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  • Title: Distinct roles of NF-kappaB p50 in the regulation of acetaminophen-induced inflammatory mediator production and hepatotoxicity.
    Author: Dambach DM, Durham SK, Laskin JD, Laskin DL.
    Journal: Toxicol Appl Pharmacol; 2006 Mar 01; 211(2):157-65. PubMed ID: 16081117.
    Abstract:
    Oxidative stress plays an important role in acetaminophen (APAP)-induced hepatotoxicity. In addition to inducing direct cellular damage, oxidants can activate transcription factors including NF-kappaB, which regulate the production of inflammatory mediators implicated in hepatotoxicity. Here, we investigated the role of APAP-induced oxidative stress and NF-kappaB in inflammatory mediator production. Treatment of mice with APAP (300 mg/kg, i.p.) resulted in centrilobular hepatic necrosis and increased serum aminotransferase levels. This was correlated with depletion of hepatic glutathione and CuZn superoxide dismutase (SOD). APAP administration also increased expression of the proinflammatory mediators, interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNFalpha), macrophage chemotactic protein-1 (MCP-1), and KC/gro, and the anti-inflammatory cytokine, interleukin-10 (IL-10). Pretreatment of mice with the antioxidant, N-acetylcysteine (NAC) prevented APAP-induced depletion of glutathione and CuZnSOD, as well as hepatotoxicity. NAC also abrogated APAP-induced increases in TNFalpha, KC/gro, and IL-10, but augmented expression of the anti-inflammatory cytokines interleukin-4 (IL-4) and transforming growth factor-beta (TGFbeta). No effects were observed on IL-1beta or MCP-1 expression. To determine if NF-kappaB plays a role in regulating mediator production, we used transgenic mice with a targeted disruption of the gene for NF-kappaB p50. As observed with NAC pretreatment, the loss of NF-kappaB p50 was associated with decreased ability of APAP to upregulate TNFalpha, KC/gro, and IL-10 expression and increased expression of IL-4 and TGFbeta. However, in contrast to NAC pretreatment, the loss of p50 had no effect on APAP-induced hepatotoxicity. These data demonstrate that APAP-induced cytokine expression in the liver is influenced by oxidative stress and that this is dependent, in part, on NF-kappaB. However, NF-kappaB p50-dependent responses do not appear to play a major role in the pathogenesis of toxicity in this model.
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