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 response of peripheral blood T cells at the level of NF(kappa)B is presented. In addition, NAC blocks the suppression of T cell mitogenesis and cytokine production by protease inhibitors such as N-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-gamma) 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 NF(kappa)B (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 mM NAC. 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 NF(kappa)B and I(kappa)B proteases play obligate roles in T cell activation and mitogenesis, roles that are enhanced significantly by NAC.