Methotrexate inhibits LPS-induced tumor necrosis factor production in vivo.
We investigated the effects of methotrexate (MTX) on the production of tumor necrosis factor (TNF), nitric oxide (NO) and interleukin-10 (IL-10) in vivo. Administration of low doses of MTX (450 mug/kg once a week for 4 weeks) in Balb/c mice resulted in a significant inhibition of the systemic release of TNF and NO upon LPS challenge, whereas the production of IL-10 remained unchanged. These anti-inflammatory effects of MTX were exerted at the macrophage level since peritoneal macrophages from mice, injected for 4 weeks with MTX produced lower levels of TNF than cells from control mice upon LPS stimulation ex vivo. In parallel, we found that MTX-treated mice were less susceptible to a lethal challenge with LPS and D-galactosamine. MTX did not inhibit TNF release after injection of Concanavalin A (ConA) or anti-CD3 monoclonal antibody (mAb), indicating that MTX does not inhibit TNF production at the T cell level. We conclude that repeated administration of a low dose of MTX in mice is associated with a decreased production of TNF by macrophages upon LPS activation.
Durez
P
P
Department of Immunology, Hôpital Erasme, 808, route de Lennik, B-1070 Brussels, Belgium.
Appelboom
T
T
Vray
B
B
Pira
C
C
Goldman
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018501:Antirheumatic Agents / Q000494:pharmacology*; D017252:CD3 Complex / Q000276:immunology; D003208:Concanavalin A / Q000494:pharmacology; D005688:Galactosamine / Q000494:pharmacology; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000096:biosynthesis / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology; D008727:Methotrexate / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000096:biosynthesis / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D017252:CD3 Complex; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D016753:Interleukin-10; D009569:Nitric Oxide; D005688:Galactosamine; D008727:Methotrexate