Effects of the active metabolite of leflunomide, A77 1726, on cytokine release and the MAPK signalling pathway in human rheumatoid arthritis synoviocytes.
Inflammatory cytokines or soluble factors are essential in the pathogenesis of rheumatoid arthritis (RA). Leflunomide is an effective disease modifying antirheumatic drug (DMARD) in RA. The objective of the present study was to evaluate for the first time the effects of A77 1726 on cytokine (interleukin (IL)-8, IL-10, IL-11 secretion and tumor necrosis factor-alpha soluble receptor I (sTNFRI)) shedding in human RA fibroblast-like synoviocytes (FLS). At 100 microM, we observed an increase in IL-10 secretion, a decrease in IL-11 release and no effect on sTNFRI shedding and IL-8 secretion in IL-1beta-stimulated human RA FLS. Furthermore, at this dose, our results also confirmed that A77 1726 decreased IL-6 and prostaglandin E2 (PGE2) synthesis while it increased IL-1 receptor antagonist secretion (IL-1Ra). The mitogen-activated protein kinases (MAPKs) represent an attractive target for RA because they can regulate cytokine expression. At 100 microM, the effect of A77 1726 on IL-10 and IL-11 secretion seemed to be associated with the status of p38 MAPK activation. Our results confirmed the immunoregulatory action of leflunomide in the cytokine network involved in RA pathogenesis. It could shift the balance from cytokine mediated inflammation to cytokine directed inhibition of the inflammatory process.
Vergne-Salle
Pascale
P
Service de Rhumatologie et Thérapeutique, CHRU Dupuytren, 2 avenue Martin Luther King, 87042 Limoges Cedex, France.
Léger
David Yannick
DY
Bertin
Philippe
P
Trèves
Richard
R
Beneytout
Jean-Louis
JL
Liagre
Bertrand
B
D021581:Active Transport, Cell Nucleus; D000814:Aniline Compounds / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D002478:Cells, Cultured; D003437:Crotonates; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000378:metabolism; D053938:DNA Fragmentation; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D006885:Hydroxybutyrates / Q000494:pharmacology*; D007249:Inflammation; D053590:Interleukin 1 Receptor Antagonist Protein; D016753:Interleukin-10 / Q000096:biosynthesis / Q000378:metabolism; D017370:Interleukin-11 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology*; D000077339:Leflunomide; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009570:Nitriles; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000096:biosynthesis; D012795:Sialoglycoproteins / Q000378:metabolism; D013582:Synovial Fluid / Q000166:cytology / Q000378:metabolism*; D013997:Time Factors; D014052:Toluidines; D014357:Trypsin / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000814:Aniline Compounds; D000893:Anti-Inflammatory Agents; D003437:Crotonates; D016207:Cytokines; D004791:Enzyme Inhibitors; D006885:Hydroxybutyrates; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D017370:Interleukin-11; D016209:Interleukin-8; D007555:Isoxazoles; D008565:Membrane Proteins; D016328:NF-kappa B; D009570:Nitriles; D047888:Receptors, Tumor Necrosis Factor, Type I; D012795:Sialoglycoproteins; D014052:Toluidines; D016753:Interleukin-10; C527525:teriflunomide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D014357:Trypsin; D000077339:Leflunomide; D015232:Dinoprostone