The Suppression of T Cell Function and NFκB Expression by Serine Protease Inhibitors Is Blocked byN-Acetylcysteine

Direct evidence thatN-acetylcysteine (NAC) enhances the immune response of peripheral blood T cells at the level of NFκB is presented. In addition, NAC blocks the suppression of T cell mitogenesis and cytokine production by protease inhibitors such asN-tosylphenylalanine chloromethyl ketone (TPCK). The proliferative responses of purified CD4+or CD8+T cells are suppressed more strongly by TPCK when anti-CD28 rather than the phorbol ester PMA is used as the mitogenic coactivator. Cytokine (IL-2, IL-6, INF-γ) production is inhibited 95–100% by concentrations of TPCK that totally suppress the mitogenesis of CD4+or CD8+cells. Using electrophoretic mobility shift assays, we find that TPCK virtually abolishes (to less than 1%) the levels of NFκB (but not Oct-1) found in nuclear and whole cell extracts of activated T cells. Strikingly, the immunosuppressive effects of TPCK are blocked when T cells are pretreated for 15 min with 5 mMNAC. NAC not 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 NFκB and IκB proteases play obligate roles in T cell activation and mitogenesis, roles that are enhanced significantly by NAC.