Inhibition of human B cell activation by a novel nonsteroidal anti-inflammatory drug, indometacin famesil.
Indometacin farnesil (INF) is a prodrug of indomethacin (IND) designed to reduce the occurrence of side-effects by esterification of the carboxyl group on IND with farnesol. Previous studies have shown that INF has the characteristics of disease-modifying anti-rheumatic drug (DMARD) in that it has a component of slow-acting effect in treatment of rheumatoid arthritis (RA), in which abnormal B cell functions are considered to be involved. The current studies therefore examined the effects of INF on human B cells. Ig production was induced from highly purified B cells obtained from healthy donors by stimulation with Staphylococcus aureus Cowan I (SA) plus IL-2. T cell proliferation and IFN-gamma production were induced from highly purified T cells by stimulation with immobilized mAb to CD3. At pharmacologically attainable concentrations, INF, but not IND, suppressed the production of IgM and IgG of B cells, whereas neither suppressed the T cell proliferation and IFN-gamma production. The inhibition of Ig production by INF is not due to its IND structure, but is most likely due to its farnesil component, since farnesol alone comparably suppressed the Ig production. INF and farnesol did not suppress the expression of early activation markers, including CD98, CD25, and CD71, on SA-stimulated B cells, but appeared to inhibit the maturation of B cells following the initial activation. These results indicate that INF preferentially suppresses the human B cell functions. Thus, the data suggest that INF may have more beneficial effects than IND in treatment of RA.
Hirohata
S
S
Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan. shunsei@med.teikyo-u.ac.jp
Yanagida
T
T
Kawai
M
M
Kikuchi
H
H
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D005204:Farnesol / Q000494:pharmacology*; D006801:Humans; D007074:Immunoglobulin G / Q000187:drug effects / Q000378:metabolism; D007075:Immunoglobulin M / Q000187:drug effects / Q000378:metabolism; D007213:Indomethacin / Q000031:analogs & derivatives* / Q000494:pharmacology; D020382:Interleukin-18 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D020382:Interleukin-18; D005204:Farnesol; C060022:indomethacin farnesil; D007213:Indomethacin