Bruccoleri A, Gallucci R, Germolec D R, Blackshear P, Simeonova P, Thurman R G, Luster M I
National Institute of Environmental Health Science, Research Triangle Park, NC, USA.
Hepatology. 1997 Jan;25(1):133-41. doi: 10.1002/hep.510250125.
We and others have shown that tumor necrosis factor alpha (TNF-alpha) expression is increased in the livers of experimental animals following exposure to the chemical hepatotoxin, carbon tetrachloride (CCl4). Because TNF-alpha is involved in mediating inflammatory responses, its elevated expression is presumed to be associated with potentiating hepatotoxicity and/or aiding in liver repair processes. To study the role of TNF-alpha in chemical-induced hepatotoxicity, mice were administered neutralizing antibodies to TNF-alpha before administration of low, but hepatotoxic, doses of CCl4. Antibody treatment prevented CCl4-mediated increases in early-immediate gene expression associated with liver regeneration, including expression of c-jun and c-fos proto-oncogenes, as well as DNA binding of the activator protein-1 (AP-1) nuclear transcription factor. Hepatocyte proliferation following CCl4 treatment was also reduced in anti-TNF-alpha antibody-treated mice, as evidenced by a lack of proliferating cell nuclear antigen (PCNA) staining. Antibody treatment slightly delayed liver repair processes, as evidenced by extending the period in which plasma liver enzyme levels were increased and hepatocellular necrosis could be observed. Consistent with the above observations, injection of recombinant TNF-alpha into control mice induced rapid expression of c-jun and c-fos proto-oncogenes. Taken together, these results indicate that TNF-alpha positively modulates liver recovery following CCl4 exposure presumably by stimulating early-immediate genes involved in hepatic mitogenesis, a phenomenon also observed following partial hepatectomy.
我们和其他研究人员已经表明，实验动物在接触化学性肝毒素四氯化碳（CCl4）后，其肝脏中肿瘤坏死因子α（TNF-α）的表达会增加。由于TNF-α参与介导炎症反应，其表达升高被认为与增强肝毒性和/或辅助肝脏修复过程有关。为了研究TNF-α在化学诱导的肝毒性中的作用，在给予低剂量但具有肝毒性的CCl4之前，给小鼠注射了抗TNF-α中和抗体。抗体处理可防止CCl4介导的与肝脏再生相关的早期即刻基因表达增加，包括c-jun和c-fos原癌基因的表达，以及激活蛋白-1（AP-1）核转录因子的DNA结合。抗TNF-α抗体处理的小鼠在CCl4处理后的肝细胞增殖也减少，这通过增殖细胞核抗原（PCNA）染色的缺乏得到证明。抗体处理略微延迟了肝脏修复过程，这通过延长血浆肝酶水平升高和可观察到肝细胞坏死的时间来证明。与上述观察结果一致，向对照小鼠注射重组TNF-α可诱导c-jun和c-fos原癌基因的快速表达。综上所述，这些结果表明，TNF-α可能通过刺激参与肝脏有丝分裂的早期即刻基因，对CCl4暴露后的肝脏恢复起到正向调节作用，这一现象在部分肝切除术后也有观察到。
