THE SUPPRESSION OF T-CELL FUNCTION AND NF-KAPPA-B EXPRESSION BY SERINE-PROTEASE INHIBITORS IS BLOCKED BY N-ACETYLCYSTEINE

Direct evidence that N-acetylcysteine (NAC) enhances the immune respon se of peripheral blood T cells at the level of NK kappa B is presented . In addition, NAC blocks the suppression of T cell mitogenesis and cy tokine production by protease inhibitors such as N-tosylphenylalanine chloromethyl ketone (TPCK). The proliferative responses of purified CD 4(+) or CD8(+) T cells are suppressed more strongly by TPCK when anti- CD28 rather than the phorbol ester PMA is used as the mitogenic coacti vator. Cytokine (IL-2, IL-6, INF-gamma) production is inhibited 95-100 % by concentrations of TPCK that totally suppress the mitogenesis of C D4(+) or CD8(+) cells. Using electrophoretic mobility shift assays, we find that TPCK virtually abolishes (to less than 1%) the levels of NF kappa B (but not Oct-1) found in nuclear and whole cell extracts of a ctivated T cells. Strikingly, the immunosuppressive effects of TPCK ar e blocked when T cells are pretreated for 15 min with 5 mM NAC. NAC no t only blocks the effect of TPCK but enhances mitogenesis and cytokine production (>2.5-fold in some cases) upon activation of unsuppressed T cells. Our data support the notion that NF kappa B and I kappa B pro teases play obligate roles in T cell activation and mitogenesis, roles that are enhanced significantly by NAC. (C) 1996 Academic Press, Inc.