Gukovsky I, Gukovskaya A S, Blinman T A, Zaninovic V, Pandol S J
Department of Medicine, Veterans Affairs Medical Center, West Los Angeles and University of California, Los Angeles, California 90073, USA.
Am J Physiol. 1998 Dec;275(6):G1402-14. doi: 10.1152/ajpgi.1998.275.6.G1402.
Inflammation and cell death are critical to pathogenesis of acute pancreatitis. Here we show that transcription factor nuclear factor-kappaB (NF-kappaB), which regulates these processes, is activated and plays a role in rat cerulein pancreatitis. NF-kappaB was strongly activated in the pancreas within 30 min of cerulein infusion; a second phase of NF-kappaB activation was prominent at 3-6 h. This biphasic kinetics could result from observed transient degradation of the inhibitory protein IkappaBalpha and slower but sustained degradation of IkappaBbeta. The hormone also caused NF-kappaB translocation and IkappaB degradation in vitro in dispersed pancreatic acini. Both p65/p50 and p50/p50, but not c-Rel, NF-kappaB complexes were manifest in pancreatitis and in isolated acini. Coinfusion of CCK JMV-180, which abolishes pancreatitis, prevented cerulein-induced NF-kappaB activation. The second but not early phase of NF-kappaB activation was inhibited by a neutralizing tumor necrosis factor-alpha antibody. Antioxidant N-acetylcysteine (NAC) blocked NF-kappaB activation and significantly improved parameters of pancreatitis. In particular, NAC inhibited intrapancreatic trypsin activation and mRNA expression of cytokines interleukin-6 and KC, which were dramatically induced by cerulein. The results suggest that NF-kappaB activation is an important early event that may contribute to inflammatory and cell death responses in acute pancreatitis.
炎症和细胞死亡对急性胰腺炎的发病机制至关重要。在此我们表明，调节这些过程的转录因子核因子-κB（NF-κB）被激活并在大鼠雨蛙肽诱导的胰腺炎中发挥作用。在注入雨蛙肽后30分钟内，胰腺中的NF-κB被强烈激活；NF-κB激活的第二阶段在3 - 6小时时最为显著。这种双相动力学可能源于观察到的抑制蛋白IκBα的短暂降解以及IκBβ较慢但持续的降解。该激素在体外分散的胰腺腺泡中也会导致NF-κB易位和IκB降解。在胰腺炎和分离的腺泡中均出现了p65/p50和p50/p50两种NF-κB复合物，但未出现c-Rel。能消除胰腺炎的CCK JMV-180共同注入可预防雨蛙肽诱导的NF-κB激活。NF-κB激活的第二阶段而非早期阶段可被中和性肿瘤坏死因子-α抗体抑制。抗氧化剂N-乙酰半胱氨酸（NAC）可阻断NF-κB激活并显著改善胰腺炎的各项指标。特别是，NAC抑制了胰腺内胰蛋白酶的激活以及细胞因子白细胞介素-6和KC的mRNA表达，而这些在雨蛙肽刺激下会显著诱导。结果表明，NF-κB激活是一个重要的早期事件，可能促成急性胰腺炎中的炎症和细胞死亡反应。
