INHIBITION OF LPS-MEDIATED ACTIVATION IN RAT KUPFFER CELLS BY N-ACETYLCYSTEINE OCCURS SUBSEQUENT TO NF-KAPPA-B TRANSLOCATION AND REQUIRES PROTEIN-SYNTHESIS

Activation of the resident hepatic macrophage population, Kupffer cell s, leads to production of mediators that initiate, potentiate, and mod ulate hepatic injury, Recent studies have shown that activation of the pluripotent transcription factor nuclei, factor-kappa B (NF-kappa B) is an important step in the induction of inflammatory cytokines, chemo kines, growth factors, cell adhesion proteins, and cytokine receptors, thus efforts have been focused to modulate its activity A common obse rvation in diverse experimental systems is that oxidant stress activat es NF-kappa B and antioxidant drugs prevent activation and subsequent inflammatory gene transcription, However, we have recently shown that the inhibitory effect of N-acetylcysteine (NAC) is independent of its role as a substrate of glutathione synthesis and NAC can inhibit Kupff er cell activation at points beyond the initiation of activation, The goal of this study was to characterize the mechanism for NAG-mediated inhibition of Kupffer cell activation, We show for the first time that this process requires a cellular synthetic response to prevent both N F-kappa B and tumor necrosis factor alpha (TNF-alpha) mRNA activation, Furthermore, NAC-mediated inhibition occurs after degradation of I ka ppa B-alpha and nuclear translocation of NF-kappa B, These data sugges t that inhibition of Kupffer cell activation by NAC is a nuclear event and offers a potential approach to modulate Kupffer cell activation d uring hepatic injury.