Inhibition of human B cell activation by a novel nonsteroidal anti-inflammatory drug, indometacin farnesil

Indometacin farnesil (INF) is a prodrug of indomethacin (IND) designed to r educe the occurrence of side-effects by esterification of the carboxyl grou p on IND with farnesol. Previous studies have shown that INF has the charac teristics 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 curr ent studies therefore examined the effects of INF on human B cells. Ig prod uction was induced from highly purified B cells obtained from healthy donor s 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 atta inable concentrations, INF, but not IND, suppressed the production of IgM a nd 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 di d not suppress the expression of early activation markers, including CD98, CD25, and CD71, on SA-stimulated B cells, but appeared to inhibit the matur ation of B cells following the initial activation. These results indicate t hat INF preferentially suppresses the human B cell functions. Thus, the dat a suggest that INF may have more beneficial effects than IND in treatment o f RA. (C) 1999 Elsevier Science B.V. All rights reserved.