inflammatory action of MTX.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine / pharmacology
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Anti-Inflammatory Agents / pharmacology*
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Antigens, Bacterial / immunology
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Antigens, Differentiation, T-Lymphocyte
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Antigens, Neoplasm
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Apoptosis / drug effects
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Apoptosis / immunology
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Cell Adhesion Molecules / antagonists & inhibitors*
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Cell Adhesion Molecules / immunology
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Flow Cytometry
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Fucosyltransferases / biosynthesis
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Fucosyltransferases / genetics
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Humans
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Integrins / immunology
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Intercellular Adhesion Molecule-1 / genetics
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Intercellular Adhesion Molecule-1 / immunology
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Leucovorin / pharmacology
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / immunology
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / immunology
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Methotrexate / pharmacology*
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RNA / chemistry
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RNA / genetics
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Receptors, Interleukin-2 / antagonists & inhibitors
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Receptors, Interleukin-2 / immunology
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Reverse Transcriptase Polymerase Chain Reaction
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Streptococcus pyogenes / immunology
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T-Lymphocytes / cytology
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T-Lymphocytes / drug effects*
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T-Lymphocytes / immunology
Substances
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Anti-Inflammatory Agents
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Antigens, Bacterial
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Antigens, Differentiation, T-Lymphocyte
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Antigens, Neoplasm
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CTAGE1 protein, human
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Cell Adhesion Molecules
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Integrins
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Membrane Glycoproteins
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P-selectin ligand protein
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RNA, Messenger
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Receptors, Interleukin-2
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Intercellular Adhesion Molecule-1
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RNA
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Fucosyltransferases
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galactoside 3-fucosyltransferase
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Adenosine
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Leucovorin
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Methotrexate