The anti-inflammatory action of methotrexate is not mediated by lymphocyte apoptosis, but by the suppression of activation and adhesion molecules.
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.
Johnston
Andrew
A
Department of Immunology, Landspitali University Hospital, 101 Reykjavik, Iceland.
Gudjonsson
Johann Eli
JE
Sigmundsdottir
Hekla
H
Ludviksson
Björn Runar
BR
Valdimarsson
Helgi
H
D000241:Adenosine / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000942:Antigens, Bacterial / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte; D000951:Antigens, Neoplasm; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors* / Q000276:immunology; D005434:Flow Cytometry; D005647:Fucosyltransferases / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D016023:Integrins / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology; D002955:Leucovorin / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D008727:Methotrexate / Q000494:pharmacology*; D012313:RNA / Q000737:chemistry / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000037:antagonists & inhibitors / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013297:Streptococcus pyogenes / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology
D000893:Anti-Inflammatory Agents; D000942:Antigens, Bacterial; D000945:Antigens, Differentiation, T-Lymphocyte; D000951:Antigens, Neoplasm; C063419:CTAGE1 protein, human; D015815:Cell Adhesion Molecules; D016023:Integrins; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D018799:Intercellular Adhesion Molecule-1; D012313:RNA; D005647:Fucosyltransferases; C031692:galactoside 3-fucosyltransferase; D000241:Adenosine; D002955:Leucovorin; D008727:Methotrexate