Regulation of p38 MAP kinase in CD4+ lymphocytes by infliximab therapy in patients with rheumatoid arthritis.
Tumor necrosis factor alpha (TNFalpha) plays a key role in the pathogenesis of rheumatoid arthritis (RA) and most patients treated with anti-TNFalpha agents show significant improvement in both signs and symptoms. While TNFalpha inhibitors rapidly reduce joint inflammation, the mechanisms by which these agents exert their long-term effects remain unclear. The p38 MAP kinase pathway is one of the signaling pathways triggered by TNFalpha and pharmacological inhibitors of this kinase are being developed for use in RA. Since p38 MAP kinase is involved in interferon gamma (IFNgamma) production by CD4+ T helper 1 (Th1) cells and a Th1 immune response has been associated with RA, we investigated whether anti-TNFalpha therapy could affect the activation of this signaling pathway in the CD4+ T cells of RA patients. We show that in five patients, treatment with infliximab caused a marked reduction of activated p38 MAP kinase levels in CD4+ T cells, without affecting the total levels of p38 MAPK. In contrast to T cells, infliximab therapy did not affect the levels of active p38 MAP kinase in macrophages from the same patients. The selective effect of anti-TNFalpha therapy on the p38 MAP kinase signaling pathway of CD4+ T cells in patients with RA suggests that prolonged benefit with these agents may be mediated by their effect on CD4+ T cells.
Garfield
Bruce E
BE
University of Vermont, Department of Medicine, Rheumatology Division, Burlington, VT 05405, USA.
Krahl
Troy
T
Appel
Stacia
S
Cooper
Sheldon M
SM
Rincón
Mercedes
M
D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000473:pathology; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D002452:Cell Count; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D000069285:Infliximab; D007371:Interferon-gamma / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D013997:Time Factors; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D000069285:Infliximab; D048051:p38 Mitogen-Activated Protein Kinases